franziska v schoeni-affolter

Abstract: This report updates and combines earlier versions of guidelines for the prevention and treatment of opportunistic infections (OIs) in HIV-infected adults (i.e., persons aged >/=18 years) and adolescents (i.e., persons aged 13--17 years), last published in 2002 and 2004, respectively. It has been prepared by the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America (IDSA). The guidelines are intended for use by clinicians and other health-care providers, HIV-infected patients, and policy makers in the United States. These guidelines address several OIs that occur in the United States and five OIs that might be acquired during international travel. Topic areas covered for each OI include epidemiology, clinical manifestations, diagnosis, prevention of exposure; prevention of disease by chemoprophylaxis and vaccination; discontinuation of primary prophylaxis after immune reconstitution; treatment of disease; monitoring for adverse effects during treatment; management of treatment failure; prevention of disease recurrence; discontinuation of secondary prophylaxis after immune reconstitution; and special considerations during pregnancy. These guidelines were developed by a panel of specialists from the United States government and academic institutions. For each OI, a small group of specialists with content-matter expertise reviewed the literature for new information since the guidelines were last published; they then proposed revised recommendations at a meeting held at NIH in June 2007. After these presentations and discussion, the revised guidelines were further reviewed by the co-editors; by the Office of AIDS Research, NIH; by specialists at CDC; and by HIVMA of IDSA before final approval and publication. The recommendations are rated by a letter that indicates the strength of the recommendation and a Roman numeral that indicates the quality of evidence supporting the recommendation, so that readers can ascertain how best to apply the recommendations in their practice environments. Major changes in the guidelines include 1) greater emphasis on the importance of antiretroviral therapy for the prevention and treatment of OIs, especially those OIs for which no specific therapy exists; 2) information regarding the diagnosis and management of immune reconstitution inflammatory syndromes; 3) information regarding the use of interferon-gamma release assays for the diagnosis of latent Mycobacterium tuberculosis (TB) infection; 4) updated information concerning drug interactions that affect the use of rifamycin drugs for prevention and treatment of TB; 5) the addition of a section on hepatitis B virus infection; and 6) the addition of malaria to the list of OIs that might be acquired during international travel. This report includes eleven tables pertinent to the prevention and treatment of OIs, a figure that pertains to the diagnois of tuberculosis, a figure that describes immunization recommendations, and an appendix that summarizes recommendations for prevention of exposure to opportunistic pathogens.

Abstract: OBJECTIVE: We aimed to retrieve the vital status of patients lost to follow-up (LFU), with no further visits for at least 12 months, for the 34,835 patients in the Agence Nationale de Recherche sur le SIDA CO4 French Hospital Database on HIV (ANRS CO4 FHDH) seen in 1999 and to examine how loss to follow-up might influence estimates of survival and the impact of delayed access to care (DAC) on survival. METHODS: The status of LFU patients was established by using the mid-2006 update of the FHDH in which their status 12 months after loss to follow-up was added when available and by matching with the Mortalite 2000-Epidemiological Centre for Medical Causes of Death (CepiDc) database, which included HIV-infected patients dying in 2000. We compared Kaplan-Meier and hazard ratio (HR) estimates before and after correction for the status of LFU patients. RESULTS: In the mid-2006 updated FHDH, of the patients seen in 1999, 7.5% were LFU: of these, 2.1% later returned for follow-up, with a median time without follow-up in an FHDH centre of 3.5 years, and 5.4% had no further FHDH visits whatsoever, of whom 29.8% died according to Mortalite 2000-CepiDc. After correction, the estimated 1-year survival rates following enrolment in 1999 differed between the original and updated analyses (97.1 vs. 95.9%, respectively; P=0.017); the estimates of mortality HRs associated with DAC did not differ during the first 6 months, but did differ for the 6-18-month period. CONCLUSIONS: Among LFU patients, 28.1% returned to follow-up after several years and at least 21.4% died, which led to a slight overestimation of both survival and the impact of DAC on survival.

Abstract: INTRODUCTION: The antiretroviral drug efavirenz (EFV) is extensively metabolized into three primary metabolites: 8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV. There is a wide interindividual variability in EFV plasma exposure, explained to a great extent by cytochrome P450 2B6 (CYP2B6), the main isoenzyme responsible for EFV metabolism and involved in the major metabolic pathway (8-hydroxylation) and to a lesser extent in 7-hydroxylation. When CYP2B6 function is impaired, the relevance of CYP2A6, the main isoenzyme responsible for 7-hydroxylation may increase. We hypothesize that genetic variability in this gene may contribute to the particularly high, unexplained variability in EFV exposure in individuals with limited CYP2B6 function. METHODS: This study characterized CYP2A6 variation (14 alleles) in individuals (N=169) previously characterized for functional variants in CYP2B6 (18 alleles). Plasma concentrations of EFV and its primary metabolites (8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV) were measured in different genetic backgrounds in vivo. RESULTS: The accessory metabolic pathway CYP2A6 has a critical role in limiting drug accumulation in individuals characterized as CYP2B6 slow metabolizers. CONCLUSION: Dual CYP2B6 and CYP2A6 slow metabolism occurs at significant frequency in various human populations, leading to extremely high EFV exposure.

Abstract: Antiretroviral-therapy rollout in resource-poor countries is often associated with limited, if any, HIV-RNA monitoring. The effect of variable monitoring on the emergence of resistance after therapy with commonly used drug combinations was assessed by systematic review of studies reporting resistance in patients infected with HIV with a CD4 count of fewer than 200 cells per muL treated with two nucleoside analogues (including a thymidine analogue) and a non-nucleoside reverse transcriptase inhibitor. 8376 patients from eight cohorts and two prospective studies were analysed. Resistance at virological failure to non-nucleoside reverse transcriptase inhibitors at 48 weeks was 88.3% (95% CI 82.2-92.9) in infrequently monitored patients, compared with 61.0% (48.9-72.2) in frequently monitored patients (p<0.001). Lamivudine resistance was 80.5% (72.9-86.8) and 40.3% (29.1-52.2) in infrequently and frequently monitored patients, respectively (p<0.001); the prevalence of at least one thymidine analogue mutation was 27.8% (21.2-35.2) and 12.1% (5.9-21.4), respectively (p<0.001). Genotypic resistance at 48 weeks to lamivudine, nucleoside reverse transcriptase inhibitors (thymidine analogue mutations), and non-nucleoside reverse transcriptase inhibitors appears substantially higher in less frequently monitored patients. This Review highlights the need for cheap point-of-care viral-load tests to identify early viral failures and limit the emergence of resistance.

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Abstract: PURPOSE: Human immunodeficiency virus (HIV)-positive adolescents face a number of challenges in dealing with their disease, treatment, and developmental tasks. This qualitative study describes some of the reasons why, and the extent to which, adolescents may or may not disclose their condition to others. METHODS: A semistructured interview lasting 40-110 minutes was conducted with each of 29 adolescents 12-20 years old, 22 female and seven male) living in Switzerland. Interviews were tape recorded and transcribed verbatim. The analysis of the content of interviews allowed us to identify salient topics (e.g., disclosure), which were then explored in detail. RESULTS: Of 29 participants, eight had not disclosed their condition to anyone outside the family, 19 had disclosed it to good friends, and 16 had disclosed it to some teachers. Four participants had engaged in public disclosure, and six of 10 sexually active teenagers disclosed their status to their partners. The attitudes toward disclosure among younger adolescents were mostly related to those of the parents, particularly the mother. Older adolescents, engaged in their search for autonomy, tended to decide independently what to say and to whom. Although foster/adoptive parents would often encourage disclosure, biological parents, especially HIV-positive mothers, insisted on not disclosing the adolescent's status for fear of stigma. CONCLUSION: The health care team should systematically address the issue of disclosure with the adolescent and his family (or foster parents), the aim being to balance the right of the adolescent and that adolescent's family to maintain privacy against the concerns of sexual partners, as well as the adolescent's interest in divulging HIV status to relatives, school staff, and friends.

Abstract: OBJECTIVE: We investigated the effect of descent (African versus European) on the progression of untreated HIV infections in a prospective cohort study of HIV-1-infected individuals. METHODS: We estimated the linear rate of decline of the CD4 cell count and the setpoint viral load in patients with sufficient data points. The effect of descent was assessed by microltivariate regression models including descent, sex, viral subtype, the earliest date of confirmed infection, age, and the baseline CD4 cell count; the rate of CD4 cell count decline was also analyzed with mixed-effect models and with matched comparisons between patients of African and European descent based on the baseline CD4 cell count. RESULTS: We found that the decline slope of the CD4 cell count was significantly less steep (+26.6 cells/microl per year; 95% confidence interval, 12.3-41.0; P < 0.001) in patients of African descent (n = 123) compared with patients of European descent (n = 463), and this effect was independent of differences in the infecting viral subtypes. Matched comparisons confirmed the effect of African descent (P < 0.001). Remarkably, the rate of CD4 cell count decline depended strongly on the viral setpoint in patients of European descent (-46.3 cells/microl per year/log10 RNA copies/ml; 95% confidence interval, -55.8 to -36.7; P < 0.001) but not in patients of African descent. CONCLUSION: Slower disease progression in patients of African descent might be related to host factors allowing better tolerance of high virus levels in patients of African descent compared with patients of European descent.

Abstract: OBJECTIVES: The aim of the study was to investigate the influence of continued injecting drug use, enrolment in an opiate substitution treatment programme (OSTP), or cessation of injecting drug use on the uptake and course of antiretroviral therapy (ART). Design A prospective observational study of all participants in the Swiss HIV Cohort Study followed between 1997 and 2006 was carried out. METHODS: We distinguished four groups of former or current injecting drug users (IDUs): (i) abstinent former IDUs; (ii) persons in OSTPs without concomitant injecting drug use; (iii) persons in OSTPs with concomitant injecting drug use; (vi) current IDUs. These groups were compared with a group of patients who had never been IDUs. Factors related to ART uptake and virological endpoints were analysed using logistic generalized estimating equations. RESULTS: We followed 8660 participants for 48 477 person-years; 29.7% were in the IDU HIV transmission group. The likelihood of being on ART at biannual visits was lower among individuals in OSTPs with concomitant injecting drug use [odds ratio (OR) 0.79; 95% confidence interval (CI) 0.71-0.89] and current IDUs (OR 0.80; 95% CI 0.67-0.96), compared with those who had never been IDUs (reference), abstinent former IDUs (OR 1.13; 95% CI 1.02-1.25) and individuals in OSTPs without injecting drug use (OR 1.18; 95% CI 1.06-1.31). The likelihood of suppressed viral replication on ART was similar among those who had never been IDUs, abstinent former IDUs and individuals in an OSTP without injecting drug use, and lower among those in OSTPs with concomitant drug use (OR 0.82; 95% CI 0.72-0.93) and current IDUs (OR 0.81; 0.65-1.00). Adherence to ART was decreased among persons with continued injecting drug use, and correlated with virological outcome. CONCLUSIONS: Uptake of and virological response to ART were improved among abstinent former IDUs and persons in OSTPs without concomitant injecting drug use, compared with persons with continued injecting drug use.

Abstract: OBJECTIVES: To monitor HIV-1 transmitted drug resistance (TDR) in a well defined urban area with large access to antiretroviral therapy and to assess the potential source of infection of newly diagnosed HIV individuals. METHODS: All individuals resident in Geneva, Switzerland, with a newly diagnosed HIV infection between 2000 and 2008 were screened for HIV resistance. An infection was considered as recent when the positive test followed a negative screening test within less than 1 year. Phylogenetic analyses were performed by using the maximum likelihood method on pol sequences including 1058 individuals with chronic infection living in Geneva. RESULTS: Of 637 individuals with newly diagnosed HIV infection, 20% had a recent infection. Mutations associated with resistance to at least one drug class were detected in 8.5% [nucleoside reverse transcriptase inhibitors (NRTIs), 6.3%; non-nucleoside reverse transcriptase inhibitors (NNRTIs), 3.5%; protease inhibitors, 1.9%]. TDR (P-trend = 0.015) and, in particular, NNRTI resistance (P = 0.002) increased from 2000 to 2008. Phylogenetic analyses revealed that 34.9% of newly diagnosed individuals, and 52.7% of those with recent infection were linked to transmission clusters. Clusters were more frequent in individuals with TDR than in those with sensitive strains (59.3 vs. 32.6%, respectively; P < 0.0001). Moreover, 84% of newly diagnosed individuals with TDR were part of clusters composed of only newly diagnosed individuals. CONCLUSION: Reconstruction of the HIV transmission networks using phylogenetic analysis shows that newly diagnosed HIV infections are a significant source of onward transmission, particularly of resistant strains, thus suggesting an important self-fueling mechanism for TDR.

Abstract: BACKGROUND:Accurate quantification of the prevalence of human immunodeficiency virus type 1 (HIV-1) drug resistance in patients who are receiving antiretroviral therapy (ART) is difficult, and results from previous studies vary. We attempted to assess the prevalence and dynamics of resistance in a highly representative patient cohort from Switzerland. METHODS:On the basis of genotypic resistance test results and clinical data, we grouped patients according to their risk of harboring resistant viruses. Estimates of resistance prevalence were calculated on the basis of either the proportion of individuals with a virologic failure or confirmed drug resistance (lower estimate) or the frequency-weighted average of risk group-specific probabilities for the presence of drug resistance mutations (upper estimate). RESULTS:Lower and upper estimates of drug resistance prevalence in 8064 ART-exposed patients were 50% and 57% in 1999 and 37% and 45% in 2007, respectively. This decrease was driven by 2 mechanisms: loss to follow-up or death of high-risk patients exposed to mono- or dual-nucleoside reverse-transcriptase inhibitor therapy (lower estimates range from 72% to 75%) and continued enrollment of low-risk patients who were taking combination ART containing boosted protease inhibitors or nonnucleoside reverse-transcriptase inhibitors as first-line therapy (lower estimates range from 7% to 12%). A subset of 4184 participants (52%) had >or= 1 study visit per year during 2002-2007. In this subset, lower and upper estimates increased from 45% to 49% and from 52% to 55%, respectively. Yearly increases in prevalence were becoming smaller in later years. CONCLUSIONS:Contrary to earlier predictions, in situations of free access to drugs, close monitoring, and rapid introduction of new potent therapies, the emergence of drug-resistant viruses can be minimized at the population level. Moreover, this study demonstrates the necessity of interpreting time trends in the context of evolving cohort populations.

Abstract: BACKGROUND: Yellow fever vaccine (17DV) has been investigated incompletely in human immunodeficiency virus (HIV)-infected patients, and adequate immunogenicity and safety are of concern in this population. METHODS: In the Swiss HIV Cohort Study, we identified 102 patients who received 17DV while they were HIV infected. We analyzed neutralization titers (NTs) after 17DV administration using the plaque reduction neutralization test. NTs of 1:>or=10 were defined as reactive, and those of 1:<10 were defined as nonreactive, which was considered to be nonprotective. The results were compared with data for HIV-uninfected individuals. Serious adverse events were defined as hospitalization or death within 6 weeks after receipt of 17DV. RESULTS: At the time of 17DV administration, the median CD4 cell count was 537 cells/mm(3) (range, 11-1730 cells/mm(3)), and the HIV RNA level was undetectable in 41 of 102 HIV-infected patients. During the first year after vaccination, fewer HIV-infected patients (65 [83%] of 78; P = .01) than HIV-uninfected patients revealed reactive NTs, and their NTs were significantly lower (P < .001) than in HIV-uninfected individuals. Eleven patients with initially reactive NTs lost these reactive NTs <or= 5 years after vaccination. Higher NTs during the first year after vaccination were associated with undetectable HIV RNA levels, increasing CD4 cell count, and female sex. We found no serious adverse events after 17DV administration among HIV-infected patients. CONCLUSION: Compared with HIV-uninfected individuals, HIV-infected patients respond to 17DV with lower reactive NTs, more often demonstrate nonprotective NTs, and may experience a more rapid decline in NTs during follow-up. Vaccination with 17DV appears to be safe in HIV-infected individuals who have high CD4 cell counts, although rate of serious adverse events of up to 3% cannot be excluded.

Abstract: Objectives Etravirine (ETV) is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) with reduced cross-resistance to first-generation NNRTIs, which has been primarily studied in randomized clinical trials and not in routine clinical settings. Methods ETV resistance-associated mutations (RAMs) were investigated by analysing 6072 genotypic tests. The antiviral activity of ETV was predicted using different interpretation systems: International AIDS Society-USA (IAS-USA), Stanford, Rega and Agence Nationale de Recherches sur le Sida et les hepatites virales (ANRS). Results The prevalence of ETV RAMs was higher in NNRTI-exposed patients [44.9%, 95% confidence interval (CI) 41.0-48.9%] than in treatment-naive patients (9.6%, 95% CI 8.5-10.7%). ETV RAMs in treatment-naive patients mainly represent polymorphism, as prevalence estimates in genotypic tests for treatment-naive patients with documented recent (<1 year) infection, who had acquired HIV before the introduction of NNRTIs, were almost identical (9.8%, 95% CI 3.3-21.4). Discontinuation of NNRTI treatment led to a marked drop in the detection of ETV RAMs, from 51.7% (95% CI 40.8-62.6%) to 34.5% (95% CI 24.6-45.4%, P=0.032). Differences in prevalence among subtypes were found for V90I and V179T (P<0.001). Estimates of restricted virological response to ETV varied among algorithms in patients with exposure to efavirenz (EFV)/nevirapine (NVP), ranging from 3.8% (95% CI 2.5-5.6%) for ANRS to 56.2% (95% CI 52.2-60.1%) for Stanford. The predicted activity of ETV decreased as the sensitivity of potential optimized background regimens decreased. The presence of major IAS-USA mutations (L100I, K101E/H/P and Y181C/I/V) reduced the treatment response at week 24. Conclusions Most ETV RAMs in drug-naive patients are polymorphisms rather than transmitted RAMs. Uncertainty regarding predictions of antiviral activity for ETV in NNRTI-treated patients remains high. The lowest activity was predicted for patients harbouring extensive multidrug-resistant viruses, thus limiting ETV use in those who are most in need.

Abstract: BACKGROUND: Alcohol consumption leading to morbidity and mortality affects HIV-infected individuals. Here, we aimed to study self-reported alcohol consumption and to determine its association with adherence to antiretroviral therapy (ART) and HIV surrogate markers. METHODS: Cross-sectional data on daily alcohol consumption from August 2005 to August 2007 were analysed and categorized according to the World Health Organization definition (light, moderate or severe health risk). Multivariate logistic regression models and Pearson's chi(2) statistics were used to test the influence of alcohol use on endpoints. RESULTS: Of 6,323 individuals, 52.3% consumed alcohol less than once a week in the past 6 months. Alcohol intake was deemed light in 39.9%, moderate in 5.0% and severe in 2.8%. Higher alcohol consumption was significantly associated with older age, less education, injection drug use, being in a drug maintenance programme, psychiatric treatment, hepatitis C virus coinfection and with a longer time since diagnosis of HIV. Lower alcohol consumption was found in males, non-Caucasians, individuals currently on ART and those with more ART experience. In patients on ART (n=4,519), missed doses and alcohol consumption were positively correlated (P<0.001). Severe alcohol consumers, who were pretreated with ART, were more often off treatment despite having CD4(+) T-cell count <200 cells/mul; however, severe alcohol consumption per se did not delay starting ART. In treated individuals, alcohol consumption was not associated with worse HIV surrogate markers. CONCLUSIONS: Higher alcohol consumption in HIV-infected individuals was associated with several psychosocial and demographic factors, non-adherence to ART and, in pretreated individuals, being off treatment despite low CD4(+) T-cell counts.

Abstract: Progressive multifocal leukoencephalopathy (PML) is a frequently fatal disease caused by uncontrolled polyomavirus JC (JCV) in severely immunodeficient patients. We investigated the JCV-specific cellular and humoral immunity in the Swiss HIV Cohort Study. We identified PML cases (n = 29), as well as three matched controls per case (n = 87), with prospectively cryopreserved peripheral blood mononuclear cells and plasma at diagnosis. Nested controls were matched according to age, gender, CD4(+) T-cell count, and decline. Survivors (n = 18) were defined as being alive for >1 year after diagnosis. Using gamma interferon enzyme-linked immunospot assays, we found that JCV-specific T-cell responses were lower in nonsurvivors than in their matched controls (P = 0.08), which was highly significant for laboratory- and histologically confirmed PML cases (P = 0.004). No difference was found between PML survivors and controls or for cytomegalovirus-specific T-cell responses. PML survivors showed significant increases in JCV-specific T cells (P = 0.04) and immunoglobulin G (IgG) responses (P = 0.005). IgG responses in survivors were positively correlated with CD4(+) T-cell counts (P = 0.049) and negatively with human immunodeficiency virus RNA loads (P = 0.03). We conclude that PML nonsurvivors had selectively impaired JCV-specific T-cell responses compared to CD4(+) T-cell-matched controls and failed to mount JCV-specific antibody responses. JCV-specific T-cell and IgG responses may serve as prognostic markers for patients at risk.

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Abstract: Besides CYP2B6, other polymorphic enzymes contribute to efavirenz (EFV) interindividual variability. This study was aimed at quantifying the impact of multiple alleles on EFV disposition. Plasma samples from 169 human immunodeficiency virus (HIV) patients characterized for CYP2B6, CYP2A6, and CYP3A4/5 allelic diversity were used to build up a population pharmacokinetic model using NONMEM (non-linear mixed effects modeling), the aim being to seek a general approach combining genetic and demographic covariates. Average clearance (CL) was 11.3 l/h with a 65% interindividual variability that was explained largely by CYP2B6 genetic variation (31%). CYP2A6 and CYP3A4 had a prominent influence on CL, mostly when CYP2B6 was impaired. Pharmacogenetics fully accounted for ethnicity, leaving body weight as the only significant demographic factor influencing CL. Square roots of the numbers of functional alleles best described the influence of each gene, without interaction. Functional genetic variations in both principal and accessory metabolic pathways demonstrate a joint impact on EFV disposition. Therefore, dosage adjustment in accordance with the type of polymorphism (CYP2B6, CYP2A6, or CYP3A4) is required in order to maintain EFV within the therapeutic target levels.Clinical Pharmacology &#38; Therapeutics (2009); advance online publication 18 February 2009. doi:10.1038/clpt.2008.271.

Abstract: Background The principal causes of liver enzyme elevation among HIV-hepatitis B virus (HBV) co-infected patients are the hepatotoxic effects of antiretroviral therapy (ART), alcohol abuse, ART-induced immune reconstitution and the exacerbation of chronic HBV infection. Objectives To investigate the incidence and severity of liver enzyme elevation, liver failure and death following lamivudine (3TC) withdrawal in HIV-HBV co-infected patients. Methods Retrospective analysis of the Swiss HIV Cohort Study database to assess the clinical and biological consequences of the discontinuation of 3TC. Variables considered for analysis included liver enzyme, HIV virological and immunological parameters, and medication prescribed during a 6-month period following 3TC withdrawal. Results 3TC was discontinued in 255 patients on 363 occasions. On 147 occasions (109 patients), a follow-up visit within 6 months following 3TC withdrawal was recorded. Among these patients, liver enzyme elevation occurred on 42 occasions (29%), three of them (2%) with severity grade III and five of them (3.4%) with severity grade IV elevations (as defined by the AIDS Clinical Trials Group). Three patients presented with fulminant hepatitis. One death (0.7%) was recorded. Conclusions HBV reactivation leading to liver dysfunction may be an under-reported consequence of 3TC withdrawal in HIV-HBV co-infected patients. Regular monitoring of HBV markers is warranted if active therapy against HBV is discontinued.

Abstract: Gregory Bisson and Jeffrey Stringer discuss the implications of a new study showing how loss to follow-up affects the effectiveness of a public sector HIV program in Cote d'Ivoire.

Abstract: Besides CYP2B6, other polymorphic enzymes contribute to efavirenz (EFV) interindividual variability. This study was aimed at quantifying the impact of multiple alleles on EFV disposition. Plasma samples from 169 human immunodeficiency virus (HIV) patients characterized for CYP2B6, CYP2A6, and CYP3A4/5 allelic diversity were used to build up a population pharmacokinetic model using NONMEM (non-linear mixed effects modeling), the aim being to seek a general approach combining genetic and demographic covariates. Average clearance (CL) was 11.3 l/h with a 65% interindividual variability that was explained largely by CYP2B6 genetic variation (31%). CYP2A6 and CYP3A4 had a prominent influence on CL, mostly when CYP2B6 was impaired. Pharmacogenetics fully accounted for ethnicity, leaving body weight as the only significant demographic factor influencing CL. Square roots of the numbers of functional alleles best described the influence of each gene, without interaction. Functional genetic variations in both principal and accessory metabolic pathways demonstrate a joint impact on EFV disposition. Therefore, dosage adjustment in accordance with the type of polymorphism (CYP2B6, CYP2A6, or CYP3A4) is required in order to maintain EFV within the therapeutic target levels.

