Adeeba Kamarulzaman

Abstract: Background: Brucella species are easily transmitted by aerosols and can be acquired in the laboratory. Aim: To report the management of a large exposure to Brucella melitensis that occurred over six days in a hospital diagnostic laboratory. Methods: Fifty-one exposed staff were managed according to Centers for Disease Control and Prevention guidelines. A further 96 non-exposed laboratory staff were tested for seroprevalence. Testing was carried out using the Brucella sp. serum agglutination test. Findings: Twenty-seven people had high-risk exposure and 24 had low-risk exposure. High-risk staff were offered post-exposure prophylaxis. Twelve (44.4%) agreed to this, of whom eight (66.7%) completed the course. Overall compliance with serological follow-up at baseline, 2, 4, 6 weeks and 8 months was 45.9%. Despite this poor compliance there were no clinical brucellosis cases and no seroconversion in the 47.1% of staff tested at 8 months. Brucella sp. seroprevalence among all staff tested was 3/147 (2.0%). Conclusion: Lack of experience with Brucella spp. and lack of policies for handling potentially hazardous organisms contributed to this prolonged exposure. As compliance with current recommendations may be poor, the optimum frequency of serological follow-up and target groups for prophylaxis should be reassessed. Laboratories in low- or non-endemic areas must prepare for potential isolation of Brucella spp. The impact of human brucellosis in Malaysia requires further study. (C) 2011 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

Abstract: Polymorphisms in cell surface receptors of natural killer cells and their ligands on target cells can affect susceptibility to viral infections including human immunodeficiency virus (HIV)-1. We found that the carriage of the human leukocyte antigen (HLA)-G minus 14-bp polymorphism, LILRB1 single nucleotide polymorphism rs1061680, and activating and inhibitory killer immunoglobulin-like receptors (KIRs) were different when data were compared between Caucasian, African Americans and Asian populations. However, carriage was similar when HIV-1 patients were compared with control donors, with the exception of the African American cohort.

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Abstract: The need to improve access to care and treatment for chronic hepatitis C virus (HCV) infection in resource-limited settings is receiving increasing attention. Key priorities for scaling up HCV treatment and care include reducing the cost of current and future treatment; simplifying the package of care; identifying opportunities to shift specific tasks to nonspecialists to overcome human resource constraints; service integration with human immunodeficiency virus (HIV) clinics, prison health services, and needle syringe and oral substitution therapy programs; improving surveillance, monitoring, and research; encouraging patient and community engagement; focusing specifically on the needs of vulnerable groups; and increasing financial and political commitment. Many of these obstacles have been addressed in rolling out treatment for human immunodeficiency virus during the last decade, and a number of lessons can be drawn to help improve access to HCV care.

Abstract: BACKGROUND: Global programs of anti-HIV treatment depend on sustained laboratory capacity to assess treatment initiation thresholds and treatment response over time. Currently, there is no valid alternative to CD4 count testing for monitoring immunologic responses to treatment, but laboratory cost and capacity limit access to CD4 testing in resource-constrained settings. Thus, methods to prioritize patients for CD4 count testing could improve treatment monitoring by optimizing resource allocation. xD; xD;METHODS AND FINDINGS: Using a prospective cohort of HIV-infected patients (n=1,956) monitored upon antiretroviral therapy initiation in seven clinical sites with distinct geographical and socio-economic settings, we retrospectively apply a novel prediction-based classification (PBC) modeling method. The model uses repeatedly measured biomarkers (white blood cell count and lymphocyte percent) to predict CD4(+) T cell outcome through first-stage modeling and subsequent classification based on clinically relevant thresholds (CD4(+) T cell count of 200 or 350 cells/µl). The algorithm correctly classified 90% (cross-validation estimate=91.5%, standard deviation [SD]=4.5%) of CD4 count measurements <200 cells/µl in the first year of follow-up; if laboratory testing is applied only to patients predicted to be below the 200-cells/µl threshold, we estimate a potential savings of 54.3% (SD=4.2%) in CD4 testing capacity. A capacity savings of 34% (SD=3.9%) is predicted using a CD4 threshold of 350 cells/µl. Similar results were obtained over the 3 y of follow-up available (n=619). Limitations include a need for future economic healthcare outcome analysis, a need for assessment of extensibility beyond the 3-y observation time, and the need to assign a false positive threshold. xD; xD;CONCLUSIONS: Our results support the use of PBC modeling as a triage point at the laboratory, lessening the need for laboratory-based CD4(+) T cell count testing; implementation of this tool could help optimize the use of laboratory resources, directing CD4 testing towards higher-risk patients. However, further prospective studies and economic analyses are needed to demonstrate that the PBC model can be effectively applied in clinical settings. Please see later in the article for the Editors' Summary.

