Abstract: Many studies in various research areas have designs that involve repeated measurements over time of a continuous variable across a group of subjects. A frequent and serious problem in such studies is the occurrence of missing data. In many cases, missing data are caused by an event that leads to a premature termination of the series of repeated measurements on some subjects. When the probability of the occurrence of this event is related to the subject-specific underlying trend of the variable of interest, this missingness process is called informative censoring or informative drop-out. Standard likelihood-based methods (for example, linear mixed models) fail to give consistent estimates. In such cases, one needs to apply methods that simultaneously model the observed data and the missingness process. In this article, we review a method proposed by Touloumi et al. (1999, Statistics in Medicine 18: 1215-1233) to adjust for informative drop-out in longitudinal data analysis. We also present the jmre1 command, which can be used to fit the proposed model. The estimation method combines the restricted iterative generalized least-squares method with a nested expectation-maximization algorithm. The method is implemented mainly using Stata's matrix programming language, Mata. Our example is derived from the epidemiology of the HIV infection.
Abstract: This study investigated the optimal schedule for home blood pressure (HBP) monitoring that has the greatest prognostic ability and provides the most reliable assessment of HBP. The Didima study assessed the value of HBP (duplicate morning and evening measurements, 3 days) in predicting cardiovascular events in the general population (662 adults, 8.2+/-0.2 years follow-up). Criteria for the optimal monitoring schedule were stabilization of mean HBP, its variability (standard deviation (s.d.)) and hazard ratios (HRs) of cardiovascular events per 1 mm Hg HBP increase. By averaging more readings (1-12), there was a progressive decline in average HBP and its s.d. and increase in HR, with most of these benefits achieved on the second day (8 readings) and little additional benefit obtained on the third day (12 readings). The first day gave higher and more unstable HBP values (higher s.d.) with less prognostic ability (lower HR). The first HBP readings per occasion gave higher values but with similar prognostic ability as the second readings taken 1 min later. There was little difference in average HBP between morning and evening readings with no prognostic superiority of morning readings. In conclusion, by averaging more readings the average HBP and its variability are reduced and the prognostic ability improved. Any aspect of HBP monitoring (first or second readings, morning or evening) has similar prognostic ability. The first day gives higher and unstable values with lower prognostic ability and should be better discarded. These data validate the HBP monitoring schedule proposed by the European Society of Hypertension.
Abstract: BACKGROUND:: Studies based on seroconverters have increased our understanding of HIV disease. It is not clear, however, whether their disease progression differs from that of the general HIV population, given their reasons for presenting for testing. METHODS:: Using linear mixed models we compared CD4 decline rates for a seroconverter (CASCADE) and seroprevalent group (Concorde trial) with time origin being dates of seroconversion and randomization, respectively. Follow-up was censored at the earlier of last alive date and 1 January 1996. Analyses were adjusted for risk group, age and sex. To explore the role of symptomatic seroconversion we further categorized seroconverters into two groups: with and without an HIV test interval below 30 days as proxy. RESULTS:: The 7226 seroconverter and 1746 seroprevalent eligible individuals were mainly men (78 and 85%, respectively) infected through sex between men (52 and 63%) with mean [95% confidence interval (CI)] baseline CD4 cell count of 610 (602, 619) and 492 (479, 505) cells/μl, respectively. There was no evidence that rate of CD4 decline differs between the two groups even after adjusting for potential confounders (P = 0.67). Estimated loss in the year after reaching an arbitrary threshold of 400 cells/μl was 67 (95% CI 65, 69) and 67 (64, 69) cells/μl in the seroconverter and seroprevalent group, respectively. Whereas seroconverters with test interval below 30 days (n = 310) experienced faster decline, there was no difference in rates between other seroconverters and seroprevalent individuals (P = 0.87). CONCLUSIONS:: These data suggest that estimates of HIV progression derived from seroconverters are likely to hold more generally for the HIV-infected population.