Abstract: OBJECTIVE: To analyse the early loss of patients to antiretroviral therapy (ART) programmes in resource-limited settings. METHODS: Using data on 5491 adult patients starting ART (median age 35 years, 46% female) in 15 treatment programmes in Africa, Asia and South America with (3) 12 months of follow-up, we investigated risk factors for no follow-up after treatment initiation, and loss to follow-up or death in the first 6 months. FINDINGS: Overall, 211 patients (3.8%) had no follow-up, 880 (16.0%) were lost to follow-up and 141 (2.6%) were known to have died in the first 6 months. The probability of no follow-up was higher in 2003-2004 than in 2000 or earlier (odds ratio, OR: 5.06; 95% confidence interval, CI: 1.28-20.0), as was loss to follow-up (hazard ratio, HR: 7.62; 95% CI: 4.55-12.8) but not recorded death (HR: 1.02; 95% CI: 0.44-2.36). Compared with a baseline CD4-cell count (3) 50 cells/microl, a count < 25 cells/microl was associated with a higher probability of no follow-up (OR: 2.49; 95% CI: 1.43-4.33), loss to follow-up (HR: 1.48; 95% CI: 1.23-1.77) and death (HR: 3.34; 95% CI: 2.10-5.30). Compared to free treatment, fee-for-service programmes were associated with a higher probability of no follow-up (OR: 3.71; 95% CI: 0.97-16.05) and higher mortality (HR: 4.64; 95% CI: 1.11-19.41). CONCLUSION: Early patient losses were increasingly common when programmes were scaled up and were associated with a fee for service and advanced immunodeficiency at baseline. Measures to maximize ART programme retention are required in resource-poor countries.

Abstract: BACKGROUND: The human immunodeficiency virus type 1 reverse-transcriptase mutation K65R is a single-point mutation that has become more frequent after increased use of tenofovir disoproxil fumarate (TDF). We aimed to identify predictors for the emergence of K65R, using clinical data and genotypic resistance tests from the Swiss HIV Cohort Study. METHODS: A total of 222 patients with genotypic resistance tests performed while receiving treatment with TDF-containing regimens were stratified by detectability of K65R (K65R group, 42 patients; undetected K65R group, 180 patients). Patient characteristics at start of that treatment were analyzed. RESULTS: In an adjusted logistic regression, TDF treatment with nonnucleoside reverse-transcriptase inhibitors and/or didanosine was associated with the emergence of K65R, whereas the presence of any of the thymidine analogue mutations D67N, K70R, T215F, or K219E/Q was protective. The previously undescribed mutational pattern K65R/G190S/Y181C was observed in 6 of 21 patients treated with efavirenz and TDF. Salvage therapy after TDF treatment was started for 36 patients with K65R and for 118 patients from the wild-type group. Proportions of patients attaining human immunodeficiency virus type 1 loads <50 copies/mL after 24 weeks of continuous treatment were similar for the K65R group (44.1%; 95% confidence interval, 27.2%-62.1%) and the wild-type group (51.9%; 95% confidence interval, 42.0%-61.6%). CONCLUSIONS: In settings where thymidine analogue mutations are less likely to be present, such as at start of first-line therapy or after extended treatment interruptions, combinations of TDF with other K65R-inducing components or with efavirenz or nevirapine may carry an enhanced risk of the emergence of K65R. The finding of a distinct mutational pattern selected by treatment with TDF and efavirenz suggests a potential fitness interaction between K65R and nonnucleoside reverse-transcriptase inhibitor-induced mutations.

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Abstract: OBJECTIVE: Particularly for therapy-experienced patients, resistance assessment by genotypic or phenotypic methods produces discordances. This study seeks proof that differences may arise from the fact that genotyping produces a single summary sequence whereas replicative phenotyping (rPhenotyping) functionally detects and assigns resistances in mixed HIV populations. METHODS: For validation, defined mixes of wild-type and M184V mutant were analysed by rPhenotyping or standard genotyping. Allele-specific and quantitative polymerase chain reaction (PCR) set detection and quantification limits for minor virus populations in vitro and in authentic clinical samples showing geno-/pheno-discrepant lamivudine resistance. RESULTS: Allele-specific and real-time PCR methods detected down to 0.3% of mutant M184V. The functional assessment was sensitive enough to reveal <1% of mutant M184V in mixed samples. Also in discordant samples from the diagnostic routine, in which rPhenotyping had identified drug resistance, real-time PCR confirmed minute amounts of mutant M184V. CONCLUSION: By utilizing the replication dynamics of HIV under drug pressure, a rPhenotyping format potently reveals relevant therapy-resistant minority species, even of HIV known to possess reduced replicative fitness. With its rapid turnaround of 8 days and its high sensitivity, our rPhenotyping system may be a valuable diagnostic tool for detecting the early emergence of therapy-threatening HIV minorities or the persistence of residual resistant virus.

Abstract: Advances in large-scale analysis of human genomic variability provide unprecedented opportunities to study the genetic basis of susceptibility to infectious agents. We report here the use of an in vitro system for the identification of a locus on HSA8q24.3 associated with cellular susceptibility to HIV-1. This locus was mapped through quantitative linkage analysis using cell lines from multigeneration families, validated in vitro, and followed up by two independent association studies in HIV-positive individuals. Single nucleotide polymorphism rs2572886, which is associated with cellular susceptibility to HIV-1 in lymphoblastoid B cells and in primary T cells, was also associated with accelerated disease progression in one of two cohorts of HIV-1-infected patients. Biological analysis suggests a role of the rs2572886 region in the regulation of the LY6 family of glycosyl-phosphatidyl-inositol (GPI)-anchored proteins. Genetic analysis of in vitro cellular phenotypes provides an attractive approach for the discovery of susceptibility loci to infectious agents.

Abstract: OBJECTIVE: Virologic failure of HIV-positive patients is of special concern during pregnancy. We compared virologic failure and the frequency of treatment changes in pregnant and non-pregnant women of the Swiss HIV Cohort Study. METHODS: Using data on 372 pregnancies in 324 women we describe antiretroviral therapy during pregnancy. Pregnant women on HAART at conception (n = 131) were matched to 228 non-pregnant women (interindividual comparison) and to a time period of equal length before and after pregnancy (intraindividual comparison). Women starting HAART during pregnancy (n = 145) were compared with 578 non-pregnant women starting HAART. FINDINGS: The median age at conception was 31 years, 16% (n = 50) were infected through injecting drug use and the median CD4 cell count was 489 cells/microl. In the majority of pregnancies (n = 220, 59%), women had started ART before conception. When ART was started during pregnancy (n = 145, 39%), it was mainly during the second trimester (n = 100, 69%). Two thirds (n = 26) of 35 women starting in the third trimester were diagnosed with HIV during pregnancy. The risk of virologic failure tended to be lower in pregnant than in non-pregnant women [adjusted odds ratio 0.52 (95% confidence interval 0.25-1.09, P = 0.08)], but was similar in the intraindividual comparison (adjusted odds ratio 1.04, 95% confidence interval 0.48-2.28). Women starting HAART during pregnancy changed the treatment less often than non-pregnant women. CONCLUSION: Despite the physiological changes occurring during pregnancy, HIV infected pregnant women are not at higher risk of virologic failure.

Abstract: Rapid rebound of plasma viremia in patients after interruption of long-term combination antiretroviral therapy (cART) suggests persistence of low-level replicating cells or rapid reactivation of latently infected cells. To further characterize rebounding virus, we performed extensive longitudinal clonal evolutionary studies of HIV env C2-V3-C3 regions and exploited the temporal relationships of rebounding plasma viruses with regard to pretreatment sequences in 20 chronically HIV-1-infected patients having undergone multiple 2-week structured treatment interruptions (STI). Rebounding virus during the short STI was homogeneous, suggesting mono- or oligoclonal origin during reactivation. No evidence for a temporal structure of rebounding virus in regard to pretreatment sequences was found. Furthermore, expansion of distinct lineages at different STI cycles emerged. Together, these findings imply stochastic reactivation of different clones from long-lived latently infected cells rather than expansion of viral populations replicating at low levels. After treatment was stopped, diversity increased steadily, but pretreatment diversity was, on average, achieved only >2.5 years after the start of STI when marked divergence from preexisting quasispecies also emerged. In summary, our results argue against persistence of ongoing low-level replication in patients on suppressive cART. Furthermore, a prolonged delay in restoration of pretreatment viral diversity after treatment interruption demonstrates a surprisingly sustained evolutionary bottleneck induced by punctuated antiretroviral therapy.

Abstract: Resistance to antiretroviral drugs remains an important limitation to successful human immunodeficiency virus type 1 (HIV-1) therapy. Resistance testing can improve treatment outcomes for infected individuals. The availability of new drugs from various classes, standardization of resistance assays, and the development of viral tropism tests necessitate new guidelines for resistance testing. The International AIDS Society-USA convened a panel of physicians and scientists with expertise in drug-resistant HIV-1, drug management, and patient care to review recently published data and presentations at scientific conferences and to provide updated recommendations. Whenever possible, resistance testing is recommended at the time of HIV infection diagnosis as part of the initial comprehensive patient assessment, as well as in all cases of virologic failure. Tropism testing is recommended whenever the use of chemokine receptor 5 antagonists is contemplated. As the roll out of antiretroviral therapy continues in developing countries, drug resistance monitoring for both subtype B and non-subtype B strains of HIV will become increasingly important.

Abstract: BACKGROUND: Although combination antiretroviral therapy (cART) dramatically reduces rates of AIDS and death, a minority of patients experience clinical disease progression during treatment. OBJECTIVE: To investigate whether detection of CXCR4(X4)-specific strains or quantification of X4-specific HIV-1 load predict clinical outcome. METHODS: From the Swiss HIV Cohort Study, 96 participants who initiated cART yet subsequently progressed to AIDS or death were compared with 84 contemporaneous, treated nonprogressors. A sensitive heteroduplex tracking assay was developed to quantify plasma X4 and CCR5 variants and resolve HIV-1 load into coreceptor-specific components. Measurements were analyzed as cofactors of progression in multivariable Cox models adjusted for concurrent CD4 cell count and total viral load, applying inverse probability weights to adjust for sampling bias. RESULTS: Patients with X4 variants at baseline displayed reduced CD4 cell responses compared with those without X4 strains (40 versus 82 cells/microl; P = 0.012). The adjusted multivariable hazard ratio (HR) for clinical progression was 4.8 [95% confidence interval (CI) 2.3-10.0] for those demonstrating X4 strains at baseline. The X4-specific HIV-1 load was a similarly independent predictor, with HR values of 3.7 (95% CI, 1.2-11.3) and 5.9 (95% CI, 2.2-15.0) for baseline loads of 2.2-4.3 and > 4.3 log10 copies/ml, respectively, compared with < 2.2 log10 copies/ml. CONCLUSIONS: HIV-1 coreceptor usage and X4-specific viral loads strongly predicted disease progression during cART, independent of and in addition to CD4 cell count or total viral load. Detection and quantification of X4 strains promise to be clinically useful biomarkers to guide patient management and study HIV-1 pathogenesis.

Abstract: OBJECTIVES: To describe temporal trends in baseline clinical characteristics, initial treatment regimens and monitoring of patients starting antiretroviral therapy (ART) in resource-limited settings. METHODS: We analysed data from 17 ART programmes in 12 countries in sub-Saharan Africa, South America and Asia. Patients aged 16 years or older with documented date of start of highly active ART (HAART) were included. Data were analysed by calculating medians, interquartile ranges (IQR) and percentages by regions and time periods. Not all centres provided data for 2006 and 2005 and 2006 were therefore combined. RESULTS: A total of 36,715 patients who started ART 1996-2006 were included in the analysis. Patient numbers increased substantially in sub-Saharan Africa and Asia, and the number of initial regimens declined, to four and five, respectively, in 2005-2006. In South America 20 regimes were used in 2005-2006. A combination of 3TC/D4T/NVP was used for 56% of African patients and 42% of Asian patients; AZT/3TC/EFV was used in 33% of patients in South America. The median baseline CD4 count increased in recent years, to 122 cells/microl (IQR 53-194) in 2005-2006 in Africa, 134 cells/microl (IQR 72-191) in Asia, and 197 cells/microl (IQR 61-277) in South America, but 77%, 78% and 51%, respectively, started with <200 cells/microl in 2005-2006. In all regions baseline CD4 cell counts were higher in women than men: differences were 22cells/microl in Africa, 65 cells/microl in Asia and 10 cells/microl in South America. In 2005-2006 a viral load at 6 months was available in 21% of patients Africa, 8% of Asian patients and 73% of patients in South America. Corresponding figures for 6-month CD4 cell counts were 74%, 77% and 81%. CONCLUSIONS: The public health approach to providing ART proposed by the World Health Organization has been implemented in sub-Saharan Africa and Asia. Although CD4 cell counts at the start of ART have increased in recent years, most patients continue to start with counts well below the recommended threshold. Particular attention should be paid to more timely initiation of ART in HIV-infected men.

Abstract: BACKGROUND: Combination antiretroviral therapy has led to significant increases in survival and quality of life, but at a population-level the effect on life expectancy is not well understood. Our objective was to compare changes in mortality and life expectancy among HIV-positive individuals on combination antiretroviral therapy. METHODS: The Antiretroviral Therapy Cohort Collaboration is a multinational collaboration of HIV cohort studies in Europe and North America. Patients were included in this analysis if they were aged 16 years or over and antiretroviral-naive when initiating combination therapy. We constructed abridged life tables to estimate life expectancies for individuals on combination antiretroviral therapy in 1996-99, 2000-02, and 2003-05, and stratified by sex, baseline CD4 cell count, and history of injecting drug use. The average number of years remaining to be lived by those treated with combination antiretroviral therapy at 20 and 35 years of age was estimated. Potential years of life lost from 20 to 64 years of age and crude mortality rates were also calculated. FINDINGS: 18 587, 13 914, and 10 854 eligible patients initiated combination antiretroviral therapy in 1996-99, 2000-02, and 2003-05, respectively. 2056 (4.7%) deaths were observed during the study period, with crude mortality rates decreasing from 16.3 deaths per 1000 person-years in 1996-99 to 10.0 deaths per 1000 person-years in 2003-05. Potential years of life lost per 1000 person-years also decreased over the same time, from 366 to 189 years. Life expectancy at age 20 years increased from 36.1 (SE 0.6) years to 49.4 (0.5) years. Women had higher life expectancies than did men. Patients with presumed transmission via injecting drug use had lower life expectancies than did those from other transmission groups (32.6 [1.1] years vs 44.7 [0.3] years in 2003-05). Life expectancy was lower in patients with lower baseline CD4 cell counts than in those with higher baseline counts (32.4 [1.1] years for CD4 cell counts below 100 cells per muL vs 50.4 [0.4] years for counts of 200 cells per muL or more). INTERPRETATION: Life expectancy in HIV-infected patients treated with combination antiretroviral therapy increased between 1996 and 2005, although there is considerable variability between subgroups of patients. The average number of years remaining to be lived at age 20 years was about two-thirds of that in the general population in these countries.

Abstract:

Abstract: BACKGROUND: The provision of highly active antiretroviral therapy (HAART) in resource-limited settings follows a public health approach, which is characterised by a limited number of regimens and the standardisation of clinical and laboratory monitoring. In industrialized countries doctors prescribe from the full range of available antiretroviral drugs, supported by resistance testing and frequent laboratory monitoring. We compared virologic response, changes to first-line regimens, and mortality in HIV-infected patients starting HAART in South Africa and Switzerland. METHODS AND FINDINGS: We analysed data from the Swiss HIV Cohort Study and two HAART programmes in townships of Cape Town, South Africa. We included treatment-naive patients aged 16 y or older who had started treatment with at least three drugs since 2001, and excluded intravenous drug users. Data from a total of 2,348 patients from South Africa and 1,016 patients from the Swiss HIV Cohort Study were analysed. Median baseline CD4+ T cell counts were 80 cells/mul in South Africa and 204 cells/mul in Switzerland. In South Africa, patients started with one of four first-line regimens, which was subsequently changed in 514 patients (22%). In Switzerland, 36 first-line regimens were used initially, and these were changed in 539 patients (53%). In most patients HIV-1 RNA was suppressed to 500 copies/ml or less within one year: 96% (95% confidence interval [CI] 95%-97%) in South Africa and 96% (94%-97%) in Switzerland, and 26% (22%-29%) and 27% (24%-31%), respectively, developed viral rebound within two years. Mortality was higher in South Africa than in Switzerland during the first months of HAART: adjusted hazard ratios were 5.90 (95% CI 1.81-19.2) during months 1-3 and 1.77 (0.90-3.50) during months 4-24. CONCLUSIONS: Compared to the highly individualised approach in Switzerland, programmatic HAART in South Africa resulted in similar virologic outcomes, with relatively few changes to initial regimens. Further innovation and resources are required in South Africa to both achieve more timely access to HAART and improve the prognosis of patients who start HAART with advanced disease.

Abstract: BACKGROUND: Little is known about time trends, predictors, and consequences of changes made to antiretroviral therapy (ART) regimens early after patients initially start treatment. METHODS: We compared the incidence of, reasons for, and predictors of treatment change within 1 year after starting combination ART (cART), as well as virological and immunological outcomes at 1 year, among 1866 patients from the Swiss HIV Cohort Study who initiated cART during 2000--2001, 2002--2003, or 2004--2005. RESULTS: The durability of initial regimens did not improve over time (P = .15): 48.8% of 625 patients during 2000--2001, 43.8% of 607 during 2002--2003, and 44.3% of 634 during 2004--2005 changed cART within 1 year; reasons for change included intolerance (51.1% of all patients), patient wish (15.4%), physician decision (14.8%), and virological failure (7.1%). An increased probability of treatment change was associated with larger CD4+ cell counts, larger human immunodeficiency virus type 1 (HIV-1) RNA loads, and receipt of regimens that contained stavudine or indinavir/ritonavir, but a decreased probability was associated with receipt of regimens that contained tenofovir. Treatment discontinuation was associated with larger CD4+ cell counts, current use of injection drugs, and receipt of regimens that contained nevirapine. One-year outcomes improved between 2000--2001 and 2004--2005: 84.5% and 92.7% of patients, respectively, reached HIV-1 RNA loads of <50 copies/mL and achieved median increases in CD4+ cell counts of 157.5 and 197.5 cells/microL, respectively (P < .001 for all comparisons). CONCLUSIONS: Virological and immunological outcomes of initial treatments improved between 2000--2001 and 2004--2005, irrespective of uniformly high rates of early changes in treatment across the 3 study intervals.

Abstract: AIM: To evaluate the long-term safety and effectiveness of ritonavir, nelfinavir, and lopinavir/ritonavir in antiretroviral-experienced, initially protease inhibitor (PI)-naive, human immunodeficiency virus (HIV)-1-infected children. METHODS: HIV-1-infected children enrolled in the Swiss Mother and Child HIV Cohort Study were eligible for this observational cohort study if they received at least 1 PI of interest between March 1996 and October 2003: ritonavir, nelfinavir, or lopinavir/ritonavir. Data regarding demographics, clinical disease and antiretroviral treatment history, HIV-1 RNA copies/mL, CD4 T-cell counts [absolute (cells/microL) and percentages (%)], adverse events, clinical laboratory values, reasons for discontinuation of PIs, and concomitant medications were extracted from the database for PI-naive (first-line) and PI-experienced (second- or higher-line) PI use. RESULTS: The total duration of ritonavir, nelfinavir, and lopinavir/ritonavir use for 133 HIV-1-infected children was 163.8, 235.0, and 46.1 patient-years, respectively. In an on-treatment analysis, first-line therapy with any of the PIs significantly reduced HIV-1 concentrations and increased CD4 T-cell counts and percentages from baseline throughout the 288-week study (P <or= 0.05) for ritonavir and nelfinavir and throughout 84 weeks of use for lopinavir/ritonavir, which was introduced into treatment more recently. All PIs investigated were most effective in PI-naive children. Thirteen PI-associated toxicities occurred requiring treatment changes or interruptions (neurologic symptoms, n = 2; pancreatitis, n = 1; allergic reactions, n = 4; visual symptoms, n = 3; and hyperlipidemia, n = 3). CONCLUSIONS: Long-term PI-based therapy seems to be safe and to result in durable virologic and immunologic effectiveness in HIV-1-infected antiretroviral-experienced children.

Abstract: BACKGROUND: We aimed to assess the value of a structured clinical assessment and genetic testing for refining the diagnosis of abacavir hypersensitivity reactions (ABC-HSRs) in a routine clinical setting. METHODS: We performed a diagnostic reassessment using a structured patient chart review in individuals who had stopped ABC because of suspected HSR. Two HIV physicians blinded to the human leukocyte antigen (HLA) typing results independently classified these individuals on a scale between 3 (ABC-HSR highly likely) and -3 (ABC-HSR highly unlikely). Scoring was based on symptoms, onset of symptoms and comedication use. Patients were classified as clinically likely (mean score > or =2), uncertain (mean score > or = -1 and < or = 1) and unlikely (mean score < or = -2). HLA typing was performed using sequence-based methods. RESULTS: From 131 reassessed individuals, 27 (21%) were classified as likely, 43 (33%) as unlikely and 61 (47%) as uncertain ABC-HSR. Of the 131 individuals with suspected ABC-HSR, 31% were HLA-B*5701-positive compared with 1% of 140 ABC-tolerant controls (P < 0.001). HLA-B*5701 carriage rate was higher in individuals with likely ABC-HSR compared with those with uncertain or unlikely ABC-HSR (78%, 30% and 5%, respectively, P < 0.001). Only six (7%) HLA-B*5701-negative individuals were classified as likely HSR after reassessment. CONCLUSIONS: HLA-B*5701 carriage is highly predictive of clinically diagnosed ABC-HSR. The high proportion of HLA-B*5701-negative individuals with minor symptoms among individuals with suspected HSR indicates overdiagnosis of ABC-HSR in the era preceding genetic screening. A structured clinical assessment and genetic testing could reduce the rate of inappropriate ABC discontinuation and identify individuals at high risk for ABC-HSR.

Abstract: We assessed the influence of human leukocyte antigen (HLA) alleles HLA-Bw4 and HLA-Bw6 on CD4 T cell recovery after starting successful combination antiretroviral therapy in 265 individuals. The median gains in the CD4 T cell count after 4 years were 258 cells/microL for HLA-Bw4 homozygotes, 321 cells/microL for HLA-Bw4/Bw6 heterozygotes, and 363 cells/microL for HLA-Bw6 homozygotes (P = .01, compared with HLA-Bw4 homozygotes). HLA-Bw4 homozygosity appears to predict an impaired CD4 T cell recovery after initiation of combination antiretroviral therapy.

Abstract: BACKGROUND: Because of the known relationship between exposure to combination antiretroviral therapy and cardiovascular disease (CVD), it has become increasingly important to intervene against risk of CVD in human immunodeficiency virus (HIV)-infected patients. We evaluated changes in risk factors for CVD and the use of lipid-lowering therapy in HIV-infected individuals and assessed the impact of any changes on the incidence of myocardial infarction. METHODS: The Data Collection on Adverse Events of Anti-HIV Drugs Study is a collaboration of 11 cohorts of HIV-infected patients that included follow-up for 33,389 HIV-infected patients from December 1999 through February 2006. RESULTS: The proportion of patients at high risk of CVD increased from 35.3% during 1999-2000 to 41.3% during 2005-2006. Of 28,985 patients, 2801 (9.7%) initiated lipid-lowering therapy; initiation of lipid-lowering therapy was more common for those with abnormal lipid values and those with traditional risk factors for CVD (male sex, older age, higher body mass index [calculated as the weight in kilograms divided by the square of the height in meters], family and personal history of CVD, and diabetes mellitus). After controlling for these, use of lipid-lowering drugs became relatively less common over time. The incidence of myocardial infarction (0.32 cases per 100 person-years [PY]; 95% confidence interval [CI], 0.29-0.35 cases per 100 PY) appeared to remain stable. However, after controlling for changes in risk factors for CVD, the rate decreased over time (relative rate in 2003 [compared with 1999-2000], 0.73 cases per 100 PY [95% CI, 0.50-1.05 cases per 100 PY]; in 2004, 0.64 cases per 100 PY [95% CI, 0.44-0.94 cases per 100 PY]; in 2005-2006, 0.36 cases per 100 PY [95% CI, 0.24-0.56 cases per 100 PY]). Further adjustment for lipid levels attenuated the relative rates towards unity (relative rate in 2003 [compared with 1999-2000], 1.06 cases per 100 PY [95% CI, 0.63-1.77 cases per 100 PY]; in 2004, 1.02 cases per 100 PY [95% CI, 0.61-1.71 cases per 100 PY]; in 2005-2006, 0.63 cases per 100 PY [95% CI, 0.36-1.09 cases per 100 PY]). CONCLUSIONS: Although the CVD risk profile among patients in the Data Collection on Adverse Events of Anti-HIV Drugs Study has decreased since 1999, rates have remained relatively stable, possibly as a result of a more aggressive approach towards managing the risk of CVD.