Abstract: This study examined characteristics of HIV-infected patients in the TREAT Asia HIV Observational Database who were lost to follow-up (LTFU) from treatment and care. Time from last clinic visit to 31 March 2009 was analysed to determine the interval that best classified LTFU. Patients defined as LTFU were then categorised into permanently LTFU (never returned) and temporary LTFU (re-entered later), and these groups compared. A total of 3626 patients were included (71% male). No clinic visits for 180 days was the best-performing LTFU definition (sensitivity 90.6%, specificity 92.3%). During 7697 person-years of follow-up, 1648 episodes of LFTU were recorded (21.4 per 100-person-years). Patients LFTU were younger (P = 0.002), had HIV viral load ≥500copies/mL or missing (P = 0.021), had shorter history of HIV infection (P = 0.048), and received no, single- or double-antiretroviral therapy, or a triple-drug regimen containing a protease inhibitor (P < 0.001). 48% of patients LTFU never returned. These patients were more likely to have low or missing haemoglobin (P < 0.001), missing recent HIV viral load (P < 0.001), negative hepatitis C test (P = 0.025), and previous temporary LTFU episodes (P < 0.001). Our analyses suggest that patients not seen at a clinic for 180 days are at high risk of permanent LTFU, and should be aggressively traced.

Abstract: Background: Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended for patients with CD4 counts of less than 200 cells/mm(3). This study examines the proportion of patients in the TREAT Asia HIV Observational Database (TAHOD) receiving PCP prophylaxis, and its effect on PCP and mortality. Methods: TAHOD patients with prospective follow up had data extracted for prophylaxis using co-trimoxazole, dapsone or pentamidine. The proportion of patients on prophylaxis was calculated for each calendar year since 2003 among patients with CD4 counts of less than 200 cells/mm3. The effect of prophylaxis on PCP and survival were assessed using random-effect Poisson regression models. Results: There were a total of 4050 patients on prospective follow up, and 90% of them were receiving combination antiretroviral therapy. Of those with CD4 counts of less than 200 cells/mm(3), 58% to 72% in any given year received PCP prophylaxis, predominantly co-trimoxazole. During follow up, 62 patients developed PCP (0.5 per 100 person-years) and 169 died from all causes (1.36/100 person-years). After stratifying by site and adjusting for age, CD4 count, CDC stage and antiretroviral treatment, those without prophylaxis had no higher risk of PCP, but had a significantly higher risk of death (incident rate ratio 10.8, p < 0.001). PCP prophylaxis had greatest absolute benefit in patients with CD4 counts of less than 50 cells/mm3, lowering mortality rates from 33.5 to 6.3 per 100 person-years. Conclusions: Approximately two-thirds of TAHOD patients with CD4 counts of less than 200 cells/mm3 received PCP prophylaxis. Patients without prophylaxis had significantly higher mortality, even in the era of combination ART. Although PCP may be under-diagnosed, these data suggest that prophylaxis is associated with important survival benefits.

Abstract: Objective xD; xD;To assess the effectiveness of treatment for hepatitis C virus (HCV) infection in low- and middle-income countries and identify factors associated with successful outcomes. xD; xD;Methods xD; xD;We performed a systematic review and meta-analysis of studies of HCV treatment programmes in low- and middle-income countries. The primary outcome was a sustained virological response (SVR). Factors associated with treatment outcomes were identified by random-effects meta-regression analysis. xD; xD;Findings xD; xD;The analysis involved data on 12213 patients included in 93 studies from 17 countries. The overall SVR rate was 52% (95% confidence interval, CI: 48–56). For studies in which patients were predominantly infected with genotype 1 or 4 HCV, the pooled SVR rate was 49% (95% CI: 43–55). This was significantly lower than the rate of 59% (95% CI: 54–64) found in studies in which patients were predominantly infected with other genotypes (P=0.012). Factors associated with successful outcomes included treatment with pegylated interferon and ribavirin, infection with an HCV genotype other than genotype 1 or 4 and the absence of liver damage or human immunodeficiency virus infection at baseline. No significant difference in the SVR rate was observed between weight-adjusted and fixed-dose ribavirin treatment. Overall, 17% (95% CI: 13–23) of adverse events resulted in treatment interruption or dose modification, but only 4% (95% CI: 3–5) resulted in treatment discontinuation. xD; xD;Conclusion xD; xD;The outcomes of treatment for HCV infection in low- and middle-income countries were similar to those reported in high-income countries.

Abstract: Introduction: Dried blood spot (DBS) collection is an appealing alternative to whole blood or plasma sampling, as it has technical and economic advantages over the latter. Materials and Methods: A prospective cross-sectional study was conducted at a Malaysian tertiary referral hospital from November 2009 to March 2010. One hundred and fifty paired specimens of DBS and plasma were analysed by the standard assays for HIV Ag/Ab, HBsAg, anti-HBS and anti-HCV, separately (total 600 paired specimens). DBS sample titres were then compared to the results of plasma testing, which was used as the gold standard. Results: For the HIV Ag/Ab assay with a cut-off point of 0.35 Relative Light Units (RLUs), the sensitivity and specificity were both 100%. For the HBsAg assay, the sensitivity was 96.5% and the specificity was 97.8%, with a cut-off point of 1.72 RLUs. Sensitivity for the anti-HBs test was 74.2% and the specificity was 86.9%, using a cut-off point of 0.635 RLUs. For the anti-HCV assay, the sensitivity was 97.3% and the specificity was 100%, with a cut-off point of 0.10 RLUs. Conclusion: DBS is an ideal choice to be used as a screening tool for the detection of HIV, Hepatitis B and Hepatitis C virus infections. However, different cut-off values need to be used for the validation of test positivity in DBS samples because the small amount of blood in the DBS specimens leads to lower assay titres.