Abstract: Objective: To provide information on responses to combination antiretroviral therapy in children, adolescents and older HIV-infected persons. Design and setting: Multicohort collaboration of 33 European cohorts. Subjects: Forty-nine thousand nine hundred and twenty-one anti retroviral-naive individuals starting combination antiretroviral therapy from 1998 to 2006. Outcome measures: Time from combination antiretroviral therapy initiation to HIV RNA less than 50copies/ml (virological response), CD4 increase of more than 100cells/mu l (immunological response) and new AIDS/death were analysed using survival methods. Ten age strata were chosen: less than 2, 2-5, 6-12, 13-17, 18-29, 30-39 (reference group), 40-49, 50-54, 55-59 and 60 years or older; those aged 6 years or more were included in multivariable analyses. Results: The four youngest age groups had 223, 184, 219 and 201 individuals and the three oldest age groups had 2693, 1656 and 1613 individuals. Precombination antiretroviral therapy CD4 cell counts were highest in young children and declined with age. By 12 months, 53.7% (95% confidence interval: 53.2-54.1%) and 59.2% (58.7-59.6%) had experienced a virological and immunological response. The probability of virological response was lower in those aged 6-12 (adjusted hazard ratio: 0.87) and 13-17 (0.78) years, but was higher in those aged 50-54 (1.24), 55-59 (1.24) and at least 60 (1.18) years. The probability of immunological response was higher in children and younger adults and reduced in those 60 years or older. Those aged 55-59 and 60 years or older had poorer clinical outcomes after adjusting for the latest CD4 cell count. Conclusion: Better virological responses but poorer immunological responses in older individuals, together with low precombination antiretroviral therapy CD4 cell counts, may place this group at increased clinical risk. The poorer virological responses in children may increase the likelihood of emergence of resistance. (C) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
Abstract: OBJECTIVE: To investigate the quality of root canal fillings and coronal restorations in relation to periapical status in a Greek population. METHOD AND MATERIALS: A total of 320 patients who required full-mouth radiographic examination were included. The quality of root canal fillings and the periapical status, as well as the quality of coronal restorations, were assessed by radiographic criteria. Results were analyzed using random effects logistic regression models. RESULTS: Root canals with adequate filling length had a lower incidence of apical periodontitis than root canals with inadequate filling length (51.7% versus 63.4%, P ;= .002). Root-filled canals with adequate coronal restorations showed a lower incidence of apical periodontitis than those with inadequate restorations (47.3% versus 67.4%, P; < .001). When both root filling and coronal restoration were assessed, the incidence of apical periodontitis ranged from 39.2% to 67.6%. CONCLUSION: Quality of root canal treatment, as well as quality of coronal restoration, are strongly associated with the incidence of apical periodontitis.
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: To describe CD4 and HIV RNA changes during treatment resumption (TR) after treatment interruption (TI) compared with response to first highly active antiretroviral therapy (HAART) and to investigate predictors. METHODS: Using Concerted Action on SeroConversion to AIDS and Death in Europe (CASCADE) data, we identified subjects who interrupted first HAART, not initiated during primary infection. We estimated rate of CD4 change during TR and time from TR to HIV RNA<500 copies per milliliter and subsequent rebound and factors associated with these outcomes. RESULTS: Of 281 persons treated for median 18.4 months before interrupting, 259 resumed HAART. CD4 increases in the first 3 months on HAART were similar pre-TI and post-TI but after 3 months were significantly higher during pre-TI HAART, with median +106 and +172 cells per microliter at 3 and 18 months, respectively, during initial HAART compared with +99 and +142 cells per microliter during post-TI HAART, respectively. Subjects with lower CD4 counts at TI, aged older than 40 years, and those resuming the same HAART as their pre-TI regimen had lower CD4 increases during the first 3 months of TR. The majority (86%) of individuals reinitiating therapy achieved HIV RNA<500 copies per milliliter. CONCLUSIONS: Immune reconstitution after TI is generally poorer than after first HAART, particularly for patients aged older than 40 years at TI and those with poorer immunological responses to pre-TI HAART. Reinitiation of the same HAART regimen as pre-TI also seems to have unfavorable outcomes.