Abstract: BACKGROUND: Whether nucleoside reverse transcriptase inhibitors increase the risk of myocardial infarction in HIV-infected individuals is unclear. Our aim was to explore whether exposure to such drugs was associated with an excess risk of myocardial infarction in a large, prospective observational cohort of HIV-infected patients. METHODS: We used Poisson regression models to quantify the relation between cumulative, recent (currently or within the preceding 6 months), and past use of zidovudine, didanosine, stavudine, lamivudine, and abacavir and development of myocardial infarction in 33 347 patients enrolled in the D:A:D study. We adjusted for cardiovascular risk factors that are unlikely to be affected by antiretroviral therapy, cohort, calendar year, and use of other antiretrovirals. FINDINGS: Over 157,912 person-years, 517 patients had a myocardial infarction. We found no associations between the rate of myocardial infarction and cumulative or recent use of zidovudine, stavudine, or lamivudine. By contrast, recent-but not cumulative-use of abacavir or didanosine was associated with an increased rate of myocardial infarction (compared with those with no recent use of the drugs, relative rate 1.90, 95% CI 1.47-2.45 [p=0.0001] with abacavir and 1.49, 1.14-1.95 [p=0.003] with didanosine); rates were not significantly increased in those who stopped these drugs more than 6 months previously compared with those who had never received these drugs. After adjustment for predicted 10-year risk of coronary heart disease, recent use of both didanosine and abacavir remained associated with increased rates of myocardial infarction (1.49, 1.14-1.95 [p=0.004] with didanosine; 1.89, 1.47-2.45 [p=0.0001] with abacavir). INTERPRETATION: There exists an increased risk of myocardial infarction in patients exposed to abacavir and didanosine within the preceding 6 months. The excess risk does not seem to be explained by underlying established cardiovascular risk factors and was not present beyond 6 months after drug cessation.

Abstract: In studies of the natural history of HIV-1 infection, the time scale of primary interest is the time since infection. Unfortunately, this time is very often unknown for HIV infection and using the follow-up time instead of the time since infection is likely to provide biased results because of onset confounding. Laboratory markers such as the CD4 T-cell count carry important information concerning disease progression and can be used to predict the unknown date of infection. Previous work on this topic has made use of only one CD4 measurement or based the imputation on incident patients only. However, because of considerable intrinsic variability in CD4 levels and because incident cases are different from prevalent cases, back calculation based on only one CD4 determination per person or on characteristics of the incident sub-cohort may provide unreliable results. Therefore, we propose a methodology based on the repeated individual CD4 T-cells marker measurements that use both incident and prevalent cases to impute the unknown date of infection. Our approach uses joint modelling of the time since infection, the CD4 time path and the drop-out process. This methodology has been applied to estimate the CD4 slope and impute the unknown date of infection in HIV patients from the Swiss HIV Cohort Study. A procedure based on the comparison of different slope estimates is proposed to assess the goodness of fit of the imputation. Results of simulation studies indicated that the imputation procedure worked well, despite the intrinsic high volatility of the CD4 marker.

Abstract: BACKGROUND: Two nucleos(t)ide reverse transcriptase inhibitors (NRTIs)--abacavir and didanosine--may each be associated with excess risk of myocardial infarction. The reproducibility of this finding in an independent dataset was explored and plausible biological mechanisms were sought. METHODS: Biomarkers, ischemic changes on the electrocardiogram, and rates of various predefined types of cardiovascular disease (CVD) events according to NRTIs used were explored in the Strategies for Management of Anti-Retroviral Therapy (SMART) study. Patients receiving abacavir and not didanosine were compared with those receiving didanosine, and to those receiving NRTIs other than abacavir or didanosine (other NRTIs). Patients randomly assigned to the continuous antiretroviral therapy arm of SMART were included in all analyses (N = 2752); for the study of biomarkers, patients from the antiretroviral therapy interruption arm were also included. RESULTS: Current use of abacavir was associated with an excess risk of CVD compared with other NRTIs. Adjusted hazard ratios for clinical myocardial infarction (n = 19), major CVD (myocardial infarction, stroke, surgery for coronary artery disease, and CVD death; n = 70), expanded CVD (major CVD plus congestive heart failure, peripheral vascular disease, coronary artery disease requiring drug treatment, and unwitnessed deaths; n = 112) were 4.3 [95% confidence interval (CI): 1.4-13.0], 1.8 (1.0-3.1), and 1.9 (1.3-2.9). At baseline in a subset of patients with biomarker data, high sensitivity-C-reactive protein and interleukin-6 were 27% (P = 0.02) and 16% (P = 0.02) higher for patients receiving abacavir (N = 175) compared with those receiving other NRTIs (N = 500). Didanosine was associated neither with altered risk of CVD nor with altered levels of biomarkers. CONCLUSION: Abacavir was associated with an increased risk of CVD. The drug may cause vascular inflammation, which may precipitate a CVD event.

Abstract: BACKGROUND: The aim of this study was to evaluate the effect of CD4+ T-cell counts and other characteristics of HIV-infected individuals on hepatitis C virus (HCV) RNA levels. METHODS: All HIV-HCV-coinfected Swiss HIV Cohort Study participants with available HCV RNA levels and concurrent CD4+ T-cell counts before starting HCV therapy were included. Potential predictors of HCV RNA levels were assessed by multivariate censored linear regression models that adjust for censored values. RESULTS: The study included 1,031 individuals. Low current and nadir CD4+ T-cell counts were significantly associated with higher HCV RNA levels (P = 0.004 and 0.001, respectively). In individuals with current CD4+ T-cell counts < 200/microl, median HCV RNA levels (6.22 log10 IU/ml) were +0.14 and +0.24 log10 IU/ml higher than those with CD4+ T-cell counts of 200-500/microl and > 500/microl. Based on nadir CD4+ T-cell counts, median HCV RNA levels (6.12 log10 IU/ml) in individuals with < 200/microl CD4+ T-cells were +0.06 and +0.44 log10 IU/ml higher than those with nadir T-cell counts of 200-500/microl and > 500/microl. Median HCV RNA levels were also significantly associated with HCV genotype: lower values were associated with genotype 4 and higher values with genotype 2, as compared with genotype 1. Additional significant predictors of lower HCV RNA levels were female gender and HIV transmission through male homosexual contacts. In multivariate analyses, only CD4+ T-cell counts and HCV genotype remained significant predictors of HCV RNA levels. Conclusions: Higher HCV RNA levels were associated with CD4+ T-cell depletion. This finding is in line with the crucial role of CD4+ T-cells in the control of HCV infection.

Abstract: OBJECTIVE: To assess the long-term effect of HAART on non-Hodgkin lymphoma (NHL) incidence in people with HIV (PHIV). DESIGN: Follow-up of the Swiss HIV Cohort Study (SHCS). METHODS: Between 1984 and 2006, 12 959 PHIV contributed a total of 75 222 person-years (py), of which 36 787 were spent under HAART. Among these PHIV, 429 NHL cases were identified from the SHCS dataset and/or by record linkage with Swiss Cantonal Cancer Registries. Age- and gender-standardized incidence was calculated and Cox regression was used to estimate hazard ratios (HR). RESULTS: NHL incidence reached 13.6 per 1000 py in 1993-1995 and declined to 1.8 in 2002-2006. HAART use was associated with a decline in NHL incidence [HR = 0.26; 95% confidence interval (CI), 0.20-0.33], and this decline was greater for primary brain lymphomas than other NHL. Among non-HAART users, being a man having sex with men, being 35 years of age or older, or, most notably, having low CD4 cell counts at study enrollment (HR = 12.26 for < 50 versus >or= 350 cells/microl; 95% CI, 8.31-18.07) were significant predictors of NHL onset. Among HAART users, only age was significantly associated with NHL risk. The HR for NHL declined steeply in the first months after HAART initiation (HR = 0.46; 95% CI, 0.27-0.77) and was 0.12 (95% CI, 0.05-0.25) 7 to10 years afterwards. CONCLUSIONS: HAART greatly reduced the incidence of NHL in PHIV, and the influence of CD4 cell count on NHL risk. The beneficial effect remained strong up to 10 years after HAART initiation.

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Abstract: OBJECTIVE: To evaluate deaths from AIDS-defining malignancies (ADM) and non-AIDS-defining malignancies (nADM) in the D:A:D Study and to investigate the relationship between these deaths and immunodeficiency. DESIGN: Observational cohort study. METHODS: Patients (23 437) were followed prospectively for 104 921 person-years. We used Poisson regression models to identify factors independently associated with deaths from ADM and nADM. Analyses of factors associated with mortality due to nADM were repeated after excluding nADM known to be associated with a specific risk factor. RESULTS: Three hundred five patients died due to a malignancy, 298 prior to the cutoff for this analysis (ADM: n = 110; nADM: n = 188). The mortality rate due to ADM decreased from 20.1/1000 person-years of follow-up [95% confidence interval (CI) 14.4, 25.9] when the most recent CD4 cell count was <50 cells/microl to 0.1 (0.03, 0.3)/1000 person-years of follow-up when the CD4 cell count was more than 500 cells/microl; the mortality rate from nADM decreased from 6.0 (95% CI 3.3, 10.1) to 0.6 (0.4, 0.8) per 1000 person-years of follow-up between these two CD4 cell count strata. In multivariable regression analyses, a two-fold higher latest CD4 cell count was associated with a halving of the risk of ADM mortality. Other predictors of an increased risk of ADM mortality were homosexual risk group, older age, a previous (non-malignancy) AIDS diagnosis and earlier calendar years. Predictors of an increased risk of nADM mortality included lower CD4 cell count, older age, current/ex-smoking status, longer cumulative exposure to combination antiretroviral therapy, active hepatitis B infection and earlier calendar year. CONCLUSION: The severity of immunosuppression is predictive of death from both ADM and nADM in HIV-infected populations.

Abstract: OBJECTIVE: To determine whether differences in short-term virologic failure among commonly used antiretroviral therapy (ART) regimens translate to differences in clinical events in antiretroviral-naive patients initiating ART. DESIGN: Observational cohort study of patients initiating ART between January 2000 and December 2005. SETTING: The Antiretroviral Therapy Cohort Collaboration (ART-CC) is a collaboration of 15 HIV cohort studies from Canada, Europe, and the United States. STUDY PARTICIPANTS: A total of 13 546 antiretroviral-naive HIV-positive patients initiating ART with efavirenz, nevirapine, lopinavir/ritonavir, nelfinavir, or abacavir as third drugs in combination with a zidovudine and lamivudine nucleoside reverse transcriptase inhibitor backbone. MAIN OUTCOME MEASURES: Short-term (24-week) virologic failure (>500 copies/ml) and clinical events within 2 years of ART initiation (incident AIDS-defining event, death, and a composite measure of these two outcomes). RESULTS: Compared with efavirenz as initial third drug, short-term virologic failure was more common with all other third drugs evaluated; nevirapine (adjusted odds ratio = 1.87, 95% confidence interval (CI) = 1.58-2.22), lopinavir/ritonavir (1.32, 95% CI = 1.12-1.57), nelfinavir (3.20, 95% CI = 2.74-3.74), and abacavir (2.13, 95% CI = 1.82-2.50). However, the rate of clinical events within 2 years of ART initiation appeared higher only with nevirapine (adjusted hazard ratio for composite outcome measure 1.27, 95% CI = 1.04-1.56) and abacavir (1.22, 95% CI = 1.00-1.48). CONCLUSION: Among antiretroviral-naive patients initiating therapy, between-ART regimen, differences in short-term virologic failure do not necessarily translate to differences in clinical outcomes. Our results should be interpreted with caution because of the possibility of residual confounding by indication.

Abstract: BACKGROUND AND OBJECTIVES: Combination antiretroviral therapy (cART) is changing, and this may affect the type and occurrence of side effects. We examined the frequency of lipodystrophy (LD) and weight changes in relation to the use of specific drugs in the Swiss HIV Cohort Study (SHCS). METHODS: In the SHCS, patients are followed twice a year and scored by the treating physician as having 'fat accumulation', 'fat loss', or neither. Treatments, and reasons for change thereof, are recorded. Our study sample included all patients treated with cART between 2003 and 2006 and, in addition, all patients who started cART between 2000 and 2003. RESULTS: From 2003 to 2006, the percentage of patients taking stavudine, didanosine and nelfinavir decreased, the percentage taking lopinavir, nevirapine and efavirenz remained stable, and the percentage taking atazanavir and tenofovir increased by 18.7 and 22.2%, respectively. In life-table Kaplan-Meier analysis, patients starting cART in 2003-2006 were less likely to develop LD than those starting cART from 2000 to 2002 (P<0.02). LD was quoted as the reason for treatment change or discontinuation for 4% of patients on cART in 2003, and for 1% of patients treated in 2006 (P for trend <0.001). In univariate and multivariate regression analysis, patients with a weight gain of >or=5 kg were more likely to take lopinavir or atazanavir than patients without such a weight gain [odds ratio (OR) 2, 95% confidence interval (CI) 1.3-2.9, and OR 1.7, 95% CI 1.3-2.1, respectively]. CONCLUSIONS: LD has become less frequent in the SHCS from 2000 to 2006. A weight gain of more than 5 kg was associated with the use of atazanavir and lopinavir.

Abstract: BACKGROUND: Atherosclerosis has been assessed in human immunodeficiency virus (HIV)-infected persons by using various methods. Peripheral arterial disease (PAD) has not been evaluated, however. We studied the cross-sectional prevalence of lower limb PAD in an HIV-infected population. METHODS: PAD was assessed using the Edinburgh Claudication Questionnaire and by measuring the systolic ankle-brachial blood pressure index (ABI) at rest and after exercise. Patients with PAD were further evaluated by duplex scan of lower limb arteries. RESULTS: Ninety-two consecutive HIV-infected patients were evaluated (23.9% women; mean age, 49.5 years; 61.9% current smokers). Claudication was reported by 15.2% of the patients. PAD was found in 20.7% of the patients: 9.8% had an abnormal ABI (<0.90) at rest, and 10.9% had normal ABI at rest but a >25% decrease after exercise. Of the patients with PAD, 84.2% were investigated with duplex scan, all of whom had atherosclerotic occlusions or stenoses of the iliac or femoral arteries. Age, diabetes, smoking, and low CD4+ T lymphocyte counts were identified as independent predictors of PAD. CONCLUSIONS: The prevalence of symptomatic and asymptomatic PAD is high in the HIV-infected population and is much higher than expected (prevalence in the general population, approximately 3% at 60 years). This study suggests the presence of an epidemic of PAD approximately 20 years earlier in the HIV-infected than in the general population. Larger epidemiological studies are needed to better define risk factors and to evaluate whether PAD is associated with increased mortality, as it is in the general population.

Abstract: OBJECTIVES: To compare immunological, virological and clinical outcomes in persons initiating combination antiretroviral therapy (cART of different durations within 6 months of seroconversion (early treated) with those who deferred therapy (deferred group). DESIGN: CD4 cell and HIV-RNA measurements for 'early treated' individuals following treatment cessation were compared with the corresponding ART-free period for the 'deferred' group using piecewise linear mixed models. Individuals identified during primary HIV infection were included if they seroconverted from 1st January 1996 and were at least 15 years of age at seroconversion. Those with at least 2 CD4 less than 350 cells/microl or AIDS within the first 6 months following seroconversion were excluded. RESULTS: Of 348 'early treated' patients, 147 stopped cART following treatment for at least 6 (n = 38), more than 6-12 (n = 40) or more than 12 months (n = 69). CD4 cell loss was steeper for the first 6 months following cART cessation, but subsequent loss rate was similar to the 'deferred' group (n = 675, P = 0.26). Although those treated for more than 12 months appeared to maintain higher CD4 cell counts following cART cessation, those treated for 12 months or less had CD4 cell counts 6 months after cessation comparable to those in the 'deferred' group. There was no difference in HIV-RNA set points between the 'early' and 'deferred' groups (P = 0.57). AIDS rates were similar but death rates, mainly due to non-AIDS causes, were higher in the 'deferred' group (P = 0.05). CONCLUSION: Transient cART, initiated within 6 months of seroconversion, seems to have no effect on viral load set point and limited beneficial effect on CD4 cell levels in individuals treated for more than 12 months. Its long-term effects remain inconclusive and need further investigation.

Abstract: OBJECTIVE: The aim of this work was to assess loss to follow-up (LTFU) in EuroSIDA, an international multicentre observational cohort study. METHODS: LTFU was defined as no follow-up visit, CD4 cell count measurement or viral load measurement after 1 January 2006. Poisson regression was used to describe factors related to LTFU. RESULTS: The incidence of LTFU in 12 304 patients was 3.72 per 100 person-years of follow-up [95% confidence interval (CI) 3.58-3.86; 2712 LTFU] and varied among countries from 0.67 to 13.35. After adjustment, older patients, those with higher CD4 cell counts, and those who had started combination antiretroviral therapy all had lower incidences of LTFU, while injecting drug users had a higher incidence of LTFU. Compared with patients from Southern Europe and Argentina, patients from Eastern Europe had over a twofold increased incidence of LTFU after adjustment (incidence rate ratio 2.16; 95% CI 1.84-2.53; P<0.0001). A total of 2743 patients had a period of >1 year with no CD4 cell count or viral load measured during the year; 743 (27.1%) subsequently returned to follow-up. CONCLUSIONS: Some patients thought to be LTFU may have died, and efforts should be made to ascertain vital status wherever possible. A significant proportion of patients who have a year with no follow-up visit, CD4 cell count measurement or viral load measurement subsequently return to follow-up.

Abstract: BACKGROUND: In recent years, treatment options for human immunodeficiency virus type 1 (HIV-1) infection have changed from nonboosted protease inhibitors (PIs) to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and boosted PI-based antiretroviral drug regimens, but the impact on immunological recovery remains uncertain. METHODS: During January 1996 through May 2007, all patients in the Swiss HIV Cohort were included if they received the first combination antiretroviral therapy (cART) and had known baseline CD4(+) T cell counts and HIV-1 RNA values (n = 3293). The mean (+/-SD) duration of follow-up was 26.8 +/- 20.5 months. The follow-up time was limited to the duration of the first cART. CD4(+) T cell recovery was analyzed in 3 different treatment groups: nonboosted PI, NNRTI, or boosted PI. The end point was the absolute increase of CD4(+) T cell count in the 3 treatment groups after the initiation of cART. RESULTS: Two thousand five hundred ninety individuals (78.7%) initiated a nonboosted-PI regimen, 452 (13.7%) initiated an NNRTI regimen, and 251 (7.6%) initiated a boosted-PI regimen. Absolute CD4(+) T cell count increases at 48 months were as follows: in the nonboosted-PI group, from 210 to 520 cells/muL; in the NNRTI group, from 220 to 475 cells/muL; and in the boosted-PI group, from 168 to 511 cells/muL. In a multivariate analysis, the treatment group did not affect the response of CD4(+) T cells; however, increased age, pretreatment with nucleoside reverse-transcriptase inhibitors, serological tests positive for hepatitis C virus, Centers for Disease Control and Prevention stage C infection, lower baseline CD4(+) T cell count, and lower baseline HIV-1 RNA level were risk factors for smaller increases in CD4(+) T cell count. CONCLUSION: CD4(+) T cell recovery was similar in patients receiving nonboosted PI-, NNRTI-, and boosted PI-based cART.

Abstract: OBJECTIVE: The aims of this study were to determine the incidence of diabetes among HIV-infected patients in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort, to identify demographic, HIV-related, and combination antiretroviral therapy (cART)-related factors associated with the onset of diabetes, and to identify possible mechanisms for any relationships found. RESEARCH DESIGN AND METHODS: D:A:D is a prospective observational study of 33,389 HIV-infected patients; diabetes is a study end point. Poisson regression models were used to assess the relation between diabetes and exposure to cART after adjusting for known risk factors for diabetes, CD4 count, lipids, and lipodystrophy. RESULTS: Over 130,151 person-years of follow-up (PYFU), diabetes was diagnosed in 744 patients (incidence rate of 5.72 per 1,000 PYFU [95% CI 5.31-6.13]). The incidence of diabetes increased with cumulative exposure to cART, an association that remained significant after adjustment for potential risk factors for diabetes. The strongest relationship with diabetes was exposure to stavudine; exposures to zidovudine and didanosine were also associated with an increased risk of diabetes. Time-updated measurements of total cholesterol, HDL cholesterol, and triglycerides were all associated with diabetes. Adjusting for each of these variables separately reduced the relationship between cART and diabetes slightly. Although lipodystrophy was significantly associated with diabetes, adjustment for this did not modify the relationship between cART and diabetes. CONCLUSION: Stavudine and zidovudine are significantly associated with diabetes after adjustment for risk factors for diabetes and lipids. Adjustment for lipodystrophy did not modify the relationship, suggesting that the two thymidine analogs probably directly contribute to insulin resistance, potentially through mitochondrial toxicity.

Abstract: Between 1984 and 2006, 12 959 people with HIV/AIDS (PWHA) in the Swiss HIV Cohort Study contributed a total of 73 412 person-years (py) of follow-up, 35 551 of which derived from PWHA treated with highly active antiretroviral therapy (HAART). Five hundred and ninety-seven incident Kaposi sarcoma (KS) cases were identified of whom 52 were among HAART users. Cox regression was used to estimate hazard ratios (HR) and corresponding 95% confidence intervals (CI). Kaposi sarcoma incidence fell abruptly in 1996-1998 to reach a plateau at 1.4 per 1000 py afterwards. Men having sex with men and birth in Africa or the Middle East were associated with KS in both non-users and users of HAART but the risk pattern by CD4 cell count differed. Only very low CD4 cell count (<50 cells microl(-1)) at enrollment or at HAART initiation were significantly associated with KS among HAART users. The HR for KS declined steeply in the first months after HAART initiation and continued to be low 7-10 years afterwards (HR, 0.06; 95% CI, 0.02-0.17). Thirty-three out of 52 (63.5%) KS cases among HAART users arose among PWHA who had stopped treatment or used HAART for less than 6 months.

Abstract: OBJECTIVE: To investigate HIV-related immunodeficiency as a risk factor for hepatocellular carcinoma (HCC) among persons infected with HIV, while controlling for the effect of frequent coinfection with hepatitis C and B viruses. DESIGN: A case-control study nested in the Swiss HIV Cohort Study. METHODS: Twenty-six HCC patients were identified in the Swiss HIV Cohort Study or through linkage with Swiss Cancer Registries, and were individually matched to 251 controls according to Swiss HIV Cohort Study centre, sex, HIV-transmission category, age and year at enrollment. Odds ratios and corresponding confidence intervals were estimated by conditional logistic regression. RESULTS: All HCC patients were positive for hepatitis B surface antigen or antibodies against hepatitis C virus. HCC patients included 14 injection drug users (three positive for hepatitis B surface antigen and 13 for antibodies against hepatitis C virus) and 12 men having sex with men/heterosexual/other (11 positive for hepatitis B surface antigen, three for antibodies against hepatitis C virus), revealing a strong relationship between HIV transmission route and hepatitis viral type. Latest CD4+ cell count [Odds ratio (OR) per 100 cells/mul decrease = 1.33, 95% confidence interval (CI) 1.06-1.68] and CD4+ cell count percentage (OR per 10% decrease = 1.65, 95% CI 1.01-2.71) were significantly associated with HCC. The effects of CD4+ cell count were concentrated among men having sex with men/heterosexual/other rather than injecting drug users. Highly active antiretroviral therapy use was not significantly associated with HCC risk (OR for ever versus never = 0.59, 95% confidence interval 0.18-1.91). CONCLUSION: Lower CD4+ cell counts increased the risk for HCC among persons infected with HIV, an effect that was particularly evident for hepatitis B virus-related HCC arising in non-injecting drug users.

Abstract: Human immunodeficiency virus type 2 (HIV-2) RNA quantification assays used in nine laboratories of the ACHI(E)V(2E) (A Collaboration on HIV-2 Infection) study group were evaluated. In a blinded experimental design, laboratories quantified three series of aliquots of an HIV-2 subtype A strain, each at a different theoretical viral load. Quantification varied between laboratories, and international standardization of quantification assays is strongly needed.

Abstract: BACKGROUND: Combination antiretroviral therapy has led to significant increases in survival and quality of life, but at a population-level the effect on life expectancy is not well understood. Our objective was to compare changes in mortality and life expectancy among HIV-positive individuals on combination antiretroviral therapy. METHODS: The Antiretroviral Therapy Cohort Collaboration is a multinational collaboration of HIV cohort studies in Europe and North America. Patients were included in this analysis if they were aged 16 years or over and antiretroviral-naive when initiating combination therapy. We constructed abridged life tables to estimate life expectancies for individuals on combination antiretroviral therapy in 1996-99, 2000-02, and 2003-05, and stratified by sex, baseline CD4 cell count, and history of injecting drug use. The average number of years remaining to be lived by those treated with combination antiretroviral therapy at 20 and 35 years of age was estimated. Potential years of life lost from 20 to 64 years of age and crude mortality rates were also calculated. FINDINGS: 18 587, 13 914, and 10 854 eligible patients initiated combination antiretroviral therapy in 1996-99, 2000-02, and 2003-05, respectively. 2056 (4.7%) deaths were observed during the study period, with crude mortality rates decreasing from 16.3 deaths per 1000 person-years in 1996-99 to 10.0 deaths per 1000 person-years in 2003-05. Potential years of life lost per 1000 person-years also decreased over the same time, from 366 to 189 years. Life expectancy at age 20 years increased from 36.1 (SE 0.6) years to 49.4 (0.5) years. Women had higher life expectancies than did men. Patients with presumed transmission via injecting drug use had lower life expectancies than did those from other transmission groups (32.6 [1.1] years vs 44.7 [0.3] years in 2003-05). Life expectancy was lower in patients with lower baseline CD4 cell counts than in those with higher baseline counts (32.4 [1.1] years for CD4 cell counts below 100 cells per muL vs 50.4 [0.4] years for counts of 200 cells per muL or more). INTERPRETATION: Life expectancy in HIV-infected patients treated with combination antiretroviral therapy increased between 1996 and 2005, although there is considerable variability between subgroups of patients. The average number of years remaining to be lived at age 20 years was about two-thirds of that in the general population in these countries.