Abstract: OBJECTIVE: To investigate the effect of a short course of HAART during primary HIV infection (PHI) on rate of CD4 cell and viral load change. METHODS: Data following HAART cessation from 89 individuals (seroconverting 1999-2003) who chose to take a 3 month course of HAART at PHI were compared with 179 untreated controls in CASCADE, using linear and nonlinear random effects models. Participants were non-randomized but frequency matched for age, sex, risk factor, year of seroconversion and presentation within the first 6 months of seroconversion. Time to CD4 cell count < 350 cells/microl and initiation of clinically indicated antiretroviral therapy (ART) were also compared as competing risks. RESULTS: The rate of CD4 cell decline following therapy cessation appeared significantly slower among treated participants than untreated controls: losses of 51 cells/microl [95% confidence interval (CI), 32-69] and 77 cells/microl (95% CI, 65-89), respectively, 3 years after seroconversion (P = 0.011). Based on extrapolated data, viral loads also differed significantly at this point (4.09 and 4.53 copies/ml, respectively). At 2 years, there was no significant difference in mean viral load levels: 4.31 copies/ml (95% CI, 4.14-4.48) and 4.47 copies/ml (95% CI, 4.28-4.66), respectively. CASCADE seroconverters were more likely to reach CD4 cell count < 350 cells/microl or initiate clinically indicated ART (hazard ratio, 1.45; 95% CI, 1.02-2.05; P = 0.039). CONCLUSION: A short course of ART at PHI may delay CD4 cell decline. Confirmation of this requires a randomized clinical trial powered to address definitively the role of ART intervention in PHI (currently underway through SPARTAC).
Abstract: Repeated measurements of surrogate markers are frequently used to track disease progression, but these series are often prematurely terminated due to disease progression or death. Analysing such data through standard likelihood-based approaches can yield severely biased estimates if the censoring mechanism is non-ignorable. Motivated by this problem, we have proposed the bivariate joint multivariate random effects (JMRE) model, which has shown that when correctly specified it performs well in terms of bias reduction and precision. The bivariate JMRE model is fully parametric and belongs to the class of shared parameters joint models where a survival model for the dropouts and a mixed model for the markers' evolution are linked through a multivariate normal distribution of random effects. As in every parametric model, robustness under violations of its distributional assumptions is of great importance. In this study we generated 500 simulated data sets assuming that random effects jointly follow a heavy-tailed distribution, two skewed distributions or a mixture of two normal distributions. Moreover, we generated data where level-1 errors or residuals in the survival part of the model follow a skewed distribution. Further sensitivity analysis on the effects of reduced sample size, increased level-1 variances and altered fixed effects values was also performed. We found that fixed effects estimates are almost unaffected, but their standard errors (SEs) may be underestimated especially under heavily skewed distributions. The proposed model seems robust enough, but its performance on smaller data sets or under more extreme departures of its assumptions needs further investigation.
Abstract: OBJECTIVE: To characterize the magnitude and the predictors of highly active antiretroviral therapy (HAART) interruption (TI) and to investigate its immunologic and virological consequences. METHODS: Using Concerted Action on Seroconversion to AIDS and Death in Europe data from 8,300 persons with well-documented seroconversion dates, we identified subjects with stable first HAART (for at least 90 days) not initiated during primary infection. A TI was defined as an interruption of all antiretroviral therapy drugs for at least 14 days. RESULTS: Of 1,551 subjects starting HAART, 299 (19.3%) interrupted treatment. Median (interquartile range) duration of the TI was 189 (101-382) days. The cumulative probability (95% confidence interval) of TI at 2 years was 15.9% (14.0%-18.1%). Women were more likely to have a TI than men in the same exposure group (35.8% vs 24.2% among drug users, 22.1% vs 13.3% among heterosexuals; P < 0.05). Higher baseline viremia and poor immunologic response to HAART were associated with higher probabilities of TI. Median (interquartile range) individual CD4 cell loss during TI was 94 (1-220) cells/microL. Older age at HAART (>40 yr), lower pre-HAART nadir (<200 cells/microL), and lower CD4 at start of TI (<350 cells/microL) were significantly associated with greater relative CD4 loss during TI. CONCLUSIONS: We estimate that almost 1 in 6 subjects on HAART interrupts treatment by 2 years. Further research is needed to investigate the reasons why TI is higher in women. We have identified characteristics of subjects with the greatest risk for CD4 loss in whom TI may have greater risks.
Abstract: The main statistical problem in many epidemiological studies which involve repeated measurements of surrogate markers is the frequent occurrence of missing data. Standard likelihood-based approaches like the linear random-effects model fail to give unbiased estimates when data are non-ignorably missing. In human immunodeficiency virus (HIV) type 1 infection, two markers which have been widely used to track progression of the disease are CD4 cell counts and HIV-ribonucleic acid (RNA) viral load levels. Repeated measurements of these markers tend to be informatively censored, which is a special case of non-ignorable missingness. In such cases, we need to apply methods that jointly model the observed data and the missingness process. Despite their high correlation, longitudinal data of these markers have been analysed independently by using mainly random-effects models. Toulourni and co-workers have proposed a model termed the joint multivariate random-effects model which combines a linear random-effects model for the underlying pattern of the marker with a log-normal survival model for the drop-out process. We extend the joint multivariate random-effects model to model simultaneously the CD4 cell and viral load data while adjusting for informative drop-outs due to disease progression or death. Estimates of all the model's parameters are obtained by using the restricted iterative generalized least squares method or a modified version of it using the EM algorithm as a nested algorithm in the case of censored survival data taking also into account non-linearity in the HIV-RNA trend. The method proposed is evaluated and compared with simpler approaches in a simulation study. Finally the method is applied to a subset of the data from the 'Concerted action on seroconversion to AIDS and death in Europe' study.
Abstract: AIM: To investigate the prevalence of root filled teeth and apical periodontitis (AP) in a Greek population. METHODOLOGY: A random sample of 320 patients who required full mouth periapical radiographic examination as a part of diagnostic and planning procedures were included. The age of the patients ranged from 16 to 77 years. A total of 7664 teeth were assessed and the frequency of root filled teeth and periapical status was recorded. Two observers evaluated the radiographs under standardized conditions. AP was defined as distinct periapical radiolucency or widening of the periodontal ligament space exceeding two times the normal width. Statistical evaluation of differences in proportions between groups was performed using random effects logistic regression models. RESULTS: The periapical status of 286 (3.7%) teeth was impossible to evaluate because of radiographic faults; these teeth were excluded from further analysis. A total of 1040 (13.6%) teeth had radiographic signs of AP and 680 (9.2%) teeth had been root filled. Of the root filled teeth, 408 (60.0%) had AP. There was no difference in the number of root filled teeth between males and females; the prevalence of root filled teeth increased with age. Significantly more molars (13.1%) and premolars (11.9%) than anterior teeth (5.8%) had been root filled (P < 0.001). The prevalence of AP was significantly higher (P < 0.001) in molars (23.9%) and premolars (14.0%) than anterior teeth (9.4%). CONCLUSIONS: The prevalence of AP and the frequency of root filled teeth with AP in this Greek population were higher than those found in many other European countries. The frequency of root filled teeth was comparable with findings in other epidemiological studies.
Abstract: OBJECTIVE: To assess whether cellular HIV-1 DNA prior to highly active antiretroviral therapy (HAART) initiation predicts its outcome. DESIGN AND METHODS: Patients included all 51 hemophiliacs of the Greek component of the Multicenter Hemophilia Cohort Study who had initiated HAART and for whom cryopreserved lymphocyte samples before HAART initiation were available. Cellular HIV-1 DNA quantification was performed by a molecular beacon-based real-time PCR assay in multiple samples per patient with a median (interquartile range) follow-up of 76 (45-102) weeks. RESULTS: The median (range) baseline HIV-1 DNA load was 297 (< 10 to 3468) copies per 1 x 10(6) peripheral blood mononuclear cells. Baseline HIV-1 DNA load did not predict initial virological response (VR). None of the patients with initial VR and baseline HIV-1 DNA load at or below the median experienced a subsequent virological rebound, while the cumulative probability of virological rebound by week 104 was 55% among those with HIV-1 DNA load greater than the median (P < 0.008). Cellular HIV-1 DNA load was the only parameter associated with sustained virological response as shown by univariate or multivariate analyses [adjusted odds ratio (95% confidence interval) 0.197 (0.048-0.801) per 1 log10 increase in DNA copies, P = 0.023]. CONCLUSION: Low cellular HIV-1 DNA load is a marker of sustained virological response in patients with initial VR and it can reliably predict the long-term success of HAART.