Abstract: BACKGROUND: Tenofovir (TDF) use has been associated with proximal renal tubulopathy, reduced calculated glomerular filtration rates (cGFR) and losses in bone mineral density. Bone resorption could result in a compensatory osteoblast activation indicated by an increase in serum alkaline phosphatase (sAP). A few small studies have reported a positive correlation between renal phosphate losses, increased bone turnover and sAP. METHODS: We analysed sAP dynamics in patients initiating (n = 657), reinitiating (n = 361) and discontinuing (n = 73) combined antiretroviral therapy with and without TDF and assessed correlations with clinical and epidemiological parameters. RESULTS: TDF use was associated with a significant increase of sAP from a median of 74 U/I (interquartile range 60-98) to a plateau of 99 U/I (82-123) after 6 months (P < 0.0001), with a prompt return to baseline upon TDF discontinuation. No change occurred in TDF-sparing regimes. Univariable and multivariable linear regression analyses revealed a positive correlation between sAP and TDF use (P < or = 0.003), but no correlation with baseline cGFR, TDF-related cGFR reduction, changes in serum alanine aminotransferase (sALT) or active hepatitis C. CONCLUSIONS: We document a highly significant association between TDF use and increased sAP in a large observational cohort. The lack of correlation between TDF use and sALT suggests that the increase in sAP is because of the bone isoenzyme and indicates stimulated bone turnover. This finding, together with published data on TDF-related renal phosphate losses, this finding raises concerns that TDF use could result in osteomalacia with a loss in bone mineral density at least in a subset of patients. This potentially severe long-term toxicity should be addressed in future studies.

Abstract: The HLA-B 5701 allele is predictive of hypersensitivity reaction to abacavir, a response herein termed "ABC-HSR." This study of 1,103 individuals infected with human immunodeficiency virus assessed the usefulness of genotyping a HCP5 single-nucleotide polymorphism (SNP), rs2395029, in relation to ABC-HSR. In populations with European ancestry, rs2395029 is in linkage disequilibrium with HLA-B 5701. The HCP5 SNP was present in all 98 HLA-B 5701-positive individuals and was absent in 999 of 1005 HLA-B 5701-negative individuals. rs2395029 was overrepresented in 25 individuals with clinically likely ABC-HSR, compared with its frequency in 175 ABC-tolerant individuals (80% vs. 2%, respectively; P < .0001). Therefore, HCP5 genotyping could serve as a simple screening tool for ABC-HSR, particularly in settings where sequence-based HLA typing is not available.

Abstract: OBJECTIVE: To assess the incidence and epidemiological pattern of respiratory viruses in HIV-infected patients and to evaluate their potential clinical impact. DESIGN AND METHODS: A prospective population-based cohort study was conducted at three Swiss university hospitals. Study participants were HIV-infected patients who underwent a bronchoalveolar lavage to rule out an opportunistic event. All bronchoalveolar lavage specimens were screened using a set of real-time reverse transcriptase-polymerase chain reaction assays targeting 17 different respiratory viruses. RESULTS: Between November 2003 and November 2006, 59 bronchoalveolar episodes from 55 HIV-infected patients were analysed. Eleven of 59 episodes (18.6%) were positive for at least one respiratory virus. Coronavirus OC43 was identified in three cases (27.3%) followed by influenza A in two (18.2%). Parainfluenza virus (PIV) 2, PIV 3, PIV 4, bocavirus, human rhinovirus A and human metapneumovirus were each identified in one case (9%). In the majority of these cases (63.6%) no other concomitant microorganism was isolated. CONCLUSIONS: Clinical investigation of respiratory viral infections in HIV-infected patients should not be restricted to prototype viruses and also need to target all the different family of viruses as it seems likely that these viruses contribute to pulmonary complications and morbidity in this population.

Abstract: BACKGROUND: Currently, there are no comparable estimates of the short-term risk of disease progression in the absence of effective antiretroviral therapy for human immunodeficiency virus (HIV)-infected adults and children. METHODS: A joint analysis of 2 large studies of children with vertically acquired HIV infection (the HIV Paediatric Prognostic Markers Collaborative Study) and adults with seroconversion (the CASCADE [Concerted Action on Sero-Conversion to AIDS and Death in Europe] collaboration) was conducted. Follow-up was censored at the end of 1995, before the introduction of combination antiretroviral therapy. The incidence rates of death and AIDS or death (AIDS/death) were estimated on the basis of age and current CD4 cell count. RESULTS: A total of 1260 deaths (over 20,500 person-years of follow-up) and 1894 initial AIDS events (over 17,200 person-years of follow-up) were observed among 6741 patients (3244 children [i.e., patients < or =15 years of age] and 3497 adults). Young children (age, <5 years) experienced high morbidity and mortality rates. After adjustment for the CD4 cell count, the effect of age on disease progression was not significant among older children, whereas the risk increased markedly in association with increasing age among adults. Death rates were similar among older children and adults aged approximately 20 years, as were the rates of progression to AIDS/death when cases of serious recurrent bacterial infection, which has a more restrictive case definition in adults, were excluded. CONCLUSIONS: Similar CD4 cell count criteria for initiation of antiretroviral therapy can be applied to adults and children > or = 5 years of age.

Abstract: BACKGROUND: The aim of this study was to explore the predictive value of longitudinal self-reported adherence data on viral rebound. METHODS: Individuals in the Swiss HIV Cohort Study on combined antiretroviral therapy (cART) with RNA <50 copies/ml over the previous 3 months and who were interviewed about adherence at least once prior to 1 March 2007 were eligible. Adherence was defined in terms of missed doses of cART (0, 1, 2 or >2) in the previous 28 days. Viral rebound was defined as RNA >500 copies/ml. Cox regression models with time-independent and -dependent covariates were used to evaluate time to viral rebound. RESULTS: A total of 2,664 individuals and 15,530 visits were included. Across all visits, missing doses were reported as follows: 1 dose 14.7%, 2 doses 5.1%, >2 doses 3.8% taking <95% of doses 4.5% and missing > or =2 consecutive doses 3.2%. In total, 308 (11.6%) patients experienced viral rebound. After controlling for confounding variables, self-reported non-adherence remained significantly associated with the rate of occurrence of viral rebound (compared with zero missed doses: 1 dose, hazard ratio [HR] 1.03, 95% confidence interval [CI] 0.72-1.48; 2 doses, HR 2.17, 95% CI 1.46-3.25; >2 doses, HR 3.66, 95% CI 2.50-5.34). Several variables significantly associated with an increased risk of viral rebound irrespective of adherence were identified: being on a protease inhibitor or triple nucleoside regimen (compared with a non-nucleoside reverse transcriptase inhibitor), >5 previous cART regimens, seeing a less-experienced physician, taking co-medication, and a shorter time virally suppressed. CONCLUSIONS: A simple self-report adherence questionnaire repeatedly administered provides a sensitive measure of non-adherence that predicts viral rebound.

Abstract: OBJECTIVES: We compared androgen and gonadotropin values in HIV-infected men who did and did not develop lipoatrophy on combination antiretroviral therapy (cART). METHODS: From a population of 136 treatment-naive male Caucasians under successful zidovudine/lamivudine-based cART, the 10 patients developing lipoatrophy (cases) were compared with 87 randomly chosen controls. Plasma levels of free testosterone (fT), dehydroepiandrosterone (DHEA), follicle-stimulating hormone and luteinizing hormone (LH) were measured at baseline and after 2 years of cART. RESULTS: At baseline, 60% of the cases and 71% of the controls showed abnormally low fT values. LH levels were normal or low in 67 and 94% of the patients, respectively, indicating a disturbance of the hypothalamic-pituitary-gonadal axis. fT levels did not significantly change after 2 years of cART. Cases showed a significant increase in LH levels, while controls showed a significant increase in DHEA levels. In a multivariate logistic regression model, lipoatrophy was associated with higher baseline DHEA levels (P=0.04), an increase in LH levels during cART (P=0.001), a lower body mass index and greater age. CONCLUSIONS: Hypogonadism is present in the majority of HIV-infected patients. The development of cART-related lipoatrophy is associated with an increase in LH and a lack of increase in DHEA levels.

Abstract: OBJECTIVE: To assess the impact of HIV infection on the reliability of the first-trimester screening for Down syndrome, using free beta-human chorionic gonadotrophin, pregnancy-associated plasma protein-A and fetal nuchal translucency, and of the second-trimester screening for neural tube defects, using alpha-fetoprotein. PATIENTS AND METHODS: Multicentre study comparing the multiples of the median of markers for Down syndrome and neural tube defect screening among 214 HIV-infected pregnant women and 856 HIV-negative controls undergoing a first-trimester Down syndrome screening test, and 209 HIV-positive women and 836 HIV-negative controls with a risk evaluation for neural tube defect. The influence of treatment, chronic hepatitis and HIV disease characteristics were also evaluated. RESULTS: Multiples of the median medians for pregnancy-associated plasma protein-A and beta-human chorionic gonadotrophin were lower in HIV-positive women than controls (0.88 vs. 1.05 and 0.84 vs. 1.09, respectively; P < 0.005), but these differences had no impact on risk estimation; no differences were observed for the other markers. No association was found between HIV disease characteristics, antiretroviral treatment use at the time of screening or chronic hepatitis and marker levels. CONCLUSION: Screening for Down syndrome during the first trimester and for neural tube defect during the second trimester is accurate for HIV-infected women and should be offered, similar to HIV-negative women.

Abstract: QUESTIONS UNDER STUDY: The number of HIV-infected persons with children and caregiving duties is likely to increase. From this statement, the present study was designed to establish how HIV infected caregivers organise their parenting routines and to determine their support needs. A further aim was to ascertain caregivers' perception of conspicuous behaviours displayed by their children. Finally, it sought to determine the extent to which the caregivers' assessment of their parenting activity is influenced by the required support and their children's perceived conspicuous behaviours. METHODS: The study design was observational and cross-sectional. Sampling was based on the 7 HIV Outpatient Clinics associated with the national population-based Swiss HIV Cohort Study. It focused on persons living with HIV who are responsible for raising children below the age of 18. A total of 520 caregivers were approached and 261 participated. An anonymous, standardised, self-administered questionnaire was used for data collection. The data were analysed using descriptive statistical procedures and backward elimination multiple regression analysis. RESULTS: The 261 respondents cared for 406 children and adolescents under 18 years of age; the median age was 10 years. The caregivers' material resources were low. 70% had a net family income in a range below the median of Swiss net family income and 30% were dependent on welfare assistance. 73% were undergoing treatment with 86% reporting no physical impairments. The proportion of single caregivers was 34%. 92% of the children were living with their HIV infected caregivers. 80% of the children attended an institution such as a school or kindergarten during the day. 89% of the caregivers had access to social networks providing support. Nevertheless, caregivers required additional support in performing their parenting duties and indicated a need for assistance on the material level, in connection with legal problems and with participation in the labour market. 46% of the caregivers had observed one or more conspicuous behaviours displayed by their children, which indicates a challenging situation. However, most of these caregivers assessed their parenting activity very favourably. Backward elimination multiple regression analysis indicated that a smaller number of support needs, younger age of the eldest child and fewer physical impairments on the part of the caregiver enhance the caregivers' assessment of their parenting activity. CONCLUSION: Physicians should speak to caregivers living with HIV about their parenting responsibilities and provide the necessary scope for this subject in their consultation sessions. Physicians are in a position to draw their patients' attention to the services available to them.

Abstract: BACKGROUND: The outcome of Kaposi sarcoma varies. While many patients do well on highly active antiretroviral therapy, others have progressive disease and need chemotherapy. In order to predict which patients are at risk of unfavorable evolution, we established a prognostic score. METHOD: The survival analysis (Kaplan-Meier method; Cox proportional hazards models) of 144 patients with Kaposi sarcoma prospectively included in the Swiss HIV Cohort Study, from January 1996 to December 2004, was conducted. OUTCOME ANALYZED: use of chemotherapy or death. VARIABLES ANALYZED: demographics, tumor staging [T0 or T1 (16)], CD4 cell counts and HIV-1 RNA concentration, human herpesvirus 8 (HHV8) DNA in plasma and serological titers to latent and lytic antigens. RESULTS: Of 144 patients, 54 needed chemotherapy or died. In the univariate analysis, tumor stage T1, CD4 cell count below 200 cells/microl, positive HHV8 DNA and absence of antibodies against the HHV8 lytic antigen at the time of diagnosis were significantly associated with a bad outcome.Using multivariate analysis, the following variables were associated with an increased risk of unfavorable outcome: T1 [hazard ratio (HR) 5.22; 95% confidence interval (CI) 2.97-9.18], CD4 cell count below 200 cells/microl (HR 2.33; 95% CI 1.22-4.45) and positive HHV8 DNA (HR 2.14; 95% CI 1.79-2.85).We created a score with these variables ranging from 0 to 4: T1 stage counted for two points, CD4 cell count below 200 cells/microl for one point, and positive HHV8 viral load for one point. Each point increase was associated with a HR of 2.26 (95% CI 1.79-2.85). CONCLUSION: In the multivariate analysis, staging (T1), CD4 cell count (<200 cells/microl), positive HHV8 DNA in plasma, at the time of diagnosis, predict evolution towards death or the need of chemotherapy.

Abstract: OBJECTIVES: To investigate delayed HIV diagnosis and late initiation of antiretroviral therapy (ART) in the Swiss HIV Cohort Study. METHODS: Two sub-populations were included: 1915 patients with HIV diagnosis from 1998 to 2007 and within 3 months of cohort registration (group A), and 1730 treatment-naive patients with CD4>or=200 cells/microL before their second cohort visit (group B). In group A, predictors for low initial CD4 cell counts were examined with a median regression. In group B, we studied predictors for CD4<200 cells/microL without ART despite cohort follow-up. RESULTS: Median initial CD4 cell count in group A was 331 cells/microL; 31% and 10% were <200 and <50 cells/microL, respectively. Risk factors for low CD4 count were age and non-White race. Homosexual transmission, intravenous drug use and living alone were protective. In group B, 30% initiated ART with CD4>or=200 cells/microL; 18% and 2% dropped to CD4 <200 and <50 cells/microL without ART, respectively. Sub-Saharan origin was associated with lower probability of CD4 <200 cells/microL without ART during follow-up. Median CD4 count at ART initiation was 207 and 253 cells/microL in groups A and B, respectively. CONCLUSIONS: CD4<200 cells/microL and, particularly, CD4<50 cells/microL before starting ART are predominantly caused by late presentation. Earlier HIV diagnosis is paramount.

Abstract: OBJECTIVE: To describe the electronic medical databases used in antiretroviral therapy (ART) programmes in lower-income countries and assess the measures such programmes employ to maintain and improve data quality and reduce the loss of patients to follow-up. METHODS: In 15 countries of Africa, South America and Asia, a survey was conducted from December 2006 to February 2007 on the use of electronic medical record systems in ART programmes. Patients enrolled in the sites at the time of the survey but not seen during the previous 12 months were considered lost to follow-up. The quality of the data was assessed by computing the percentage of missing key variables (age, sex, clinical stage of HIV infection, CD4+ lymphocyte count and year of ART initiation). Associations between site characteristics (such as number of staff members dedicated to data management), measures to reduce loss to follow-up (such as the presence of staff dedicated to tracing patients) and data quality and loss to follow-up were analysed using multivariate logit models. FINDINGS: Twenty-one sites that together provided ART to 50 060 patients were included (median number of patients per site: 1000; interquartile range, IQR: 72-19 320). Eighteen sites (86%) used an electronic database for medical record-keeping; 15 (83%) such sites relied on software intended for personal or small business use. The median percentage of missing data for key variables per site was 10.9% (IQR: 2.0-18.9%) and declined with training in data management (odds ratio, OR: 0.58; 95% confidence interval, CI: 0.37-0.90) and weekly hours spent by a clerk on the database per 100 patients on ART (OR: 0.95; 95% CI: 0.90-0.99). About 10 weekly hours per 100 patients on ART were required to reduce missing data for key variables to below 10%. The median percentage of patients lost to follow-up 1 year after starting ART was 8.5% (IQR: 4.2-19.7%). Strategies to reduce loss to follow-up included outreach teams, community-based organizations and checking death registry data. Implementation of all three strategies substantially reduced losses to follow-up (OR: 0.17; 95% CI: 0.15-0.20). CONCLUSION: The quality of the data collected and the retention of patients in ART treatment programmes are unsatisfactory for many sites involved in the scale-up of ART in resource-limited settings, mainly because of insufficient staff trained to manage data and trace patients lost to follow-up.

Abstract: INTRODUCTION: It is unknown whether the increased risk of toxicities in antiretroviral-naive HIV-infected patients initiating nevirapine-based (NVPc) combination antiretroviral therapy (cART) with high CD4+ T-cell counts is also observed when NVPc is initiated in cARTexperienced patients. PATIENTS AND METHODS: 1,571 EuroSIDA patients started NVPc after 1/1/1999, with CD4+ T-cell counts and viral load measured in the 6 months before starting treatment, and were stratified into four groups based on CD4+ T-cell counts at initiation of NVPc (high [H], > 400/mm3 or > 250/mm3 for male or female, respectively, or low [L], < or = 400/mm3 or 5250/mm3 for male or female) and prior antiretroviral experience (antiretroviral-naive [N] or -experienced [E]). Cox proportional hazards models compared the risks of discontinuation of nevirapine due to toxicities or patient/physician choice (TOXPC). RESULTS: After adjustment, there was a significantly lower risk of discontinuation of nevirapine due to TOXPC in the HE group (n = 588; proportion discontinued by 3/12 months: 10/17%, respectively) than in HN (n = 62; 21/32% respectively; overall relative hazard [RH]: 0.56; 95% confidence interval [CI]: 0.34-0.94; P = 0.027). This difference was most pronounced during the first 3 months of NVPc (RH: 0.44; 95% CI: 0.23-0.87; P = 0.017). There were no deaths in the 6 months after starting NVPc resulting from exposure to < 3 months of NVPc exposure within the HE group (incidence: 0; per 1,000 person-years follow up; 95% CI: 0-6.9). After adjustment, there were no differences between the HE and HN groups in discontinuation due to TOXPC in patients starting efavirenz-based cART (RH: 0.91; 95% CI: 0.60-1.38; P = 0.66) or protease-inhibitor-based cART (RH: 1.13; 95% CI: 0.77-1.66; P = 0.52). CONCLUSIONS: Results from this non-randomized study suggest that NVPc might be safer to initiate in antiretroviral-experienced than in antiretroviral-naive patients with high CD4+ T-cell counts.

Abstract: An estimated 2%-3% of the world's population is chronically infected with hepatitis C virus (HCV) and this is a major cause of liver disease worldwide. Following acute infection, outcome is variable with acute HCV successfully resolved in some individuals (20%-30%), but in the majority of cases the virus is able to persist. Co-infection with human immunodeficiency virus has been associated with a negative impact on the course of HCV infection. The host's immune response is an important correlate of HCV infection outcome and disease progression. Natural killer (NK) cells provide a major component of the antiviral immune response by recognising and killing virally infected cells. NK cells modulate their activity through a combination of inhibitory and activatory receptors such as the killer immunoglobulin-like receptors (KIRs) that bind to human leukocyte antigen (HLA) Class I molecules. In this workshop component, we addressed the influence of KIR genotypes and their HLA ligands on resolving HCV infection and we discuss the implications of the results of the study of Lopez-Vazquez et al. on KIR and HCV disease progression.

Abstract: BACKGROUND: The extent to which the prognosis for AIDS and death of patients initiating highly active antiretroviral therapy (HAART) continues to be affected by their characteristics at the time of initiation (baseline) is unclear. METHODS: We analyzed data on 20,379 treatment-naive HIV-1-infected adults who started HAART in 1 of 12 cohort studies in Europe and North America (61,798 person-years of follow-up, 1844 AIDS events, and 1005 deaths). RESULTS: Although baseline CD4 cell count became less prognostic with time, individuals with a baseline CD4 count <25 cells/microL had persistently higher progression rates than individuals with a baseline CD4 count >350 cells/microL (hazard ratio for AIDS = 2.3, 95% confidence interval [CI]: 1.0 to 2.3; mortality hazard ratio = 2.5, 95% CI: 1.2 to 5.5, 4 to 6 years after starting HAART). Rates of AIDS were persistently higher in individuals who had experienced an AIDS event before starting HAART. Individuals with presumed transmission by means of injection drug use experienced substantially higher rates of AIDS and death than other individuals throughout follow-up (AIDS hazard ratio = 1.6, 95% CI: 0.8 to 3.0; mortality hazard ratio = 3.5, 95% CI: 2.2 to 5.5, 4 to 6 years after starting HAART). CONCLUSIONS: Compared with other patient groups, injection drug users and patients with advanced immunodeficiency at baseline experience substantially increased rates of AIDS and death up to 6 years after starting HAART.

Abstract: BACKGROUND: Tuberculin skin testing (TST) and preventive treatment of tuberculosis (TB) are recommended for all persons with human immunodeficiency virus (HIV) infection. We aimed to assess the effect of TST and preventive treatment of TB on the incidence of TB in the era of combination antiretroviral therapy in an area with low rates of TB transmission. METHODS: We calculated the incidence of TB among participants who entered the Swiss HIV Cohort Study after 1995, and we studied the associations of TST results, epidemiological and laboratory markers, preventive TB treatment, and combination antiretroviral therapy with TB incidence. RESULTS: Of 6160 participants, 142 (2.3%) had a history of TB at study entry, and 56 (0.91%) developed TB during a total follow-up period of 25,462 person-years, corresponding to an incidence of 0.22 cases per 100 person-years. TST was performed for 69% of patients; 9.4% of patients tested had positive results (induration > or = 5 mm in diameter). Among patients with positive TST results, TB incidence was 1.6 cases per 100 person-years if preventive treatment was withheld, but none of the 193 patients who received preventive treatment developed TB. Positive TST results (adjusted hazard ratio [HR], 25; 95% confidence interval [CI], 11-57), missing TST results (HR, 12; 95% CI, 4.8-20), origin from sub-Saharan Africa (HR, 5.8; 95% CI, 2.7-12.5), low CD4+ cell counts, and high plasma HIV RNA levels were associated with an increased risk of TB, whereas the risk was reduced among persons receiving combination antiretroviral therapy (HR, 0.44; 95% CI, 0.2-0.8). CONCLUSION: Screening for latent TB using TST and administering preventive treatment for patients with positive TST results is an efficacious strategy to reduce TB incidence in areas with low rates of TB transmission. Combination antiretroviral therapy reduces the incidence of TB.

Abstract: Wilms tumor karyotypes frequently exhibit recurrent, large-scale chromosomal imbalances, among the most common of which are concurrent loss of 1p and gain of 1q. We have previously identified a novel breakpoint at 1p13 by 1 Mb-spaced array CGH, and have now undertaken a fine-tiling oligonucleotide array approach to map the region accurately in four tumors exhibiting rearrangements at this locus. The use of a 10 bp-spaced platform revealed that all four tumors in fact harbored different breakpoints, which targeted intragenic sequences in PHTF1, DCLRE1B, and NRAS, and an intergenic region immediately downstream of TRIM33. All four genes and breakpoints were within the 1.78 Mb intervals identified by the genome-wide BAC arrays. The precise breakpoint interval was in each case mapped to a 200-1,200 bp region and was confirmed for one case to lie within intron 3 of DCLRE1B by quantitative PCR. Analysis of local genome architecture revealed no convincing conservation of repetitive sequences or specific translocation/recombination-associated elements within the breakpoint regions. This study highlights the power of fine-tiling oligonucleotide arrays to delineate breakpoint regions identified by genome-wide screens.

Abstract: OBJECTIVE: To evaluate the possibility of copy number variation (CNV) of CYP2B6. METHODS: We investigated CNV in 226 HIV-1-infected individuals by quantitative PCR. Identification of a candidate CNV prompted characterization of the size of deletion by assessment of absence of exons, mapping of the recombination site by sequencing, and by southern blot. The functional consequences of CNV were assessed in silico (predicted protein), and in vivo, by evaluation of plasma drug levels of the CYP2B6 substrate efavirenz. RESULTS: Analyses identified one white individual carrying a heterozygous deletion of exons 1-4 of CYP2B6. We identified a approximately 68 kb deletion between CYP2B7 and CYP2B6, and mapped the crossover to a homologous region in intron 4 of both genes. The new hybrid allele, named CYP2B6*29, carries two amino acid substitutions, Q172H and M198T, previously associated with impaired enzyme function. Consistent with the functional prediction, the average of efavirenz area under the curve values of the patient was mean+/-SD, 81.64+/-23.62, versus 47.75+/-19.73 mug h/ml for individuals with an extensive metabolizer phenotype. CONCLUSION: CYP2B6*29 represents a new mechanism of genetic variation at the CYP2B6 locus, underscoring the highly polymorphic nature of this isoenzyme.

Abstract: OBJECTIVE: To assess the characteristics of combination antiretroviral therapy (cART) administered concomitantly with chemotherapy and to establish prognostic determinants of patients with AIDS-related non-Hodgkin's lymphoma. METHODS: The study included 91 patients with AIDS-related non-Hodgkin's lymphoma from the Swiss HIV Cohort Study enrolled between January 1997 and October 2003, excluding lymphomas of the brain. We extracted AIDS-related non-Hodgkin's lymphoma- and HIV-specific variables at the time of lymphoma diagnosis as well as treatment changes over time from charts and from the Swiss HIV Cohort Study database. Cox regression analyses were performed to study predictors of overall and progression-free survival. RESULTS: During a median follow up of 1.6 years, 57 patients died or progressed. Thirty-five patients stopped chemotherapy prematurely (before the sixth cycle) usually due to disease progression; these patients had a shorter median survival than those who completed six or more cycles (14 versus 28 months). Interruptions of cART decreased from 35% before chemotherapy to 5% during chemotherapy. Factors associated with overall survival were CD4+ T-cell count (<100 cells/microl) (hazard ratio [HR] 2.95 [95% confidence interval (CI) 1.53-5.67], hepatitis C seropositivity (HR 2.39 [95% CI 1.01-5.67]), the international prognostic index score (HR 1.98-3.62 across categories) and Burkitt histological subtypes (HR 2.56 [95% CI 1.13-5.78]). CONCLUSIONS: Interruptions of cART were usually not induced by chemotherapy. The effect of cART interruptions on AIDS-related non-Hodgkin's lymphoma prognosis remains unclear, however, hepatitis C seropositivity emerged-as a predictor of death beyond the well-known international prognostic index score and CD4+ T-cell count.

Abstract: BACKGROUND: Genotypic antiretroviral resistance testing (GRT) in HIV infection with drug resistant virus is recommended to optimize antiretroviral therapy, in particular in patients with virological failure. We estimated the clinical effect, cost and cost-effectiveness of using GRT as compared to expert opinion in patients with antiretroviral treatment failure. METHODS: We developed a mathematical model of HIV disease to describe disease progression in HIV-infected patients with treatment failure and compared the incremental impact of GRT versus expert opinion to guide antiretroviral therapy. The analysis was conducted from the health care (discount rate 4%) and societal (discount rate 2%) perspective. Outcome measures included life-expectancy, quality-adjusted life-expectancy, health care costs, productivity costs and cost-effectiveness in US Dollars per quality-adjusted life-year (QALY) gained. Clinical and economic data were extracted from the large Swiss HIV Cohort Study and clinical trials. RESULTS: Patients whose treatment was optimized with GRT versus expert opinion had an increase in discounted life-expectancy and quality-adjusted life-expectancy of three and two weeks, respectively. Health care costs with and without GRT were $US 421,000 and $US 419,000, leading to an incremental cost-effectiveness ratio of $US 35,000 per QALY gained. In the analysis from the societal perspective, GRT versus expert opinion led to an increase in discounted life-expectancy and quality-adjusted life-expectancy of three and four weeks, respectively. Health care costs with and without GRT were $US 551,000 and $US 549,000, respectively. When productivity changes were included in the analysis, GRT was cost-saving. CONCLUSIONS: GRT for treatment optimization in HIV-infected patients with treatment failure is a cost-effective use of scarce health care resources and beneficial to the society at large.

Abstract: BACKGROUND: A negative association between the polymorphism F214L and type 1 thymidine analogue (TA) mutations (TAMs) has been observed. However, the virological response to TAs according to the detection of F214L has not been evaluated. METHODS: We studied 590 patients from EuroSIDA who started TA therapy for the first time as part of potent combination antiretroviral therapy (cART) and who were tested for genotypic resistance within the past 6 months. End points were median reduction in the week 24 viral load and time to virological failure (2 consecutive VL measurements >400 copies/mL after at least 6 months of the TA-containing cART). RESULTS: In ART-naive patients, the prevalence of F214L was 17%. By 48 months after starting TA-based cART, the proportion of patients who experienced virological failure was 16% in patients with 214L and 36% in those with 214F (P=.03). In a multivariable Cox regression model, the relative hazard of virological failure for patients with 214L compared with those with 214F was 0.22 (95% confidence interval, 0.07-0.72). In ART-experienced patients, results were similar, and larger differences in virological response associated with the detection of 214L versus F were observed in patients with M41L/T215Y and mixed TAM profiles detected before the initiation of cART. CONCLUSIONS: This study provides evidence that the detection of polymorphism F214L is associated with a favorable virological response to TA-based cART.

Abstract: OBJECTIVES: To estimate changes in coronary risk factors and their implications for coronary heart disease (CHD) rates in men starting highly active antiretroviral therapy (HAART). METHODS: Men participating in the Swiss HIV Cohort Study with measurements of coronary risk factors both before and up to 3 years after starting HAART were identified. Fractional polynomial regression was used to graph associations between risk factors and time on HAART. Mean risk factor changes associated with starting HAART were estimated using multilevel models. A prognostic model was used to predict corresponding CHD rate ratios. RESULTS: Of 556 eligible men, 259 (47%) started a nonnucleoside reverse transcriptase inhibitor (NNRTI) and 297 a protease inhibitor (PI) based regimen. Levels of most risk factors increased sharply during the first 3 months on HAART, then more slowly. Increases were greater with PI- than NNRTI-based HAART for total cholesterol (1.18 vs. 0.98 mmol L(-1)), systolic blood pressure (3.6 vs. 0 mmHg) and BMI (1.04 vs. 0.55 kg m(2)) but not HDL cholesterol (0.24 vs. 0.32 mmol L(-1)) or glucose (1.02 vs. 1.03 mmol L(-1)). Predicted CHD rate ratios were 1.40 (95% CI 1.13-1.75) and 1.17 (0.95-1.47) for PI- and NNRTI-based HAART respectively. CONCLUSIONS: Coronary heart disease rates will increase in a majority of patients starting HAART: however the increases corresponding to typical changes in risk factors are relatively modest and could be offset by lifestyle changes.

Abstract: We examined the incidence of and risk factors for tuberculosis during the first year of highly active antiretroviral therapy in low-income (4540 patients) and high-income (22,217 patients) countries. Although incidence was much higher in low-income countries, the reduction in the incidence of tuberculosis associated with highly active antiretroviral therapy was similar: the rate ratio for months 7-12 versus months 1-3 was 0.48 (95% confidence interval, 0.36-0.64) in low-income countries and 0.36 (95% confidence interval, 0.26-0.50) in high-income countries. A low CD4 cell count at the start of therapy was the most important risk factor in both settings.

Abstract:

Abstract: Time is a limited resource and individuals have to decide how many hours they should allocate to work and to leisure activities. Differences in wage rate or availability of non-labour income (financial support from families and savings) may influence how individuals allocate their time between work and leisure. An increase in wage rate may induce income effects (leisure time demanded increases) and substitution effects (leisure time demanded decreases) whereas an increase in non-labour income only induces income effects. We explored the effects of differences in wage rate and non-labour income on the allocation of time in HIV-infected patients. Patients enrolled in the Swiss HIV Cohort Study (SHCS) provided information on their time allocation, i.e. number of hours worked in 1998. A multinomial logistic regression model was used to test for income and substitution effects. Our results indicate that (i) the allocation of time in HIV-infected patients does not differ with level of education (i.e., wage rate), and that (ii) availability of non-labour income induces income effects, i.e. individuals demand more leisure time.

Abstract: BACKGROUND: HIV-1 infected individuals have an increased cardiovascular risk which is partially mediated by dyslipidemia. Single nucleotide polymorphisms in multiple genes involved in lipid transport and metabolism are presumed to modulate the risk of dyslipidemia in response to antiretroviral therapy. METHODS: The contribution to dyslipidemia of 20 selected single nucleotide polymorphisms of 13 genes reported in the literature to be associated with plasma lipid levels (ABCA1, ADRB2, APOA5, APOC3, APOE, CETP, LIPC, LIPG, LPL, MDR1, MTP, SCARB1, and TNF) was assessed by longitudinally modeling more than 4400 plasma lipid determinations in 438 antiretroviral therapy-treated participants during a median period of 4.8 years. An exploratory genetic score was tested that takes into account the cumulative contribution of multiple gene variants to plasma lipids. RESULTS: Variants of ABCA1, APOA5, APOC3, APOE, and CETP contributed to plasma triglyceride levels, particularly in the setting of ritonavir-containing antiretroviral therapy. Variants of APOA5 and CETP contributed to high-density lipoprotein-cholesterol levels. Variants of CETP and LIPG contributed to non-high-density lipoprotein-cholesterol levels, a finding not reported previously. Sustained hypertriglyceridemia and low high-density lipoprotein-cholesterol during the study period was significantly associated with the genetic score. CONCLUSIONS: Single nucleotide polymorphisms of ABCA1, APOA5, APOC3, APOE, and CETP contribute to plasma triglyceride and high-density lipoprotein-cholesterol levels during antiretroviral therapy exposure. Genetic profiling may contribute to the identification of patients at risk for antiretroviral therapy-related dyslipidemia.

Abstract: BACKGROUND: Combination antiretroviral therapy (cART) has been shown to reduce mortality and morbidity in patients with HIV. As viral replication falls, the CD4 count increases, but whether the CD4 count returns to the level seen in HIV-negative people is unknown. We aimed to assess whether the CD4 count for patients with maximum virological suppression (viral load <50 copies per mL) continues to increase with long-term cART to reach levels seen in HIV-negative populations. METHODS: We compared increases in CD4 counts in 1835 antiretroviral-naive patients who started cART from EuroSIDA, a pan-European observational cohort study. Rate of increase in CD4 count (per year) occurring between pairs of consecutive viral loads below 50 copies per mL was estimated using generalised linear models, accounting for multiple measurements for individual patients. FINDINGS: The median CD4 count at starting cART was 204 cells per microL (IQR 85-330). The greatest mean yearly increase in CD4 count of 100 cells per microL was seen in the year after starting cART. Significant, but lower, yearly increases in CD4 count, around 50 cells per microL, were seen even at 5 years after starting cART in patients whose current CD4 count was less than 500 cells per microL. The only groups without significant increases in CD4 count were those where cART had been taken for more than 5 years with a current CD4 count of more than 500 cells per microL, (current mean CD4 count 774 cells per microL; 95% CI 764-783). Patients starting cART with low CD4 counts (<200 cells per microL) had significant rises in CD4 counts even after 5 years of cART. INTERPRETATION: Normalisation of CD4 counts in HIV-infected patients for all infected individuals might be achievable if viral suppression with cART can be maintained for a sufficiently long period of time.

Abstract: INTRODUCTION: A recent report described a possible interaction between tenofovir (TFV) and efavirenz (EFV). Patients developed neuropsychiatric manifestations upon introduction of TFV on a stable EFV-containing regimen. We evaluated the possibility of a pharmacokinetic interaction between TFV and EFV by assessing cross-sectional and longitudinal data in 169 individuals receiving EFV. RESULTS: EFV plasma area-under-the-curve (AUC) levels were comparable among individuals receiving (n=18) or not receiving TFV (n=151); 57,962 versus 52,293 ng*h/ml. However, under conditions of limited EFV metabolism, that is, the group of 23 individuals carrying two copies of CYP2B6 loss/diminished-function alleles, plasma AUC values were highest among individuals receiving TFV (n=5, 353,031 ng*h/ml), compared with those not receiving TFV (n=18, 180,689 ng*h/ml). Statistical analysis identified both a global, sixfold effect of CYP2B6 loss/diminished function (P < 0.0001) and a significant interaction between the number of loss/diminished-function alleles and the co-medication with TFV (P = 0.009). CONCLUSION: Although there is no clear evidence for a pharmacokinetic interaction between TFV and EFV, we cannot rule out an interaction between these drugs restricted to individuals who are slow EFV metabolizers.

Abstract: To assess the association of CYP2B6 allelic diversity with efavirenz (EFV) pharmacokinetics, we performed extensive genotyping of 15 relevant single nucleotide polymorphism in 169 study participants, and full resequencing of CYP2B6 in individuals with abnormal EFV plasma levels. Seventy-seven (45.5%) individuals carried a known (CYP2B6*6, *11, *15, or *18) or new loss/diminished-function alleles. Resequencing defined two new loss-of-function alleles: allele *27 (marked by 593T>C [M198T]), that results in 85% decrease in enzyme activity and allele *28 (marked by 1132C>T), that results in protein truncation at arginine 378. Median AUC levels were 188.5 microg h/ml for individuals homozygous for a loss/diminished-function allele, 58.6 microg h/ml for carriers, and 43.7 microg h/ml for noncarriers (P<0.0001). Individuals with a poor metabolizer genotype had a likelihood ratio of 35 (95% CI, 11-110) of presenting very high EFV plasma levels. CYP2B6 poor metabolizer genotypes explain to a large extent EFV pharmacokinetics and identify individuals at risk of extremely elevated EFV plasma levels.

Abstract: To assess the association of CYP2B6 allelic diversity with efavirenz (EFV) pharmacokinetics, we performed extensive genotyping of 15 relevant single nucleotide polymorphism in 169 study participants, and full resequencing of CYP2B6 in individuals with abnormal EFV plasma levels. Seventy-seven (45.5%) individuals carried a known (CYP2B6*6, *11, *15, or *18) or new loss/diminished-function alleles. Resequencing defined two new loss-of-function alleles: allele *27 (marked by 593T>C [M198T]), that results in 85% decrease in enzyme activity and allele *28 (marked by 1132C>T), that results in protein truncation at arginine 378. Median AUC levels were 188.5 microg h/ml for individuals homozygous for a loss/diminished-function allele, 58.6 microg h/ml for carriers, and 43.7 microg h/ml for noncarriers (P<0.0001). Individuals with a poor metabolizer genotype had a likelihood ratio of 35 (95% CI, 11-110) of presenting very high EFV plasma levels. CYP2B6 poor metabolizer genotypes explain to a large extent EFV pharmacokinetics and identify individuals at risk of extremely elevated EFV plasma levels.

Abstract: We consider tied survival data based on Cox proportional regression model. The standard approaches are the Breslow and Efron approximations and various so called exact methods. All these methods lead to biased estimates when the true underlying model is in fact a Cox model. In this paper we review the methods and suggest a new method based on the missing-data principle using EM-algorithm that leads to a score equation that can be solved directly. This score has mean zero. We also show that all the considered methods have the same asymptotic properties and that there is no loss of asymptotic efficiency when the tie sizes are bounded or even converge to infinity at a given rate. A simulation study is conducted to compare the finite sample properties of the methods.

Abstract: The chemokine receptor CXCR3 plays a significant role in regulating the migration of Th1 cells. Given the importance of Th1 immunity in the control of tuberculous infection, the results of the present study demonstrating that CXCR3-deficient BALB/c mice are more resistant to Mycobacterium tuberculosis, compared with wild-type mice, is surprising. This enhanced resistance manifests in the chronic but not the acute phase of infection. Remarkable differences in the cellular composition of the pulmonic granuloma of the CXCR3(-/-) and wild-type mice were found, the most striking being the increase in the number of CD4(+) T cells in the knockout strain. In the chronic phase of infection, the number of CD69-expressing CD4(+) T lymphocytes in the lungs of CXCR3(-/-) mice was higher than in wild-type mice. Additionally, at 1 mo postinfection, the number of IFN-gamma-producing CD4(+) T cells in the lungs and mediastinal lymph nodes of the CXCR3-deficient strain was elevated compared with wild-type mice. Pulmonic expression of IFN-gamma, IL-12, TNF-alpha, or NO synthase 2, the principal antimycobacterial factors, were equivalent in the two mouse strains. These results indicate that: 1) CXCR3 plays a role in modulating the cellular composition of tuberculous granuloma; 2) CXCR3 impairs antimycobacterial activity in chronic tuberculosis; and 3) in the absence of CXCR3, mice exhibit a heightened state of CD4(+) T lymphocyte activation in the chronic phase of infection that is associated with enhanced CD4(+) T cell priming. Therefore, CXCR3 can attenuate the host immune response to M. tuberculosis by adversely affecting T cell priming.

Abstract: BACKGROUND: Long-term retention of patients in Africa's rapidly expanding antiretroviral therapy (ART) programs for HIV/AIDS is essential for these programs' success but has received relatively little attention. In this paper we present a systematic review of patient retention in ART programs in sub-Saharan Africa. METHODS AND FINDINGS: We searched Medline, other literature databases, conference abstracts, publications archives, and the "gray literature" (project reports available online) between 2000 and 2007 for reports on the proportion of adult patients retained (i.e., remaining in care and on ART) after 6 mo or longer in sub-Saharan African, non-research ART programs, with and without donor support. Estimated retention rates at 6, 12, and 24 mo were calculated and plotted for each program. Retention was also estimated using Kaplan-Meier curves. In sensitivity analyses we considered best-case, worst-case, and midpoint scenarios for retention at 2 y; the best-case scenario assumed no further attrition beyond that reported, while the worst-case scenario assumed that attrition would continue in a linear fashion. We reviewed 32 publications reporting on 33 patient cohorts (74,192 patients, 13 countries). For all studies, the weighted average follow-up period reported was 9.9 mo, after which 77.5% of patients were retained. Loss to follow-up and death accounted for 56% and 40% of attrition, respectively. Weighted mean retention rates as reported were 79.1%, 75.0% and 61.6 % at 6, 12, and 24 mo, respectively. Of those reporting 24 mo of follow-up, the best program retained 85% of patients and the worst retained 46%. Attrition was higher in studies with shorter reporting periods, leading to monthly weighted mean attrition rates of 3.3%/mo, 1.9%/mo, and 1.6%/month for studies reporting to 6, 12, and 24 months, respectively, and suggesting that overall patient retention may be overestimated in the published reports. In sensitivity analyses, estimated retention rates ranged from 24% in the worse case to 77% in the best case at the end of 2 y, with a plausible midpoint scenario of 50%. CONCLUSIONS: Since the inception of large-scale ART access early in this decade, ART programs in Africa have retained about 60% of their patients at the end of 2 y. Loss to follow-up is the major cause of attrition, followed by death. Better patient tracing procedures, better understanding of loss to follow-up, and earlier initiation of ART to reduce mortality are needed if retention is to be improved. Retention varies widely across programs, and programs that have achieved higher retention rates can serve as models for future improvements.

Abstract: OBJECTIVES: To derive and validate a clinically applicable prognostic score for predicting short-term disease progression in HIV-infected patients taking combination antiretroviral therapy (cART). DESIGN AND METHODS: Poisson regression was used to identify prognostic markers for new AIDS/death in patients taking cART. A score was derived for 4169 patients from EuroSIDA and validated on 5150 patients from the Swiss HIV Cohort Study (SHCS). RESULTS: In EuroSIDA, 658 events occurred during 22 321 person-years of follow-up: an incidence rate of 3.0/100 person-years of follow-up [95% confidence interval (CI), 2.7-3.3]. Current levels of viral load, CD4 cell count, CD4 cell slope, anaemia, and body mass index all independently predicted new AIDS/death, as did age, exposure group, a prior AIDS diagnosis, prior antiretroviral treatment and stopping all antiretroviral drugs. The EuroSIDA risk-score was divided into four strata; a patient in the lowest strata would have predicted chance of new AIDS/death of 1 in 801, 1 in 401 and 1 in 201 within the next 3, 6 or 12 months, respectively. The corresponding figures for the highest strata were 1 in 17, 1 in 9 and 1 in 5, respectively. A single-unit increase in the risk-score was associated with a 2.70 times higher incidence of clinical progression (95% CI, 2.56-2.84) in EuroSIDA and 2.88 (95% CI, 2.75-3.02) in SHCS. CONCLUSIONS: A clinically relevant prognostic score was derived in EuroSIDA and validated within the SHCS, with good agreement. The EuroSIDA risk-score will be made available publicly via an interface that will perform all calculations for the individual.

Abstract:

Abstract: Human immunodeficiency virus type 1 (HIV-1) transcription is subject to substantial fluctuation during the viral life cycle. Due to the low frequencies of HIV-1-infected cells, and because latently and productively infected cells collocate in vivo, little quantitative knowledge has been attained about the range of in vivo HIV-1 transcription in peripheral blood mononuclear cells (PBMC). By combining cell sorting, terminal dilution of intact cells, and highly sensitive, patient-specific PCR assays, we divided PBMC obtained from HIV-1-infected patients according to their degree of viral transcription activity and their cellular phenotype. Regardless of a patient's treatment status, the bulk of infected cells exhibited a CD4+ phenotype but transcribed HIV-1 provirus at low levels, presumably insufficient for virion production. Furthermore, the expression of activation markers on the surface of these CD4+ T lymphocytes showed little or no association with enhancement of viral transcription. In contrast, HIV-infected T lymphocytes of a CD4-/CD8- phenotype, occurring exclusively in untreated patients, exhibited elevated viral transcription rates. This cell type harbored a substantial proportion of all HIV RNA+ cells and intracellular viral RNAs and the majority of cell-associated virus particles. In conjunction with the observation that the HIV quasispecies in CD4+ and CD4-)/CD8- T cells were phylogenetically closely related, these findings provide evidence that CD4 expression is downmodulated during the transition to productive infection in vivo. The abundance of viral RNA in CD4-/CD8- T cells from viremic patients and the almost complete absence of viral DNA and RNA in this cell type during antiretroviral treatment identify HIV+ CD4-/CD8 T cells as the major cell type harboring productive infection in peripheral blood.

Abstract: BACKGROUND: In chronic HIV infection, antiretroviral therapy-induced normalization of CD4(+) T cell counts (immune reconstitution [IR]) is associated with a decreased incidence of opportunistic diseases. However, some individuals remain at risk for opportunistic diseases despite prolonged normalization of CD4(+) T cell counts. Deficient Epstein-Barr virus (EBV)-specific CD4(+) T cell function may explain the occurrence of EBV-associated opportunistic malignancy-such as primary central nervous system (PCNS) lymphoma-despite recovery of absolute CD4(+) T cell counts. METHODS AND FINDINGS: Absolute CD4(+) T cell counts and EBV-specific CD4(+) T cell-dependent interferon-gamma production were assessed in six HIV-positive individuals prior to development of PCNS lymphoma ("cases"), and these values were compared with those in 16 HIV-infected matched participants with no sign of EBV-associated pathology ("matched controls") and 11 nonmatched HIV-negative blood donors. Half of the PCNS lymphoma patients fulfilled IR criteria (defined here as CD4(+) T cell counts >or=500/microl blood). EBV-specific CD4(+) T cells were assessed 0.5-4.7 y prior to diagnosis of lymphoma. In 0/6 cases versus 13/16 matched controls an EBV-specific CD4(+) T cell response was detected (p = 0.007; confidence interval for odds ratio [0-0.40]). PCNS lymphoma patients also differed with regards to this response significantly from HIV-negative blood donors (p < 0.001, confidence interval for odds ratio [0-0.14]), but there was no evidence for a difference between HIV-negative participants and the HIV-positive matched controls (p = 0.47). CONCLUSIONS: Irrespective of absolute CD4(+) T cell counts, HIV-positive patients who subsequently developed PCNS lymphoma lacked EBV-specific CD4(+) T cell function. Larger, ideally prospective studies are needed to confirm these preliminary data, and clarify the impact of pathogen-specific versus surrogate marker-based assessment of IR on clinical outcome.

Abstract: BACKGROUND: Antiretroviral therapy (ART) decreases morbidity and mortality in HIV-infected patients but is associated with considerable adverse events (AEs). METHODS: We examined the effect of AEs to ART on mortality, treatment modifications and drop-out in the Swiss HIV Cohort Study. A cross-sectional evaluation of prevalence of 13 clinical and 11 laboratory parameters was performed in 1999 in 1,078 patients on ART. AEs were defined as abnormalities probably or certainly related to ART. A score including the number and severity of AEs was defined. The subsequent progression to death, drop-out and treatment modification due to intolerance were evaluated according to the baseline AE score and characteristics of individual AEs. RESULTS: Of the 1,078 patients, laboratory AEs were reported in 23% and clinical AEs in 45%. During a median follow up of 5.9 years, laboratory AEs were associated with higher mortality with an adjusted hazard ratio (HR) of 1.3 (95% confidence interval [CI] 1.2-1.5; P < 0.001) per score point. For clinical AEs no significant association with increased mortality was found. In contrast, an increasing score for clinical AEs (HR 1.11,95% CI 1.04-1.18; P = 0.002), but not for laboratory AEs (HR 1.07, 95% CI 0.97-1.17; P = 0.17), was associated with antiretroviral treatment modification. AEs were not associated with a higher drop-out rate. CONCLUSIONS: The burden of laboratory AEs to antiretroviral drugs is associated with a higher mortality. Physicians seem to change treatments to relieve clinical symptoms, while accepting laboratory AEs. Minimizing laboratory drug toxicity seems warranted and its influence on survival should be further evaluated.