Abstract: The T cell receptor excision DNA circle (TREC) level is an independent predictor of HIV-1 disease prognosis. We studied the temporal changes in TREC levels prior to and after highly active antiretroviral therapy (HAART) in a cohort of 131 Greek men with hemophilia who were followed up for up to 20 years since seroconversion (SC). TREC levels were determined in all available cryopreserved samples of peripheral blood mononuclear cells (PBMCs) using a multiplex real-time polymerase chain reaction (PCR) assay. Trends in log(10) TREC values were described using random effects models. Prior to HAART initiation TREC levels tended to decrease over time (mean rate of drop 19% per year; 95% CI: 16-22%). Initial TREC values were higher with younger age at SC, but the subsequent rate of drop did not differ significantly by age at SC. There was a monotonic relationship between baseline HIV-RNA levels and TREC slopes with steeper slopes at higher levels of HIV-RNA. The TREC slopes differed significantly by clinical outcome being steeper in subjects who progressed to AIDS sooner. After HAART initiation, TREC values tended to increase on average by 35% per year (95% CI: -7-94%) but the increase was evident only in subjects with a pre-HAART CD4 count below 80 cells/microl. TREC values, which likely represent a simple indicator of naive T-lymphocyte reserve, may be a clinically useful marker for long-term prognosis of HIV-1 infection and for immune reconstitution after successful HAART.
Abstract: OBJECTIVE: To assess the effects of sex, risk group, age at and year of seroconversion (SC), and presentation during acute infection on HIV RNA trends before antiretroviral therapy (ART) initiation. METHODS: Multiple HIV RNA measurements from 1864 individuals with reliably estimated dates of SC, aged >/= 15 years at SC were studied using random effects models. Models were adjusted for selective HIV RNA data truncation due to ART initiation or AIDS development and for HIV RNA quantification assay. RESULTS: HIV RNA levels declined precipitously during the first 10 months after SC followed by a slow increase. Women infected heterosexually and through injecting drug use, had an average 34% [95% confidence interval (CI), 2.3-56%] and 46% (95% CI, 17-66%) lower HIV RNA load respectively, compared to men in the same risk group. Among men, those infected heterosexually and by injecting drug use had on average 56% (95% CI, 36-69%) lower HIV RNA levels than homosexual men. Older subjects tended to have higher viral levels. There was no evidence that differences by sex, risk or age group diminished over time, but follow-up was mostly before CD4 cell count had fallen below 200 x 10 cells/l. CONCLUSIONS: HIV RNA levels at the same stage of HIV-1 infection differ significantly by sex, risk group and age at SC. Given the lack of evidence of a survival difference by sex or risk group prior to initiation of effective therapy, further research on differential effects of virus load on treatment-free disease progression is needed, before a conclusion about considering these factors for ART initiation is drawn.
Abstract: We studied repeated measurements of CD4 cell counts on 5739 HIV-1-infected individuals with reliably estimated dates of seroconversion (SC) aged greater than or equal to15 years at SC prior to initiation of highly active antiretroviral therapy (HAART) or AIDS using random effects models. Estimated CD4 cell count at SC differed significantly by sex, exposure group, and age, being higher in women, hemophilic men, and injection drug users (IDUs) as well as in those aged >40 years at SC. The rate of CD4 cell count decline did not differ significantly by sex; thus, differences between men and women were stable throughout the HIV-1 incubation period. There was a monotonic relationship between CD4 slopes and age at SC, with steeper slopes in older subjects. At 5 years after SC, the median difference in CD4 cell counts between the oldest (>40 years at SC) and youngest (16-20 years at SC) subjects was around 90 cells/muL. Mean rate of CD4 decline was significantly steeper in subjects diagnosed during acute infection. There was no evidence of a faster loss of CD4 cells in subjects who seroconverted after 1994. Apart from hemophilic men, who tended to have a steeper rate of CD4 decline on average, mean CD4 slopes did not differ by exposure category. These results suggest that before the initiation of kAART or other interventions based-on immune status, consideration of demographic factors may be worthwhile.
Abstract: The aim of this study was to determine the serum levels of soluble markers reflecting different aspects of immune activation in HIV-1-infected patients, and assess their prognostic significance for occurrence of AIDS-related death before the advent of the highly active antiretroviral treatment (HAART). Serum concentrations of the soluble forms of interleukin-2 receptors (sIL-2R), intercellular adhesion molecule-1 (sICAM-1), and E-selectin (sEs) have been determined in a cohort of 64 HIV-1-infected patients, between 1990-1993. The patients were followed prospectively with regular visits at the outpatient department. Follow-up time was censored at January 1, 1997, the date after which HAART was introduced. The median follow-up time was 46 months (range, 2-78 months). By the end of follow-up, 34 subjects had died. Baseline levels of all three soluble markers were significantly lower in subjects who remained alive during the follow-up compared to subjects who died. Univariate analysis showed that individual sIL-2R and sICAM-1, but not sEs measurements, were significantly associated with time to death (p = 0.008 and 0.003, respectively). Even after adjustment for age and CD4+ T-cell counts sIL-2R measurements remained significantly prognostic. Sensitivity analysis using follow-up time to year 2000 confirmed these results. Our data suggest that assessment of the immune activation status using the easily measured levels of circulating markers may provide additional information about the risk of AIDS-related death. Further studies are needed to assess the effect of HAART on the levels of immune activation markers and their prognostic value.