Abstract: OBJECTIVES: To limit exposure to anti-HIV drugs and minimize risk of long-term side effects, studies have looked at the possibility of simplified maintenance strategies. Ritonavir-boosted protease-inhibitor (PI)-monotherapies are an attractive alternative, but limited compartmental penetration of PI remains a concern. DESIGN: Non-comparative 24-week pilot study. METHOD: Ritonavir-boosted atazanavir (ATV/r) monotherapy administered to fully suppressed patients (>3 month HIV RNA < 50 copies/ml). Plasma was obtained every 4 weeks and cerebrospinal fluid (CSF) and semen at W24. RESULTS: Two patients (7%) failed ATV/r monotherapy. One patient was subsequently identified as a protocol violator since he had a previous history of treatment failure under indinavir. The second patient deliberately decided to stop treatment after W20. Excluding failing patients, individual measurements of HIV RNA in patients having occasional viral 'blips' was found in five patients. At W24, 3/20 patients had elevated viral loads in CSF (HIV RNA > 100 copies/ml), and 2/15 in semen, despite viral suppression in plasma (< 50 copies/ml). Samples with elevated HIV RNA (> 500 copies/ml) in CSF were all wild type. The mean ATV drug concentration ratio (CSF/blood, n = 22) was 0.9%. Indicators of altered immune activation (CD8CD38 C-reactive protein) remained unchanged. CONCLUSION: This study supports previous results indicating the potential use of PI-based mono-maintenance therapies. However, our results in CSF cautions against the uncontrolled use of PI-based monotherapies.

Abstract: OBJECTIVE: This study was undertaken to determine the role of opiate use during pregnancy as a predisposing factor for sudden infant death syndrome (SIDS) in infants born to HIV-infected mothers. METHODS: In order to identify all infant deaths and their cause and association with maternal opiate use, the data of a nationwide prospective cohort study of HIV-infected mothers and their children were extracted and analysed for a 13-year period. RESULTS: 24 (5.1%) infant deaths were observed out of 466 infants followed up until death or at least 12 months of life. 3 (0.6%) of them were due to non-accidental trauma and were not associated with maternal opiate use. 7 (1.5%) died due to SIDS, which was confirmed by autopsy. All SIDS cases occurred in infants born to mothers reporting use of opiates during pregnancy (n = 124). The relative risk of SIDS compared to the general population was 18 (95% CI 9 to 38) for all infants of HIV-infected mothers, and 69 (95% CI 33 to 141) for those with intrauterine opiate exposure (p<0.001). CONCLUSIONS: Compared to the Swiss general population, the risk for SIDS in this cohort of infants born to HIV-infected mothers was greatly increased, but only for mothers reporting opiate use during pregnancy. This effect appeared not to be mediated by prematurity, low birth weight, perinatal HIV infection or antiretroviral drug exposure.

Abstract: PURPOSE: Antiretroviral therapy (ART) may induce metabolic changes and increase the risk of coronary heart disease (CHD). Based on a health care system approach, we investigated predictors for normalization of dyslipidemia in HIV-infected individuals receiving ART. METHOD: Individuals included in the study were registered in the Swiss HIV Cohort Study (SHCS), had dyslipidemia but were not on lipid-lowering medication, were on potent ART for >or= 3 months, and had >or= 2 follow-up visits. Dyslipidemia was defined as two consecutive total cholesterol (TC) values above recommended levels. Predictors of achieving treatment goals for TC were assessed using Cox models. RESULTS: Analysis included 958 individuals with median followup of 2.3 years (IQR 1.2-4.0). 454 patients (47.4%) achieved TC treatment goals. In adjusted analyses, variables significantly associated with a lower hazard of reaching TC treatment goals were as follows: older age (compared to 18-37 year olds: hazard ratio [HR] 0.62 for 45-52 year olds, 95% CI 0.47-0.82; HR 0.40 for 53-85, 95% CI 0.29-0.54), diabetes (HR 0.39, 95% CI 0.26-0.59), history of coronary heart disease (HR 0.27, 95% CI 0.10-0.71), higher baseline TC (HR 0.78, 95% CI 0.71-0.85), baseline triple nucleoside regimen (HR 0.12 compared to PI-only regimen, 95% CI 0.07-0.21), longer time on PI-only regimen (HR 0.39, 95% CI 0.33-0.46), longer time on NNRTI only regimen (HR 0.35, 95% CI 0.29-0.43), and longer time on PI/NNRTI regimen (HR 0.34, 95% CI 0.26-0.43). Switching ART regimen when viral load was undetectable was associated with a higher hazard of reaching TC treatment goals (HR 1.48, 95% CI 1.14-1.91). CONCLUSION: In SHCS participants on ART, several ART-related and not ART-related epidemiological factors were associated with insufficient control of dyslipidemia. Control of dyslipidemia in ART recipients must be further improved.

Abstract: BACKGROUND: CD4+ T-cell recovery in patients with continuous suppression of plasma HIV-1 viral load (VL) is highly variable. This study aimed to identify predictive factors for long-term CD4+ T-cell increase in treatment-naive patients starting combination antiretroviral therapy (cART). METHODS: Treatment-naive patients in the Swiss HIV Cohort Study reaching two VL measurements <50 copies/ml >3 months apart during the 1st year of cART were included (n=1816 patients). We studied CD4+ T-cell dynamics until the end of suppression or up to 5 years, subdivided into three periods: 1st year, years 2-3 and years 4-5 of suppression. Multiple median regression adjusted for repeated CD4+ T-cell measurements was used to study the dependence of CD4+ T-cell slopes on clinical covariates and drug classes. RESULTS: Median CD4+ T-cell increases following VL suppression were 87, 52 and 19 cells/microl per year in the three periods. In the multiple regression model, median CD4+ T-cell increases over all three periods were significantly higher for female gender, lower age, higher VL at cART start, CD4+ T-cell <650 cells/microl at start of the period and low CD4+ T-cell increase in the previous period. Patients on tenofovir showed significantly lower CD4+ T-cell increases compared with stavudine. CONCLUSIONS: In our observational study, long-term CD4+ T-cell increase in drug-naive patients with suppressed VL was higher in regimens without tenofovir. The clinical relevance of these findings must be confirmed in, ideally, clinical trials or large, collaborative cohort projects but could influence treatment of older patients and those starting cART at low CD4+ T-cell levels.

Abstract: BACKGROUND: The clinical course of HIV-1 infection is highly variable among individuals, at least in part as a result of genetic polymorphisms in the host. Toll-like receptors (TLRs) have a key role in innate immunity and mutations in the genes encoding these receptors have been associated with increased or decreased susceptibility to infections. OBJECTIVES: To determine whether single-nucleotide polymorphisms (SNPs) in TLR2-4 and TLR7-9 influenced the natural course of HIV-1 infection. METHODS: Twenty-eight SNPs in TLRs were analysed in HAART-naive HIV-positive patients from the Swiss HIV Cohort Study. The SNPs were detected using Sequenom technology. Haplotypes were inferred using an expectation-maximization algorithm. The CD4 T cell decline was calculated using a least-squares regression. Patients with a rapid CD4 cell decline, less than the 15th percentile, were defined as rapid progressors. The risk of rapid progression associated with SNPs was estimated using a logistic regression model. Other candidate risk factors included age, sex and risk groups (heterosexual, homosexual and intravenous drug use). RESULTS: Two SNPs in TLR9 (1635A/G and +1174G/A) in linkage disequilibrium were associated with the rapid progressor phenotype: for 1635A/G, odds ratio (OR), 3.9 [95% confidence interval (CI),1.7-9.2] for GA versus AA and OR, 4.7 (95% CI,1.9-12.0) for GG versus AA (P = 0.0008). CONCLUSION: Rapid progression of HIV-1 infection was associated with TLR9 polymorphisms. Because of its potential implications for intervention strategies and vaccine developments, additional epidemiological and experimental studies are needed to confirm this association.

Abstract: OBJECTIVES: Representative prevalence data of transmitted drug-resistant HIV-1 are essential to establish accurate guidelines addressing resistance testing and first-line treatments. METHODS: Systematic resistance testing was carried out in individuals in Switzerland with documented HIV-1 seroconversion during 1996-2005 and available samples with RNA > 1000 copies/ml obtained within 1 year of estimated seroconversion. Resistance interpretation used the Stanford list of mutations for surveillance of transmitted drug resistance and the French National Agency for AIDS Research algorithm. RESULTS: Viral sequences from 822 individuals were available. Risk groups were men having sex with men (42%), heterosexual contacts (32%) and intravenous drug users (20%); 30% were infected with non-B subtype viruses. Overall, prevalence of transmitted resistance was 7.7% [95% confidence interval (CI), 5.9-9.5] for any drug, 5.5% (95% CI, 3.9-7.1) for nucleoside reverse transcriptase inhibitors, 1.9% (95% CI, 1.0-2.8) for non-nucleoside reverse transcriptase inhibitors and 2.7% (95% CI, 1.6-3.8) for protease inhibitors. Dual- or triple-class resistance was observed in 2% (95% CI, 0.8-2.5). No significant trend in prevalence of transmitted resistance was observed over years. There were no differences according to ethnicity, risk groups or gender, but prevalence of transmitted resistance was highest among individuals infected with subtype B virus. CONCLUSIONS: The transmission rate of drug-resistant HIV-1 has been stable since 1996, with very rare transmission of dual- or triple-class resistance. These data suggest that transmission of drug resistance in the setting of easy access to antiretroviral treatment can remain stable and be kept at a low level.

Abstract:

Abstract: OBJECTIVE: Zidovudine-containing antiretroviral therapy has been associated with a lower rise in absolute CD4 cell counts in several randomized trials. We examined the predictive factors for this phenomenon and assessed its impact on clinical progression during treatment in a large patient cohort. DESIGN: An analysis of data from the Swiss HIV Cohort Study. METHODS: All 2177 treatment-naive adults who began potent antiretroviral therapy (ART) between September 1995 and September 2004 were included. Exclusion criteria were previous ART and treatment duration of less than 3 months. Follow-up was censored in the case of a treatment switch or stop. RESULTS: A total of 1312 patients initiated zidovudine-containing ART and 865 started ART without zidovudine. Except for slightly higher absolute CD4 cell counts in the zidovudine group, prognostic characteristics at baseline and viral suppression during treatment did not differ. During an observation time of 2343 and 1486 patient-years, the CD4 cell count increased by a median of 221 versus 286 cells/microl at 2 years and 290 versus 379 cells/microl at 4 years in the zidovudine versus no zidovudine group; however, the rise in the percentage of CD4 cells was similar in both groups. The zidovudine group had a significantly slower rise in total lymphocytes and haemoglobin. In multivariable Cox models, the hazard for new HIV-associated clinical events was not affected by zidovudine-containing ART. CONCLUSION: Over 4 years, zidovudine led to a smaller increase in absolute, but not percentage, CD4 cell counts. The effect can be explained as a slower rise in total lymphocytes and has no impact on clinical efficacy.

Abstract: OBJECTIVE: To investigate predictors of continued HIV RNA viral load suppression in individuals switched to abacavir (ABC), lamivudine (3TC) and zidovudine (ZDV) after successful previous treatment with a protease inhibitor or non-nucleoside reverse transcriptase inhibitor-based combination antiretroviral therapy. DESIGN AND METHODS: An observational cohort study, which included individuals in the Swiss HIV Cohort Study switching to ABC/3TC/ZDV following successful suppression of viral load. The primary endpoint was time to treatment failure defined as the first of the following events: two consecutiveviral load measurements > 400 copies/ml under ABC/3TC/ZDV, one viral load measurement > 400 copies/ml and subsequent discontinuation of ABC/3TC/ZDV within 3 months, AIDS or death. RESULTS: We included 495 individuals; 47 experienced treatment failure in 1459 person-years of follow-up [rate = 3.22 events/100 person-years; 95% confidence interval (95% CI), 2.30-4.14]. Of all failures, 62% occurred in the first year after switching to ABC/3TC/ZDV. In a Cox regression analysis, treatment failure was independently associated with earlier exposure to nucleoside reverse transcriptase inhibitor (NRTI) mono or dual therapy [hazard ratio (HR), 8.02; 95% CI, 4.19-15.35) and low CD4 cell count at the time of the switch (HR, 0.66; 95% CI, 0.51-0.87 by +100 cells/microl up to 500 cells/microl). In patients without earlier exposure to mono or dual therapy, AIDS prior to switch to simplified maintenance therapy was an additional risk factor. CONCLUSIONS: The failure rate was low in patients with suppressed viral load and switch to ABC/3TC/ZDV treatment. Patients with earlier exposure to mono or dual NRTI therapy, low CD4 cell count at time of switch, or AIDS are at increased risk of treatment failure, limiting the use of ABC/3TC/ZDV in these patient groups.

Abstract: BACKGROUND: A growing number of case reports have described tenofovir (TDF)-related proximal renal tubulopathy and impaired calculated glomerular filtration rates (cGFR). We assessed TDF-associated changes in cGFR in a large observational HIV cohort. METHODS: We compared treatment-naive patients or patients with treatment interruptions > or = 12 months starting either a TDF-based combination antiretroviral therapy (cART) (n = 363) or a TDF-sparing regime (n = 715). The predefined primary endpoint was the time to a 10 ml/min reduction in cGFR, based on the Cockcroft-Gault equation, confirmed by a follow-up measurement at least 1 month later. In sensitivity analyses, secondary endpoints including calculations based on the modified diet in renal disease (MDRD) formula were considered. Endpoints were modelled using pre-specified covariates in a multiple Cox proportional hazards model. RESULTS: Two-year event-free probabilities were 0.65 (95% confidence interval [CI] 0.58-0.72) and 0.80 (95% CI 0.76-0.83) for patients starting TDF-containing or TDF-sparing cART, respectively. In the multiple Cox model, diabetes mellitus (hazard ratio [HR] = 2.34 [95% CI 1.24-4.42]), higher baseline cGFR (HR = 1.03 [95% CI 1.02-1.04] by 10 ml/min), TDF use (HR = 1.84 [95% CI 1.35-2.51]) and boosted protease inhibitor use (HR = 1.71 [95% CI 1.30-2.24]) significantly increased the risk for reaching the primary endpoint. Sensitivity analyses showed high consistency. CONCLUSION: There is consistent evidence for a significant reduction in cGFR associated with TDF use in HIV-infected patients. Our findings call for a strict monitoring of renal function in long-term TDF users with tests that distinguish between glomerular dysfunction and proximal renal tubulopathy, a known adverse effect of TDF.

Abstract: BACKGROUND: Standard first-line combination antiretroviral treatment (cART) against human immunodeficiency virus 1 (HIV-1) contains either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI/r). Differences between these regimen types in the extent of the emergence of drug resistance on virological failure and the implications for further treatment options have rarely been assessed. METHODS: We investigated virological outcomes in patients from the Swiss HIV Cohort Study initiating cART between January 1, 1999, and December 31, 2005, with an unboosted PI, a PI/r, or an NNRTI and compared genotypic drug resistance patterns among these groups at treatment failure. RESULTS: A total of 489 patients started cART with a PI, 518 with a PI/r, and 805 with an NNRTI. A total of 177 virological failures were observed (108 [22%] PI failures, 24 [5%] PI/r failures, and 45 [6%] NNRTI failures). The failure rate was highest in the PI group (10.3 per 100 person-years; 95% confidence interval [CI], 8.5-12.4). No difference was seen between patients taking a PI/r (2.7; 95% CI, 1.8-4.0) and those taking an NNRTI (2.4; 95% CI, 1.8-3.3). Genotypic test results were available for 142 (80%) of the patients with a virological treatment failure. Resistance mutations were found in 84% (95% CI, 75%-92%) of patients taking a PI, 30% (95% CI, 12%-54%) of patients taking a PI/r, and 66% (95% CI, 49%-80%) of patients taking an NNRTI (P < .001). Multidrug resistance occurred almost exclusively as resistance against lamivudine-emtricitabine and the group-specific third drug and was observed in 17% (95% CI, 9%-26%) of patients taking a PI, 10% (95% CI, 0.1%-32%) of patients taking a PI/r, and 50% (95% CI, 33%-67%) of patients taking an NNRTI (P < .001). CONCLUSIONS: Regimens that contained a PI/r or an NNRTI exhibited similar potency as first-line regimens. However, the use of a PI/r led to less resistance in case of virological failure, preserving more drug options for the future.

Abstract: BACKGROUND: Human immunodeficiency virus (HIV)-infected persons may be at increased risk for developing type 2 diabetes mellitus because of viral coinfection and adverse effects of treatment. METHODS: We studied associations of new-onset diabetes mellitus with hepatitis B virus and hepatitis C virus coinfections and antiretroviral therapy in participants in the Swiss HIV Cohort Study, using Poisson regression. RESULTS: A total of 123 of 6513 persons experienced diabetes mellitus during 27,798 person-years of follow-up (PYFU), resulting in an incidence of 4.4 cases per 1000 PYFU (95% confidence interval [CI], 3.7-5.3 cases per 1000 PYFU). An increased incidence rate ratio (IRR) was found for male subjects (IRR, 2.5; 95% CI, 1.5-4.2), older age (IRR for subjects >60 years old, 4.3; 95% CI, 2.3-8.2), black (IRR, 2.1; 95% CI, 1.1-4.0) and Asian (IRR, 4.9; 95% CI, 2.2-10.9) ethnicity, Centers for Disease Control and Prevention disease stage C (IRR, 1.6; 95% CI, 1.04-2.4), and obesity (IRR, 4.7; 95% CI, 3.1-7.0), but results for hepatitis C virus infection or active hepatitis B virus infection were inconclusive. Strong associations were found for current treatment with nucleoside reverse-transcriptase inhibitors (IRR, 2.22; 95% CI, 1.11-4.45), nucleoside reverse-transcriptase inhibitors plus protease inhibitors (IRR, 2.48; 95% CI, 1.42-4.31), and nucleoside reverse-transcriptase inhibitors plus protease inhibitors and nonnucleoside reverse-transcriptase inhibitors (IRR, 3.25; 95% CI, 1.59-6.67) but were not found for treatment with nucleoside reverse-transcriptase inhibitors plus nonnucleoside reverse-transcriptase inhibitors (IRR, 1.47; 95% CI, 0.77-2.82). CONCLUSIONS: In addition to traditional risk factors, current treatment with protease inhibitor- and nucleoside reverse-transcriptase inhibitor-containing regimens was associated with the risk of developing type 2 diabetes mellitus. Our study did not find a significant association between viral hepatitis infection and risk of incident diabetes.

Abstract: OBJECTIVE: The ABCB1 (MDR1) gene, encoding the transporter P-glycoprotein, is known to act on a broad range of prescription medicines. For this reason a large number of studies have assessed the functional consequences of variation in this gene. Particular attention has focused on the ABCB1_3435C>T polymorphism, an exonic variant resulting in a synonymous change. This variant has been associated with mRNA, protein and serum levels, and with responses to a number of medicines. The results of association studies have, however, been variable and it is not currently clear whether this polymorphism is functional or is in linkage disequilibrium with functionally distinct alleles. RESULTS: To identify functional variation in the ABCB1 gene we assessed allelic imbalance by pyrosequencing cDNA from 80 lymphoblastoid B cell lines from the Centre d'Etude du Polymorphisme Humain (CEPH) collection, including 74 individuals heterozygous for 3435C>T. We found that the degree of ABCB1 allelic imbalance differed among B-cell lines. In an effort to fine-map variants that influence the proportion of the two allelic mRNA species we genotyped representative common variations near the 3435C>T polymorphism by using a tagging single nucleotide polymorphism (SNP) approach. In one approach, we assessed in segregating families the impact of cis-acting variants on mRNA levels by using allelic imbalance as the phenotype in a regression analysis that distinguishes the coupling arrangements (phase) among alleles. In a second approach, we assessed allelic imbalance levels in lymphoblastoid B-cell lines from unrelated HapMap individuals, and performed an association using tagSNPs in a 5-Mb region surrounding the gene. Two potential cis-acting variants, a promoter rs28656907/rs28373093 dinucleotide polymorphism (P=0.007) and the rs10245483 SNP (P=0.0003) located 2 Mb upstream from the gene, were predictors of ABCB1 expression. CONCLUSIONS: The study outlines a general experimental approach for fine mapping gene variants that influence mRNA expression by using cultured cell lines.

Abstract: The possession of some HLA class I molecules is associated with delayed progression to AIDS. The mechanism behind this beneficial effect is unclear. We tested the idea that cytotoxic T-cell responses restricted by advantageous HLA class I molecules impose stronger selection pressures than those restricted by other HLA class I alleles. As a measure of the selection pressure imposed by HLA class I alleles, we determined the extent of HLA class I-associated epitope variation in a cohort of European human immunodeficiency virus (HIV)-positive individuals (n=84). We validated our findings in a second, distinct cohort of African patients (n=516). We found that key HIV epitopes restricted by advantageous HLA molecules (B27, B57, and B51 in European patients and B5703, B5801, and B8101 in African patients) were more frequently mutated in individuals bearing the restricting HLA than in those who lacked the restricting HLA class I molecule. HLA alleles associated with clinical benefit restricted certain epitopes for which the consensus peptides were frequently recognized by the immune response despite the circulating virus's being highly polymorphic. We found a significant inverse correlation between the HLA-associated hazard of disease progression and the mean HLA-associated prevalence of mutations within epitopes (P=0.028; R2=0.34). We conclude that beneficial HLA class I alleles impose strong selection at key epitopes. This is revealed by the frequent association between effective T-cell responses and circulating viral escape mutants and the rarity of these variants in patients who lack these favorable HLA class I molecules, suggesting a significant pressure to revert.

Abstract: Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection.

Abstract: OBJECTIVES: To assess the prevalence of abnormal testosterone and gonadotropin values in HIV-infected men before and after 2 years of combination antiretroviral therapy (cART). DESIGN: Multicentre cohort of HIV-infected adults. METHODS: We identified 139 Caucasian antiretroviral-naive male patients who started zidovudine/ lamivudine-based cART that was virologically successful over a 2 year period. Ninety-seven were randomly chosen and plasma hormone determinations of free testosterone (fT) and luteinizing hormone (LH) at baseline and after 2 years of cART were evaluated. RESULTS: At baseline 68 patients (70%) had subnormal fT levels. In these, LH levels were low in 44%, normal in 47% and high in 9%. There was a trend for an association between lower CD4+ T-cell counts and hypogonadism. Most participants had normal FSH levels. No significant changes of fT, LH and FSH levels were observed after 2 years of cART. CONCLUSIONS: Low fT levels, mainly with normal or low LH levels and thus indicating secondary hypogonadism, are found in the majority of HIV-infected men and do not resolve during 2 years of successful cART.

Abstract: Understanding why some people establish and maintain effective control of HIV-1 and others do not is a priority in the effort to develop new treatments for HIV/AIDS. Using a whole-genome association strategy, we identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set-point period of infection. One of these is found within an endogenous retroviral element and is associated with major histocompatibility allele human leukocyte antigen (HLA)-B*5701, whereas a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated two genes, one of which encodes an RNA polymerase I subunit. These findings emphasize the importance of studying human genetic variation as a guide to combating infectious agents.

Abstract: BACKGROUND: We have previously demonstrated an association between combination antiretroviral therapy and the risk of myocardial infarction. It is not clear whether this association differs according to the class of antiretroviral drugs. We conducted a study to investigate the association of cumulative exposure to protease inhibitors and nonnucleoside reverse-transcriptase inhibitors with the risk of myocardial infarction. METHODS: We analyzed data collected through February 2005 from our prospective observational study of 23,437 patients infected with the human immunodeficiency virus. The incidence rates of myocardial infarction during the follow-up period were calculated, and the associations between myocardial infarction and exposure to protease inhibitors or nonnucleoside reverse-transcriptase inhibitors were determined. RESULTS: Three hundred forty-five patients had a myocardial infarction during 94,469 person-years of observation. The incidence of myocardial infarction increased from 1.53 per 1000 person-years in those not exposed to protease inhibitors to 6.01 per 1000 person-years in those exposed to protease inhibitors for more than 6 years. After adjustment for exposure to the other drug class and established cardiovascular risk factors (excluding lipid levels), the relative rate of myocardial infarction per year of protease-inhibitor exposure was 1.16 (95% confidence interval [CI], 1.10 to 1.23), whereas the relative rate per year of exposure to nonnucleoside reverse-transcriptase inhibitors was 1.05 (95% CI, 0.98 to 1.13). Adjustment for serum lipid levels further reduced the effect of exposure to each drug class to 1.10 (95% CI, 1.04 to 1.18) and 1.00 (95% CI, 0.93 to 1.09), respectively. CONCLUSIONS: Increased exposure to protease inhibitors is associated with an increased risk of myocardial infarction, which is partly explained by dyslipidemia. We found no evidence of such an association for nonnucleoside reverse-transcriptase inhibitors; however, the number of person-years of observation for exposure to this class of drug was less than that for exposure to protease inhibitors.