Abstract: There are several forms of human immunodeficiency virus type 1 (HIV-1) DNA in peripheral blood T cells and lymph nodes in untreated HIV-1-infected individuals and in patients whose plasma HIV-1 RNA levels are suppressed by long-term combination antiretroviral therapy. However, it remains to be established whether the concentration of HIV-1 DNA in cells predicts the clinical outcome of HIV-1 infection. In this report, we measured the concentration of HIV-1 DNA forms which has undergone the second template switch (STS DNA) and 2-long-terminal-repeat DNA circles in peripheral blood mononuclear cell (PBMC) samples. To do this, we used molecular-beacon-based real-time PCR assays and studied 130 patients with hemophilia in the Multicenter Hemophilia Cohort Study. We assessed the influence of baseline HIV-1 STS DNA levels on the progression of HIV-1 disease in the absence of combination antiretroviral therapy by Kaplan-Meier and Cox regression analysis. Among the patients who progressed to AIDS, the median levels (interquartile ranges) of STS HIV-1 DNA in PBMC were significantly higher than those of patients who remained AIDS free during the 16 years of follow-up (1,017 [235 to 6,059] and 286 [31 to 732] copies per 10(6) PBMC, respectively; P < 0.0001). Rates of progression to death and development of AIDS varied significantly (log rank P < 0.001) by quartile distribution of HIV-1 STS DNA levels. After adjustment for age at seroconversion, baseline CD4(+) T-cell counts, plasma viral load, and T-cell-receptor excision circles, the relative hazards (RH) of death and AIDS were significantly increased with higher HIV-1 STS DNA levels (adjusted RH, 1.84 [95% confidence interval (CI), 1.30 to 2.59] and 2.62 [95% CI, 1.75 to 3.93] per 10-fold increase per 10(6) PBMC, respectively). HIV-1 STS DNA levels in each individual remained steady in longitudinal PBMC samples during 16 years of follow-up. Our findings show that the concentration of HIV-1 STS DNA in PBMC complements the HIV-1 RNA load in plasma in predicting the clinical outcome of HIV-1 disease. This parameter may have important implications for understanding the virological response to combination antiretroviral therapy.
Abstract: CONTEXT: There is substantial debate about whether the results of nonrandomized studies are consistent with the results of randomized controlled trials on the same topic. OBJECTIVES: To compare results of randomized and nonrandomized studies that evaluated medical interventions and to examine characteristics that may explain discrepancies between randomized and nonrandomized studies. DATA SOURCES: MEDLINE (1966-March 2000), the Cochrane Library (Issue 3, 2000), and major journals were searched. STUDY SELECTION: Forty-five diverse topics were identified for which both randomized trials (n = 240) and nonrandomized studies (n = 168) had been performed and had been considered in meta-analyses of binary outcomes. DATA EXTRACTION: Data on events per patient in each study arm and design and characteristics of each study considered in each meta-analysis were extracted and synthesized separately for randomized and nonrandomized studies. DATA SYNTHESIS: Very good correlation was observed between the summary odds ratios of randomized and nonrandomized studies (r = 0.75; P<.001); however, nonrandomized studies tended to show larger treatment effects (28 vs 11; P =.009). Between-study heterogeneity was frequent among randomized trials alone (23%) and very frequent among nonrandomized studies alone (41%). The summary results of the 2 types of designs differed beyond chance in 7 cases (16%). Discrepancies beyond chance were less common when only prospective studies were considered (8%). Occasional differences in sample size and timing of publication were also noted between discrepant randomized and nonrandomized studies. In 28 cases (62%), the natural logarithm of the odds ratio differed by at least 50%, and in 15 cases (33%), the odds ratio varied at least 2-fold between nonrandomized studies and randomized trials. CONCLUSIONS: Despite good correlation between randomized trials and nonrandomized studies-in particular, prospective studies-discrepancies beyond chance do occur and differences in estimated magnitude of treatment effect are very common.