Abstract: OBJECTIVE: To estimate the prognosis over 5 years of HIV-1-infected, treatment-naive patients starting HAART, taking into account the immunological and virological response to therapy. DESIGN: A collaborative analysis of data from 12 cohorts in Europe and North America on 20,379 adults who started HAART between 1995 and 2003. METHODS: Parametric survival models were used to predict the cumulative incidence at 5 years of a new AIDS-defining event or death, and death alone, first from the start of HAART and second from 6 months after the start of HAART. Data were analysed by intention-to-continue-treatment, ignoring treatment changes and interruptions. RESULTS: During 61 798 person-years of follow-up, 1005 patients died and an additional 1303 developed AIDS. A total of 10 046 (49%) patients started HAART either with a CD4 cell count of less than 200 cells/microl or with a diagnosis of AIDS. The 5-year risk of AIDS or death (death alone) from the start of HAART ranged from 5.6 to 77% (1.8-65%), depending on age, CD4 cell count, HIV-1-RNA level, clinical stage, and history of injection drug use. From 6 months the corresponding figures were 4.1-99% for AIDS or death and 1.3-96% for death alone. CONCLUSION: On the basis of data collected routinely in HIV care, prognostic models with high discriminatory power over 5 years were developed for patients starting HAART in industrialized countries. A risk calculator that produces estimates for progression rates at years 1 to 5 after starting HAART is available from www.art-cohort-collaboration.org.

Abstract:

Abstract: BACKGROUND: Highly active antiretroviral therapy (HAART) is being scaled up in developing countries. We compared baseline characteristics and outcomes during the first year of HAART between HIV-1-infected patients in low-income and high-income settings. METHODS: 18 HAART programmes in Africa, Asia, and South America (low-income settings) and 12 HIV cohort studies from Europe and North America (high-income settings) provided data for 4810 and 22,217, respectively, treatment-naive adult patients starting HAART. All patients from high-income settings and 2725 (57%) patients from low-income settings were actively followed-up and included in survival analyses. FINDINGS: Compared with high-income countries, patients starting HAART in low-income settings had lower CD4 cell counts (median 108 cells per muL vs 234 cells per muL), were more likely to be female (51%vs 25%), and more likely to start treatment with a non-nucleoside reverse transcriptase inhibitor (NNRTI) (70%vs 23%). At 6 months, the median number of CD4 cells gained (106 cells per muL vs 103 cells per muL) and the percentage of patients reaching HIV-1 RNA levels lower than 500 copies/mL (76%vs 77%) were similar. Mortality was higher in low-income settings (124 deaths during 2236 person-years of follow-up) than in high-income settings (414 deaths during 20,532 person-years). The adjusted hazard ratio (HR) of mortality comparing low-income with high-income settings fell from 4.3 (95% CI 1.6-11.8) during the first month to 1.5 (0.7-3.0) during months 7-12. The provision of treatment free of charge in low-income settings was associated with lower mortality (adjusted HR 0.23; 95% CI 0.08-0.61). INTERPRETATION: Patients starting HAART in resource-poor settings have increased mortality rates in the first months on therapy, compared with those in developed countries. Timely diagnosis and assessment of treatment eligibility, coupled with free provision of HAART, might reduce this excess mortality.

Abstract: CONTEXT: The Zambian Ministry of Health has scaled-up human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) care and treatment services at primary care clinics in Lusaka, using predominately nonphysician clinicians. OBJECTIVE: To report on the feasibility and early outcomes of the program. DESIGN, SETTING, AND PATIENTS: Open cohort evaluation of antiretroviral-naive adults treated at 18 primary care facilities between April 26, 2004, and November 5, 2005. Data were entered in real time into an electronic patient tracking system. INTERVENTION: Those meeting criteria for antiretroviral therapy (ART) received drugs according to Zambian national guidelines. MAIN OUTCOME MEASURES: Survival, regimen failure rates, and CD4 cell response. RESULTS: We enrolled 21,755 adults into HIV care, and 16,198 (75%) started ART. Among those starting ART, 9864 (61%) were women. Of 15,866 patients with documented World Health Organization (WHO) staging, 11,573 (73%) were stage III or IV, and the mean (SD) entry CD4 cell count among the 15,336 patients with a baseline result was 143/microL (123/microL). Of 1142 patients receiving ART who died, 1120 had a reliable date of death. Of these patients, 792 (71%) died within 90 days of starting therapy (early mortality rate: 26 per 100 patient-years), and 328 (29%) died after 90 days (post-90-day mortality rate: 5.0 per 100 patient-years). In multivariable analysis, mortality was strongly associated with CD4 cell count between 50/microL and 199/microL (adjusted hazard ratio [AHR], 1.4; 95% confidence interval [CI], 1.0-2.0), CD4 cell count less than 50/microL (AHR, 2.2; 95% CI, 1.5-3.1), WHO stage III disease (AHR, 1.8; 95% CI, 1.3-2.4), WHO stage IV disease (AHR, 2.9; 95% CI, 2.0-4.3), low body mass index (<16; AHR,2.4; 95% CI, 1.8-3.2), severe anemia (<8.0 g/dL; AHR, 3.1; 95% CI, 2.3-4.0), and poor adherence to therapy (AHR, 2.9; 95% CI, 2.2-3.9). Of 11,714 patients at risk, 861 failed therapy by clinical criteria (rate, 13 per 100 patient-years). The mean (SD) CD4 cell count increase was 175/microL (174/microL) in 1361 of 1519 patients (90%) receiving treatment long enough to have a 12-month repeat. CONCLUSION: Massive scale-up of HIV and AIDS treatment services with good clinical outcomes is feasible in primary care settings in sub-Saharan Africa. Most mortality occurs early, suggesting that earlier diagnosis and treatment may improve outcomes.

Abstract: BACKGROUND: The CD4 T cell count recovery in human immunodeficiency virus type 1 (HIV-1)-infected individuals receiving potent antiretroviral therapy (ART) shows high variability. We studied the determinants and the clinical relevance of incomplete CD4 T cell restoration. METHODS: Longitudinal CD4 T cell count was analyzed in 293 participants of the Swiss HIV Cohort Study who had had a plasma HIV-1 RNA load <1000 copies/mL for > or =5 years. CD4 T cell recovery was stratified by CD4 T cell count 5 years after initiation of ART (> or =500 cells/microL was defined as a complete response, and <500 cells/microL was defined as an incomplete response). Determinants of incomplete responses and clinical events were evaluated using logistic regression and survival analyses. RESULTS: The median CD4 T cell count increased from 180 cells/microL at baseline to 576 cells/microL 5 years after ART initiation. A total of 35.8% of patients were incomplete responders, of whom 47.6% reached a CD4 T cell plateau <500 cells/microL. Centers for Disease Control and Prevention HIV-1 disease category B and/or C events occurred in 21% of incomplete responders and in 14.4% of complete responders (P>.05). Older age (adjusted odds ratio [aOR], 1.71 per 10-year increase; 95% confidence interval [CI], 1.21-2.43), lower baseline CD4 T cell count (aOR, 0.37 per 100-cell increase; 95% CI, 0.28-0.49), and longer duration of HIV infection (aOR, 2.39 per 10-year increase; 95% CI, 1.19-4.81) were significantly associated with a CD4 T cell count <500 cells/microL at 5 years. The median increases in CD4 T cell count after 3-6 months of ART were smaller in incomplete responders (P<.001) and predicted, in conjunction with baseline CD4 T cell count and age, incomplete response with 80% sensitivity and 72% specificity. CONCLUSION: Individuals with incomplete CD4 T cell recovery to <500 cells/microL had more advanced HIV-1 infection at baseline. CD4 T cell changes during the first 3-6 months of ART already reflect the capacity of the immune system to replenish depleted CD4 T lymphocytes.

Abstract: BACKGROUND: Data on the incidence of hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected persons are sparse. It is controversial whether and how frequently HCV is transmitted by unprotected sexual intercourse. METHODS: We assessed the HCV seroprevalence and incidence of HCV infection in the Swiss HIV Cohort Study between 1988 and 2004. We investigated the association of HCV seroconversion with mode of HIV acquisition, sex, injection drug use (IDU), and constancy of condom use. Data on condom use or unsafe sexual behavior were prospectively collected between 2000 and 2004. RESULTS: The overall seroprevalence of HCV infection was 33% among a total of 7899 eligible participants and 90% among persons reporting IDU. We observed 104 HCV seroconversions among 3327 participants during a total follow-up time of 16,305 person-years, corresponding to an incidence of 0.64 cases per 100 person-years. The incidence among participants with a history of IDU was 7.4 cases per 100 person-years, compared with 0.23 cases per 100 person-years in patients without such a history (P<.001). In men who had sex with men (MSM) without a history of IDU who reported unsafe sex, the incidence was 0.7 cases per 100 person-years, compared with 0.2 cases per 100 person-years in those not reporting unsafe sex (P=.02), corresponding to an incidence rate ratio of 3.5 (95% confidence interval, 1.2-10.0). The hazard of acquiring HCV infection was elevated among younger participants who were MSM. CONCLUSIONS: HCV infection incidence in the Swiss HIV Cohort Study was mainly associated with IDU. In HIV-infected MSM, HCV infection was associated with unsafe sex.

Abstract: BACKGROUND: Persons infected with human immunodeficiency virus (HIV) have an increased risk for several cancers, but the influences of behavioral risk factors, such as smoking and intravenous drug use, and highly active antiretroviral therapy (HAART) on cancer risk are not clear. METHODS: Patient records were linked between the Swiss HIV Cohort Study and Swiss cantonal cancer registries. Observed and expected numbers of incident cancers were assessed in 7304 persons infected with HIV followed for 28,836 person-years. Relative risks for cancer compared with those for the general population were determined by estimating cancer registry-, sex-, age-, and period-standardized incidence ratios (SIRs). RESULTS: Highly elevated SIRs were confirmed in persons infected with HIV for Kaposi sarcoma (KS) (SIR = 192, 95% confidence interval [CI] = 170 to 217) and non-Hodgkin lymphoma (SIR = 76.4, 95% CI = 66.5 to 87.4). Statistically significantly elevated SIRs were also observed for anal cancer (SIR = 33.4, 95% CI = 10.5 to 78.6); Hodgkin lymphoma (SIR = 17.3, 95% CI = 10.2 to 27.4); cancers of the cervix (SIR = 8.0, 95% CI = 2.9 to 17.4); liver (SIR = 7.0, 95% CI = 2.2 to 16.5); lip, mouth, and pharynx (SIR = 4.1, 95% CI = 2.1 to 7.4); trachea, lung, and bronchus (SIR = 3.2, 95% CI = 1.7 to 5.4); and skin, nonmelanomatous (SIR = 3.2, 95% CI = 2.2 to 4.5). In HAART users, SIRs for KS (SIR = 25.3, 95% CI = 10.8 to 50.1) and non-Hodgkin lymphoma (SIR = 24.2, 95% CI = 15.0 to 37.1) were lower than those for nonusers (KS SIR = 239, 95% CI = 211 to 270; non-Hodgkin lymphoma SIR = 99.3, 95% CI = 85.8 to 114). Among HAART users, however, the SIR (although not absolute numbers) for Hodgkin lymphoma (SIR = 36.2, 95% CI = 16.4 to 68.9) was comparable to that for KS and non-Hodgkin lymphoma. No clear impact of HAART on SIRs emerged for cervical cancer or non-acquired immunodeficiency syndrome-defining cancers. Cancers of the lung, lip, mouth, or pharynx were not observed among nonsmokers. CONCLUSION: In persons infected with HIV, HAART use may prevent most excess risk of KS and non-Hodgkin lymphoma, but not that of Hodgkin lymphoma and other non-acquired immunodeficiency syndrome-defining cancers. No cancers of the lip, mouth, pharynx, or lung were observed in nonsmokers.

Abstract: BACKGROUND: Unconjugated hyperbilirubinemia results from Gilbert syndrome and from antiretroviral therapy (ART) containing protease inhibitors. An understanding of the interaction between genetic predisposition and ART may help to identify individuals at highest risk for developing jaundice. METHODS: We quantified the contribution of UGT1A1*28 and ART to hyperbilirubinemia by longitudinally modeling 1386 total bilirubin levels in 96 human immunodeficiency virus (HIV)-infected individuals during a median of 6 years. RESULTS: The estimated average bilirubin level was 8.8 micromol/L (0.51 mg/dL). Atazanavir increased bilirubin levels by 15 mu mol/L (0.87 mg/dL), and indinavir increased bilirubin levels by 8 micromol/L (0.46 mg/dL). Ritonavir, lopinavir, saquinavir, and nelfinavir had no or minimal effect on bilirubin levels. Homozygous UGT1A1*28 increased bilirubin levels by 5.2 micromol/L (0.3 mg/dL). As a consequence, 67% of individuals homozygous for UGT1A1*28 and receiving atazanavir or indinavir had > or =2 episodes of hyperbilirubinemia in the jaundice range (>43 micromol/L [>2.5 mg/dL]), versus 7% of those with the common allele and not receiving either of those protease inhibitors (P<.001). Efavirenz resulted in decreased bilirubin levels, which is consistent with the induction of UDP-glucuronosyltransferase 1A1. CONCLUSIONS: Genotyping for UGT1A1*28 before initiation of ART would identify HIV-infected individuals at risk for hyperbilirubinemia and decrease episodes of jaundice.

Abstract: OBJECTIVES: To assess the long-term safety of discontinuation of secondary anti-Pneumocystis prophylaxis in HIV-infected adults treated with antiretroviral combination therapy and who have a sustained increase in CD4 cell counts. DESIGN: Prospective observational multicentre study. PATIENTS AND METHODS: The incidence of P. jirovecii pneumonia after discontinuation of secondary prophylaxis was studied in 78 HIV-infected patients on antiretroviral combination therapy after they experienced a sustained increase in CD4 cell counts to at least 200 x 10(6) cells/l and 14% of total lymphocytes measured twice at least 12 weeks apart. RESULTS: Secondary prophylaxis was discontinued at a median CD4 cell count of 380 x 10(6) cells/l. The median follow-up period after discontinuation of secondary prophylaxis was 40.2 months, yielding a total of 235 person-years of follow-up. No cases of recurrent P. jirovecii pneumonia occurred during this period. The incidence was thus 0 per 100 person-years with a 95% upper of confidence limit of 1.3 cases per 100 patient-years. CONCLUSIONS: Discontinuation of secondary prophylaxis against P. jirovecii pneumonia is safe even in the long term in patients who have a sustained immunologic response on antiretroviral combination therapy.

Abstract: OBJECTIVE: Pancreatic disorders in HIV-positive patients are frequent. CFTR and SPINK-1 mutations have been reported to increase the risk of pancreatitis, but no data are available in HIV-positive patients. This study will evaluate the frequency of CFTR mutations and SPINK-1 polymorphisms in HIV-positive patients with clinical pancreatitis or asymptomatic elevation of serum pancreatic enzymes. METHOD: Cases (patients with hyperamylasemia) were identified during a toxicity study conducted in August 1999 among 1152 participants of the Swiss HIV Cohort Study. We designed a case-control study in which each case was matched one to one to an HIV-infected control according to sex, age, CD4 cell count, viraemia and medication use. CFTR mutations and SPINK-1 polymorphisms were studied using polymerase chain reaction techniques. RESULTS: Fifty-one HIV-positive patients with hyperamylasemia were detected among 1152 participants in the toxicity study (4.4%). There were 13 carriers of CFTR and SPINK-1 mutations (12.7%). Amylase levels were 316 +/- 130 U/l for the group with mutations, and 135 +/- 18 U/l for non-carriers (P = 0.79). However, among patients with hyperamylasemia, those with CFTR or SPINK-1 mutations had 648 +/- 216 U/l amylase levels compared with 232 +/- 28 U/l for those without (P = 0.025). Ten patients had acute pancreatitis, four of whom had CFTR mutations or SPINK-1 polymorphisms (40%) compared with seven of the control patients (14%) (P = 0.01). CONCLUSION: CFTR mutations and SPINK-1 polymorphisms are frequent among HIV-positive patients suffering from acute pancreatitis. These mutations may increase the susceptibility to pancreatitis when exposed to environmental risk factors.

Abstract: OBJECTIVE: To examine the proportion of migrants from Sub-Saharan Africa entering the Swiss HIV Cohort Study (SHCS) and to compare these participants with participants from Northwestern Europe for access to antiretroviral therapy, progression to AIDS and survival. DESIGN: Prospective national cohort study of HIV-1-infected adults from seven HIV centres in Switzerland. METHODS: Trends in the proportion of participants from Sub-Saharan Africa were followed in 11 872 HIV-infected adults entering the SHCS from 1984 to 2001. Survival methods were used to compare uptake of antiretroviral therapy, survival and progression to AIDS in the 2684 participants from Sub-Saharan Africa and Northwest Europe enrolled from 1997-2001. RESULTS: There was a steady increase in the proportion of Sub-Saharan African participants over time, reaching 11.9% in 1997-2001. These participants were more likely to be younger, female, to have been infected by heterosexual intercourse and had lower CD4 cell counts at presentation. There were no differences between Sub-Saharan Africans and Northwest Europeans in uptake of triple antiretroviral therapy, progression to AIDS or survival up to 48 months after starting treatment. Tuberculosis was the most frequent AIDS-defining event in Sub-Saharan African patients. CONCLUSIONS: There is no evidence that access to potent antiretroviral therapy is influenced by geographic origin of participants. The prognosis of Sub-Saharan African patients on triple therapy is equivalent to that of Northwest European patients. Future research should address wider issues about access to specialist health services for HIV-infected people from Sub-Saharan Africa.

Abstract: BACKGROUND: Highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV)-1 infection allows recovery of CD4 T lymphocytes. Few studies have explored the long-term T-lymphocyte responses to HAART. METHODS: Plasma HIV-1 RNA levels and CD4 and CD8 T-lymphocyte counts were longitudinally analyzed over 4 years in 2235 participants of the Swiss HIV Cohort, commencing HAART between 1996 and 1997. The CD4 T-lymphocyte count increase, the percentage of individuals with a CD4 T-lymphocyte count of 500/microL or greater and less than 200/microL, and the determinants of CD4 T-lymphocyte recovery were evaluated in individuals treated with continuous (CONT; n = 985) and discontinuous (DISCONT; n = 1250) HAART. RESULTS: At 4 years, 69.5% of subjects (CONT, 84.5%; DISCONT, 53.6%; P<.001) showed HIV-1 RNA levels below 400 copies/mL, while the median CD4 T-lymphocyte count increased from 190/microL to 423/microL (CONT, 486/microL; DISCONT, 343/microL; P<.001). Of the 2235 participants, 38.8% (CONT, 47.7%; DISCONT, 29.4%; P<.001) reached a CD4 T-lymphocyte count of 500/microL or greater, but in 15.6%, CD4 T-lymphocyte count remained below 200/microL (CONT, 5.9%; DISCONT, 25.9%; P<.001). Larger increases in CD4 T-lymphocyte count were associated with higher baseline HIV-1 RNA, a larger percentage of undetectable HIV-1 RNA levels, lower baseline CD8 T-lymphocyte count, and younger age. Individuals reaching a CD4 T-lymphocyte count of 500/microL or greater at 4 years were characterized by higher nadir and baseline CD4 T-lymphocyte counts and a more sustained reduction of HIV-1 RNA levels. CONCLUSIONS: At 4 years, only 39% of individuals treated with HAART reached a CD4 T-lymphocyte count of 500/microL or greater, and 16% with CD4 T-lymphocyte counts less than 200/microL remained susceptible to opportunistic infections. Treatment interruptions, a poor virologic response, and older age were the major factors negatively affecting the recovery of CD4 T lymphocytes.

Abstract: OBJECTIVE: To determine whether genotypic resistance testing leads to selection of more potent drug regimens when compared to regimens based on treatment history only. DESIGN: Prospective, tertiary care centre-based study. PATIENTS: One-hundred-and-forty-five HIV-infected adults on stable antiretroviral therapy (ART) for >6 months experiencing virological failure. METHODS: The physicians' decision-making process when choosing a salvage regimen was prospectively documented: at time of virological failure, on 'failing ART', genotyping was performed and a hypothetical 'clinical expert ART' based upon patient's drug history was documented. Subsequently, data on resistance mutations, rating by a decision support software and drug history were used to define 'genotyping ART'. After discussion with the patient, final treatment, 'new personalized ART' was chosen and prescribed. To compare the relative potency of the four ART regimens in a standardized manner, a resistance score ranging from 1 (best) to 8 (worst) based on drug ranking by decision support software was attributed to each ART regimen. Virological and immunological outcomes were analysed based on the magnitude of the resistance score. RESULTS: Median follow-up was 1.5 years. In all 145 patients, median resistance scores for the stepwise selected ART regimens were: 'failing ART': 4.5, 'clinical expert ART': 1.8, 'genotyping ART': 1.5 and 'new personalized ART': 2. The latter was 1.5 in patients who effectively switched to 'new personalized ART' (n=89). Lower resistance scores translated into significantly improved virological response after initiation of 'new personalized ART'. In multivariable analysis, lower resistance scores, lower baseline HIV RNA levels and use of novel antiretroviral drugs were associated with the probability of reducing plasma viraemia to <50 copies/ml. CONCLUSIONS: This study suggests that treatment choices including genotype and decision support software were virologically superior to those based on drug history only.

Abstract: BACKGROUND: The safety of interrupting maintenance therapy for previous opportunistic infections other than Pneumocystis carinii pneumonia among patients with HIV infection who respond to potent antiretroviral therapy has not been well documented. OBJECTIVE: To assess the safety of interrupting maintenance therapy for cytomegalovirus (CMV) end-organ disease, disseminated Mycobacterium avium complex (MAC) infection, cerebral toxoplasmosis, and extrapulmonary cryptococcosis in patients receiving antiretroviral therapy. DESIGN: Observational study. SETTING: Seven European HIV cohorts. PATIENTS: 358 patients taking potent antiretroviral therapy (> or =3 drugs) who interrupted maintenance therapy at a CD4 lymphocyte count greater than 50 x 10(6) cells/L. MEASUREMENTS: Recurrence of opportunistic infection after interruption of maintenance therapy. RESULTS: 379 interruptions of maintenance therapy were identified: 162 for CMV disease, 103 for MAC infection, 75 for toxoplasmosis, and 39 for cryptococcosis. During 781 person-years of follow-up, five patients had relapse. Two relapses (one of CMV disease and one of MAC infection) were diagnosed after maintenance therapy was interrupted when the CD4 lymphocyte count was less than 100 x 10(6) cells/L or when only one recent measurement exceeded this value. Two relapses (one of CMV disease and one of MAC infection) were diagnosed after maintenance therapy was interrupted once CD4 counts were greater than 100 x 10(6) cells/L for 10 and 8 months, respectively. One relapse (toxoplasmosis) was diagnosed after maintenance therapy interruption at a CD4 lymphocyte count greater than 200 x 10(6) cells/L for 15 months. The overall incidences of recurrent CMV disease, MAC infection, toxoplasmosis, and cryptococcosis were 0.54 per 100 person-years (95% CI, 0.07 to 1.95 per 100 person-years), 0.90 per 100 person-years (CI, 0.11 to 3.25 per 100 person-years), 0.84 per 100 person-years (CI, 0.02 to 4.68 per 100 person-years), and 0.00 per 100 person-years (CI, 0.00 to 5.27 per 100 person-years), respectively. CONCLUSION: Maintenance therapy against previous infection with CMV, MAC, Toxoplasma gondii, or Cryptococcus neoformans in patients with HIV infection can be interrupted after sustained CD4 count increases to greater than 200 (or possibly 100 to 200) x 10(6) cells/L for at least 6 months after the start of potent antiretroviral therapy.

Abstract: BACKGROUND: Data on adverse events to antiretroviral treatment have been recorded in clinical trials, post-marketing analyses, and anecdotal reports. Such data might not be an up-to-date or comprehensive assessment of all possible treatment combinations defined as potent antiretroviral treatment. METHODS: Using a standard clinical and laboratory method, we assessed prevalence of adverse events in 1160 patients who were receiving antiretroviral treatment. We measured the toxic effects associated with the drug regimen (protease inhibitor [PI], non-nucleoside and nucleoside analogue reverse transcriptase inhibitor) and specific compounds using multivariate analyses. FINDINGS: 47% (545 of 1160) of patients presented with clinical and 27% (194 of 712) with laboratory adverse events probably or definitely attributed to antiretroviral treatment. Among these, 9% (47 of 545) and 16% (30 of 194), respectively, were graded as serious or severe. Single-PI and PI-sparing-antiretroviral treatment were associated with a comparable prevalence of adverse events. Compared with single-PI treatment, use of dual-PI-antiretroviral treatment and three-class-antiretroviral treatment was associated with higher prevalence of adverse events (odds ratio [OR] 2.0 [95% CI 1.0-4.0], and 3.9 [1.2-12.9], respectively). Compound specific associations were identified for zidovudine, lamivudine, stavudine, didanosine, abacavir, ritonavir, saquinavir, indinavir, nelfinavir, efavirenz, and nevirapine. INTERPRETATION: We recorded a high prevalence of toxic effects attributed to antiretroviral treatment for HIV-1. Such data provides a reference for regimen-specific and compound-specific adverse events and could be useful in postmarketing analyses of toxic effects.

Abstract: BACKGROUND: Patients with human immunodeficiency virus (HIV) infection and a history of Pneumocystis carinii pneumonia are at high risk for relapse if they are not given secondary prophylaxis. Whether secondary prophylaxis against P. carinii pneumonia can be safely discontinued in patients who have a response to highly active antiretroviral therapy is not known. METHODS: We analyzed episodes of recurrent P. carinii pneumonia in 325 HIV-infected patients (275 men and 50 women) in eight prospective European cohorts. Between October 1996 and January 2000, these patients discontinued secondary prophylaxis during treatment with at least three anti-HIV drugs after they had at least one peripheral-blood CD4 cell count of more than 200 cells per cubic millimeter. RESULTS: Secondary prophylaxis was discontinued at a median CD4 cell count of 350 per cubic millimeter; the median nadir CD4 cell count had been 50 per cubic millimeter. The median duration of the increase in the CD4 cell count to more than 200 per cubic millimeter after discontinuation of secondary prophylaxis was 11 months. The median follow-up period after discontinuation of secondary prophylaxis was 13 months, yielding a total of 374 person-years of follow-up; for 355 of these person-years, CD4 cell counts remained at or above 200 per cubic millimeter. No cases of recurrent P. carinii pneumonia were diagnosed during this period; the incidence was thus 0 per 100 patient-years (99 percent confidence interval, 0 to 1.2 per 100 patient-years, on the basis of the entire follow-up period, and 0 to 1.3 per 100 patient-years, on the basis of the follow-up period during which CD4 cell counts remained at or above 200 per cubic millimeter). CONCLUSIONS: It is safe to discontinue secondary prophylaxis against P. carinii pneumonia in patients with HIV infection who have an immunologic response to highly active antiretroviral therapy.

Abstract: BACKGROUND: Hepatitis C virus (HCV) infection is highly prevalent among HIV-1-infected individuals, but its contribution to the morbidity and mortality of coinfected patients who receive potent antiretroviral therapy is controversial. We used data from the ongoing Swiss HIV Cohort Study to analyse clinical progression of HIV-1, and the virological and immunological response to potent antiretroviral therapy in HIV-1-infected patients with or without concurrent HCV infection. METHODS: We analysed prospective data on survival, clinical disease progression, suppression of HIV-1 replication, CD4-cell recovery, and frequency of changes in antiretroviral therapy according to HCV status in 3111 patients starting potent antiretroviral therapy. RESULTS: 1157 patients (37.2%) were coinfected with HCV, 1015 of whom (87.7%) had a history of intravenous drug use. In multivariate Cox's regression, the probability of progression to a new AIDS-defining clinical event or to death was independently associated with HCV seropositivity (hazard ratio 1.7 [95% CI 1.26-2.30]), and with active intravenous drug use (1.38 [1.02-1.88]). Virological response to antiretroviral therapy and the probability of treatment change were not associated with HCV serostatus. In contrast, HCV seropositivity was associated with a smaller CD4-cell recovery (hazard ratio for a CD4-cell count increase of at least 50 cells/microL=0.79 [0.72-0.87]). INTERPRETATION: HCV and active intravenous drug use could be important factors in the morbidity and mortality among HIV-1-infected patients, possibly through impaired CD4-cell recovery in HCV seropositive patients receiving potent antiretroviral therapy. These findings are relevant for decisions about optimum timing for HCV treatment in the setting of HIV infection.

Abstract: OBJECTIVE: To assess the association between type and timing of initiation of antiretroviral therapy in pregnancy and duration of pregnancy. DESIGN: Prospective study. METHODS: Data on 3920 mother-child pairs were examined (3015 mother-child pairs from the European Collaborative Study and 905 from the Swiss Mother + Child HIV Cohort Study). Factors examined included gestational age, antiretroviral therapy during pregnancy, maternal CD4 count, viral load, illicit drug use (IDU) and mode of delivery. Deliveries at less than 37 weeks were defined as premature. RESULTS: The prematurity rate was 17% and median gestational age 39 weeks. Twenty-three per cent (896 of 3920) of women received antiretroviral therapy during pregnancy: 64% (573 of 896) zidovudine monotherapy, 24% (215) combination therapy without protease inhibitors (PI) and 12% (108) combination therapy with PI. In multivariate analysis, adjusted for maternal CD4 count and IDU, odds ratio (OR) of prematurity was 2.60 [95% confidence interval (CI), 1.43-4.75] and 1.82 (95% CI, 1.13-2.92) for infants exposed to combination therapy with and without a PI, respectively, compared to no treatment. Exposure to monotherapy was not associated with prematurity, but severe immunosuppression and IDU in pregnancy were. Women on combination therapy from before pregnancy were twice as likely to deliver prematurely as those starting therapy in the third trimester (OR, 2.17; 95% CI, 1.03-4.58). CONCLUSIONS: Pregnancy issues should be discussed when making decisions about initiation of combination antiretroviral therapy for HIV-infected women. Elective caesarean section to reduce vertical transmission at 36 weeks rather than 38 weeks may be advisable in women on combination therapy with PI.

Abstract: OBJECTIVE: To assess the safety of discontinuing or withholding primary prophylaxis against disseminated Mycobacterium avium infection (MAC) in HIV infected patients on successful antiretroviral combination therapy. SETTING: National prospective multicentre cohort study. DESIGN: HIV-infected patients were eligible for the analysis if: (i) they had a history of at least two CD4 cell counts < 50 x 10(6)/l; (ii) they had never had MAC; (iii) they had discontinued or never begun primary prophylaxis against MAC; (iv) they received antiretroviral therapy and demonstrated an increase in CD4 cell counts to > or = 100 x 10(6)/l that was sustained for at least 12 weeks. From this time point until last follow-up, incidence of disseminated MAC disease was measured, and 99% confidence intervals were calculated assuming a Poisson distribution of events. RESULTS: Two-hundred and fifty-three patients (22.5% female; median age, 37 years, 30% injecting drug users) were eligible for analysis. Sixty-six per cent were in Centers for Disease Control and Prevention (CDC) stage C, and 28% were in CDC stage B. Their median nadir CD4 cell count was 10 x 10(6)/l, the median duration of CD4 cell count < 50 x 10(6)/l was 12 months. During a total follow-up of 364.3 patient-years there was no case of disseminated MAC. The one-sided 99% confidence limit for incidence density of MAC was 1.3 per 100 person-years. CONCLUSION: Discontinuing or withholding primary prophylaxis against MAC is safe in patients who have a sustained increase in their CD4 cell count to > or = 100 x 10(6)/l.

Abstract: BACKGROUND: The efficacy of highly active antiretroviral therapy (HAART) in suppression of HIV-1 is well documented. We investigated virological and clinical outcomes of HAART in routine practice. METHODS: We analysed prospective data from the Swiss HIV Cohort Study on suppression of viral load and progression to AIDS or death in 2674 outpatients (median age 36 years, 27.3% women) who started HAART in 1995-98. Viral rebound was defined as two consecutive HIV-1-RNA measurements of more than 400 copies/mL. We analysed separately outcomes in patients with a history of antiretroviral treatment and in treatment-naive patients. FINDINGS: An estimated 90.7% of treatment-naive patients reached undetectable viral load (<400 copies/mL) by 12 months. Among pretreated patients, estimates ranged from 70.3% treated with one new drug to 78.7% on three new drugs. 2 years after reaching undetectable concentrations, an estimated 20.1% of treatment-naive patients and 35.7-40.1% of pretreated patients had viral rebound. At 30 months, an estimated 6.6% (95% CI 4.6-8.6) of patients who had maintained undetectable concentrations, 9.0% (5.5-12.5) who had viral rebound, and 20.1% (15.3-24.9) who had never reached undetectable concentrations developed AIDS or died. Compared with patients who maintained undetectable viral load, the adjusted relative hazard of AIDS or death was 1.00 (0.66-1.55) for patients with viral rebound, and 2.40 (1.72-3.33) for patients who failed to reach undetectable concentrations. INTERPRETATION: The rate of virological failure of HAART was high among these patients, but the probability of clinical progression was low even in patients with viral rebound.

Abstract: In this cross-sectional survey conducted at the end of 1997 among the physicians of participants of the Swiss HIV Cohort Study (SHCS), 1487 of 2154 patients (69.0%) were treated with highly active antiretroviral treatment (HAART) defined as triple therapy with a combination of one or two reverse transcriptase inhibitors, and one or two protease inhibitors; 541 patients (25.1%) had never received such treatment. The physician's perception that the patient would not comply with treatment was one reason for not prescribing HAART to 20% of these patients (110). Physicians indicated that the most common reasons for the patient to refuse HAART were the fear of side effects (18%) and the patient's perception that treatment was too complicated (18%). Among 126 patients (5.8%) no longer receiving HAART, the most common reasons for discontinuing treatment were actual side effects (61%) or the fear of side effects (25%). Overall, 16% of patients did not receive therapy in accord with official Swiss guidelines. Multivariate logistic regression analysis indicated that patients with lower education, active intravenous drug users outside of a drug substitution program, and those who acquired HIV infection through intravenous drug use had a significantly higher risk of inadequate treatment. The physician's judgment of patient adherence and the physician's perception of the patient's fear of side effects are critical for the prescription of HAART. Physicians should address these issues to prevent unilateral withholding of treatment and increase the proportion of patients who may benefit from current antiretroviral therapy.

Abstract: A topic that has received attention in both the statistical and medical literature is the estimation of the probability of failure for endpoints that are subject to competing risks. Despite this, it is not uncommon to see the complement of the Kaplan-Meier estimate used in this setting and interpreted as the probability of failure. If one desires an estimate that can be interpreted in this way, however, the cumulative incidence estimate is the appropriate tool to use in such situations. We believe the more commonly seen representations of the Kaplan-Meier estimate and the cumulative incidence estimate do not lend themselves to easy explanation and understanding of this interpretation. We present, therefore, a representation of each estimate in a manner not ordinarily seen, each representation utilizing the concept of censored observations being 'redistributed to the right.' We feel these allow a more intuitive understanding of each estimate and therefore an appreciation of why the Kaplan-Meier method is inappropriate for estimation purposes in the presence of competing risks, while the cumulative incidence estimate is appropriate.

Abstract: BACKGROUND: It is unclear whether primary prophylaxis against Pneumocystis carinii pneumonia can be discontinued in patients infected with the human immunodeficiency virus (HIV) who are successfully treated with combination antiretroviral therapy. We prospectively studied the safety of stopping prophylaxis among patients in the Swiss HIV Cohort Study. METHODS: Patients were eligible for our study if their CD4 counts had increased to at least 200 cells per cubic millimeter and 14 percent of total lymphocytes while they were receiving combination antiretroviral therapy, with these levels sustained for at least 12 weeks. Prophylaxis was stopped at study entry, and patients were examined every three months thereafter. The development of P. carinii pneumonia was the primary end point, and the development of toxoplasmic encephalitis the secondary end point. RESULTS: Of the 262 patients included in our analysis, 121 (46.2 percent) were positive for IgG antibodies to Toxoplasma gondii at base line. The median CD4 count at study entry was 325 per cubic millimeter (range, 210 to 806); the median nadir CD4 count was 110 per cubic millimeter (range, 0 to 240). During a median follow-up of 11.3 months (range, 3.0 to 18.8), prophylaxis was resumed in nine patients, and two patients died. There were no cases of P. carinii pneumonia or toxoplasmic encephalitis. The one-sided upper 99 percent confidence limit for the incidence of P. carinii pneumonia was 1.9 cases per 100 patient-years (based on 238 patient-years of follow-up). The corresponding figure for toxoplasmic encephalitis was 4.2 per 100 patient-years (based on 110 patient-years of follow-up). CONCLUSIONS: Stopping primary prophylaxis against P. carinii pneumonia appears to be safe in HIV-infected patients who are receiving combination antiretroviral treatment and who have had a sustained increase in their CD4 counts to at least 200 cells per cubic millimeter and to at least 14 percent of total lymphocytes.

Abstract: BACKGROUND: Different levels of experience of physicians caring for patients with HIV infection have been found to be associated with differences in survival amongst their patients. We examined whether early participation in the Swiss HIV Cohort Study (SHCS), an ongoing prospective study with regular follow-up visits at specialized clinics, improved survival of HIV-infected patients. METHODS: We studied 3553 HIV-infected individuals who joined the Swiss HIV Cohort Study (SHCS) with different levels of immunosuppression: mild (CD4 count above 500 x 106 cells L-1; n x 2038); severe (100-199 cells; n = 960); and very severe (50-99 cells; n = 555). Characteristics at different CD4 cell levels were compared and Cox proportional hazards regression was used to examine the mortality experience during a total of 16 201 person-years of follow-up. RESULTS: Participants joining the cohort early with mild immunodeficiency were younger, more likely to be female, and more likely to have a history of intravenous drug use. At CD4 cell counts below 200 x 106 cells L-1, they were less likely to have a history of Pneumocystis carinii pneumonia or AIDS, more likely to be on prophylaxis against P. carinii and more likely to be on antiretroviral therapy than those joining with severe or very severe immunodeficiency. For example, at the time of the first CD4 cell count in the range of 50-99 x 106 cells L-1, 8.9, 15.0 and 21.6% of participants who joined with mild, severe and very severe immunodeficiency had suffered an episode of P. carinii pneumonia. In Cox models adjusted for CD4 cell count at entry and other relevant baseline differences, mortality was increased amongst participants who joined with severe and very severe immunodeficiency. Hazard ratios (95% confidence intervals (CI)) were 1.71 (1.21-2.42) for participants with severe immunodeficiency at entry and 2.61 (1.70-4. 01) for those with very severe immunodeficiency, compared with 1.0 for those with mild immunodeficiency at entry. CONCLUSIONS: Individuals who were seen regularly at specialized HIV units from early stages of the infection onwards were, at comparable levels of immunodeficiency, less likely to progress to AIDS, and mortality during subsequent follow-up was reduced. This is likely to be explained by better access to prophylactic regimens and antiretroviral therapy.

Abstract: OBJECTIVE: To study the effect of elective Cesarean section and zidovudine prophylaxis on vertical HIV transmission. DESIGN: Prospective study. SETTING: Obstetric and paediatric clinics in Switzerland. PARTICIPANTS: Children of mothers with HIV infection identified before or at delivery. INTERVENTIONS: Routine use of elective Cesarean section for HIV-infected parturients by some Swiss centres since 1985. National recommendation for zidovudine prophylaxis in mid-1994. MAIN OUTCOME MEASURE: HIV infection status of children. RESULTS: In a cohort of 494 children born at least 6 months before the analysis date, 67 out of 414 children with known infection status were found to be infected, giving an overall transmission rate of 16.2% [95% confidence interval (CI), 13.0-18.51. Elective Cesarean section with intact membranes and without previous labour was associated with a lower transmission rate of 6% [odds ratio (OR), 0.29; 95% CI, 0.12-0.70; P = 0.006 versus other delivery modes]. Transmission rate was intermediate after spontaneous delivery or non-elective Cesarean section (18%), and higher after obstetric interventions (27%; test for trend, P < 0.001). Since mid-1994, 78% of all women with registered pregnancies have received some form of zidovudine prophylaxis. Transmission rate was reduced from 17 to 7% after any zidovudine exposure (OR, 0.4; 95% CI, 0.11-1.41). Combined use of elective Cesarean section and zidovudine resulted in a 0% transmission rate (none out of 31), compared with 8% (seven out of 86) after elective Cesarean section without zidovudine, 17% (four out of 24) after zidovudine alone, and 20% (55 out of 271) after no intervention. CONCLUSIONS: Elective Cesarean section and zidovudine prophylaxis appear to have an additive effect in the prevention of vertical HIV transmission.

Abstract: BACKGROUND: The introduction of combination antiretroviral therapy and protease inhibitors has led to reports of falling mortality rates among people infected with HIV-1. We examined the change in these mortality rates of HIV-1-infected patients across Europe during 1994-98, and assessed the extent to which changes can be explained by the use of new therapeutic regimens. METHODS: We analysed data from EuroSIDA, which is a prospective, observational, European, multicentre cohort of 4270 HIV-1-infected patients. We compared death rates in each 6 month period from September, 1994, to March, 1998. FINDINGS: By March, 1998, 1215 patients had died. The mortality rate from March to September, 1995, was 23.3 deaths per 100 person-years of follow-up (95% CI 20.6-26.0), and fell to 4.1 per 100 person-years of follow-up (2.3-5.9) between September, 1997, and March, 1998. From March to September, 1997, the death rate was 65.4 per 100 person-years of follow-up for those on no treatment, 7.5 per 100 person-years of follow-up for patients on dual therapy, and 3.4 per 100 person-years of follow-up for patients on triple-combination therapy. Compared with patients who were followed up from September, 1994, to March, 1995, patients seen between September, 1997, and March, 1998, had a relative hazard of death of 0.16 (0.08-0.32), which rose to 0.90 (0.50-1.64) after adjustment for treatment. INTERPRETATION: Death rates across Europe among patients infected with HIV-1 have been falling since September, 1995, and at the beginning of 1998 were less than a fifth of their previous level. A large proportion of the reduction in mortality could be explained by new treatments or combinations of treatments.

Abstract: BACKGROUND: Therapies containing two reverse transcriptase inhibitors (RTI) with or without protease inhibitors are used with increasing frequency in pregnant HIV-infected women. OBJECTIVE: To assess the safety of antiretroviral therapy in pregnant women and their newborns. METHODS: All clinical events and laboratory abnormalities in pregnant women on RTI with or without protease inhibitors and in their newborns were collected through an observational study. RESULTS: A total of 37 HIV-infected pregnant women have given birth to 30 children (by 30 April 1998). All received RTI, which were combined with protease inhibitors in 16 cases. Twelve women became pregnant while on treatment. Drugs used were as follows: zidovudine (n = 33), lamivudine (n = 33), stavudine (n = 4), indinavir (n = 9), ritonavir (n = 4), nelfinavir (n = 2) and saquinavir (n = 2). Adverse events during pregnancy were anaemia (n = 15), elevation of transaminases (n = 4), nausea/vomiting (n = 4), glucose intolerance (n = 2), nephrolithiasis (n = 2), diarrhoea (n = 2), hypertension (n = 1), insulin-requiring diabetes (n = 1). Adverse events in neonates were prematurity (n = 10), anaemia (n = 8), cutaneous angioma (n = 2), cryptorchidism (n = 2), transient hepatitis (n = 1). Non-life-threatening intracerebral haemorrhage occurred in a premature baby (33 weeks gestation) exposed during fetal life to zidovudine-lamivudine-indinavir, and in a term baby exposed to stavudine-lamivudine-indinavir. Extrahepatic biliary atresia occurred in one newborn exposed to zidovudine-lamivudine-indinavir. Maternal viral load was below 400 copies/ml in 18 out of 30 patients who delivered. One case of mother-to-child HIV transmission was identified. CONCLUSIONS: In HIV-infected pregnant women treated with two RTI with or without protease inhibitors, one or more adverse events occurred in 29 out of 37 women and in 14 out of 30 babies. In newborns, frequent prematurity, one case of biliary malformation and one intracerebral haemorrhage in a term baby are of concern. These observations do not preclude combination therapies during pregnancy but emphasize the necessity to maintain updated registers on their safety.

Abstract: Survival-time studies sometimes do not yield distinct failure times. Several methods have been proposed to handle the resulting ties. The goal of this paper is to compare these methods. Simulations were conducted, in which failure times were generated for a two-sample problem with an exponential hazard, a constant hazard ratio, and no censoring. Failure times were grouped to produce heavy, moderate, and light ties, corresponding to a mean of 10.0, 5.0, and 2.5 failures per interval. Cox proportional hazards models were fit using each of three approximations for handling ties with each interval size for sample sizes of n = 25, 50, 250, and 500 in each group. The Breslow (1974, Biometrics 30, 89-99) approximation tends to underestimate the true beta, while the Kalbfleisch-Prentice (1973, Biometrika 60, 267-279) approximation tends to overestimate beta. As the ties become heavier, the bias of these approximations increases. The Efron (1977, Journal of the American Statistical Association 72, 557-565) approximation performs far better than the other two, particularly with moderate or heavy ties; even with n = 25 in each group, the bias is under 2%, and for sample sizes larger than 50 per group, it is less than 1%. Except for the heaviest ties in the smallest sample, confidence interval coverage for all three estimators fell in the range of 94-96%. However, the tail probabilities were asymmetric with the Breslow and Kalbfleisch-Prentice formulas; using the Efron approximation, they were closer to the nominal 2.5%. Although the Breslow approximation is the default in many standard software packages, the Efron method for handling ties is to be preferred, particularly when the sample size is small either from the outset or due to heavy censoring.

Abstract: OBJECTIVES: To examine trends in disease progression and survival among patients enrolled in the Swiss HIV cohort study during 1988-96 and to assess the influence of new antiretroviral combination therapies. DESIGN: Prospective multicentre study, with follow up visits planned at six monthly intervals. SETTING: Seven HIV units at university centres and cantonal hospitals in Switzerland. PATIENTS: 3785 men (mean age 35.0 years) and 1391 women (30.3 years) infected with HIV. 2023 participants had a history of intravenous drug misuse; 1764 were men who had sex with men; 1261 were infected heterosexually; and 164 had other or unknown modes of transmission. 601 participants had had an AIDS defining illness. RESULTS: During more than 15,000 years of follow up, there were 1456 first AIDS defining diagnoses and 1903 deaths. Compared with those enrolled during 1988-90, the risk of progression to a first AIDS diagnosis was reduced by 18% (relative risk 0.82 (95% confidence interval 0.73 to 0.93)) among participants enrolled in 1991-2, by 23% (0.77 (0.65 to 0.91)) among those enrolled in 1993-4, and by 73% (0.27 (0.18 to 0.39)) among those enrolled in 1995-6. Mortality was reduced by 19% (0.81 (0.73 to 0.90)), 26% (0.74 (0.63 to 0.87)), and 62% (0.38 (0.25 to 0.97)) respectively. Compared with no antiretroviral treatment, the risk of an initial AIDS diagnosis after CD4 lymphocyte counts fell to < 200 cells x 10(6)/1 was reduced by 16% (0.84 (0.73 to 0.97)) with monotherapy, 24% (0.76 (0.63 to 0.91)) with dual therapy, and 42% (0.58 (0.37 to 0.92)) with triple therapy. Mortality was reduced by 23% (0.77 (0.68 to 0.88)), 31% (0.69 (0.60 to 0.80)), and 65% (0.35 (0.20 to 0.60)) respectively. CONCLUSIONS: The introduction of antiretroviral combination therapies outside the selected patient groups included in clinical trials has led to comparable reductions in disease progression and mortality.

Abstract: Two methods are given for the joint estimation of parameters in models for competing risks in survival analysis. In both cases Cox's proportional hazards regression model is fitted using a data duplication method. In principle either method can be used for any number of different failure types, assuming independent risks. Advantages of the augmented data approach are that it limits over-parametrisation and it runs immediately on existing software. The methods are used to reanalyse data from two well-known published studies, providing new insights.

Abstract: OBJECTIVES: This paper describes the rationale and design features of the Swiss HIV Cohort Study (SHCS) and the baseline characteristics of participants enrolled up to March 31st 1993. The objectives include epidemiological, clinical and laboratory research. DESIGN: The SHCS is a prospective cohort study of HIV infected adolescents and adults seen at the outpatient clinics of the Swiss University Hospitals in Basle, Berne, Geneva, Lausanne and Zurich and the Cantonal Hospital St. Gall. The multicentre collaboration was initiated in September 1988 by the Swiss Federal Office of Public Health. Data collected prior to this date by several participating centers using a similar protocol were included, the earliest records dating back to 1982. Follow-up visits are scheduled every 6 months. ENROLLMENT: As of March 31st 1993, 6253 participants (M: 4580, F: 1675) were included with a total of 16015 person-years of follow-up (mean 2.6 years). HIV transmission categories were 46% intravenous drug users (IDU), 32% men who had sex with men (MSM), 18% heterosexual contacts (HET) and 4% other. The proportion of MSM among male participants decreased from 62% in 1985 to 40% in 1987, to remain stable thereafter. The proportion of IDU among males was around 40% throughout, whereas in females, there was a pronounced decline from 90% IDU in 1985 to 50% in 1992. Conversely, there was a striking increase in registrations of women presumably infected by HET, from 8% in 1985 to 50% in 1992. Among men, the proportion classified as HET increased from 2% to 15%. It is estimated, that a large proportion of all Swiss AIDS patients (70%) and HIV infected individuals (32%-47%) are enrolled in the Swiss HIV Cohort Study. Losses to follow-up, however, are common. CONCLUSIONS: The SHCS serves multiple purposes as a research project, as infrastructure for multidisciplinary research and as a tool to improve patient care. Several international and national trials, post-marketing surveillances and expanded access protocols were or still are based upon its infrastructure. The large number of female participants and of participants AIDS-free at entry, make the database especially valuable.

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