Abstract: Aim: Immune restoration disease (IRD) associated with Mycobacterium tuberculosis parallels the reconstitution of a pathogen-specific Th1 response. However, it is not clear whether humoral responses to M. tuberculosis antigens also rise, or whether antibody levels predict IRD. Here, humoral immunity to M. tuberculosis antigens was investigated in four Asian cohorts. Methods: Plasma samples were obtained from longitudinal prospective studies of HIV patients beginning antiretroviral therapy (ART) in New Delhi (India), Kuala Lumpur (Malaysia), Jakarta (Indonesia) and Phnom Penh (Cambodia). IgG antibodies to purified protein derivative, lipoarabinomannan and 38-kDa antigens of M. tuberculosis were quantitated using in-house ELISAs. IRD was defined as exacerbated symptoms of tuberculosis in patients on anti-tuberculosis therapy or a novel presentation of tuberculosis on ART. Results: Pre-ART IgG levels to purified protein derivative, lipoarabinomannan and 38-kDa antigen were similar in the IRD and control groups from each site. Compared with non-IRD controls, a higher proportion of IRD patients had elevated IgG levels to lipoarabinomannan (defined as a greater than twofold increase) over 12 weeks of ART. However, this trend was not significant for the other antigens and longitudinal analyses did not reveal clear rises in antibody levels at the time of IRD. Conclusion: Levels of antibody to mycobacterial antigens do not predict IRD, but levels of antibody reactive with lipoarabinomannan rise during an IRD in some patients.

Abstract: In human immunodeficiency virus (HIV) patients, neuropathy is a common adverse side effect to some antiretroviral treatments, particularly stavudine. As stavudine is cheap, it is widely used in Asia and Africa. We showed that increasing age and height moderately predict the development of neuropathy. This was improved by the inclusion of tumour necrosis factor (TNF)-1031 (rs1799964). To investigate this association, Malay (n = 64), Chinese (n = 74) and Caucasian patients (n = 37) exposed to stavudine were screened for neuropathy. DNA samples were genotyped for polymorphisms in the central major histocompatibility complex (MHC) near TNF, and haplotypes were derived. The haplotype group FVa6,7,8 (incorporating TNF-1031) was found to be associated with neuropathy in Chinese patients in bivariate analyses (P = 0.03), and in Malays and Chinese in a multivariate analysis correcting for age and height (P = 0.02, P = 0.03, respectively). This trend was also confirmed in Caucasians.

Abstract: Background: Pre-incarceration HIV transmission behaviors and current attitudes toward opioid substitution therapy (OST) among HIV-infected male prisoners in Malaysia have important implications for secondary HIV prevention efforts. Methods: In June 2007, 102 HIV-infected male prisoners within 6 months of community-release were anonymously surveyed in Kota Bharu, Malaysia. Results: Nearly all subjects (95%) met criteria for opioid dependence. Overall, 66% of participants reported sharing needles, and 37% reported unprotected sex in the 30 days prior to incarceration. During this period, 77% reported injection drug use, with 71% injecting daily and 65% injecting more than one substance. Injection of buprenorphine (28%), benzodiazepines (28%) and methamphetamines (49%) was reported. Nearly all (97%) of those reporting unprotected sex did so with someone not known to be HIV-infected. While 51% believed that opioid substitution therapy COST) would be helpful, only 33% believed they needed it to prevent relapse after prison release. Most participants (70%) expressed interest in learning more about OST. Those reporting the highest injection risks were more likely to believe OST would be helpful (p < 0.05), to believe that it was needed to prevent relapse post-release (p < 0.05), and to express interest in learning more about OST (p < 0.01). Conclusions: Secondary HIV prevention among prisoners in Malaysia is crucial to reduce community HIV transmission after release. Effectively reducing HIV risk associated with opioid injection will require OST expansion, including social marketing to improve its acceptability and careful monitoring. Access to sterile injection equipment, particularly for non-opioid injectors, and behavioral interventions that reduce sexual risk will also be required. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Abstract: This research aimed to determine HIV prevalence, risk behaviour and knowledge of transmission methods among men who have sex with men (MSM) in Kuala Lumpur, Malaysia. Venue-day-time sampling (VDTS) was applied to identify venues where men congregate to solicit sex from other men. Participants recruited from clubs, massage parlours, saunas and one park self-completed a computerized behavioural questionnaire, were administered an oral rapid HIV test and given the opportunity to return later to receive full counselling and learn their HIV status. A total of 517 men were enrolled into the study. The majority were Malays (47.0%) and Chinese (43.7%). Twenty tested HIV positive (3.9%). Significant predictors of HIV infection included having unprotected anal sex with a casual partner (44.9% of participants, odds ratio [OR] = 2.99; 95% confidence interval [CI] 1.13-7.90; P = 0.027), having unprotected receptive anal sex (27.9%, OR = 2.71; 95% CI 1.10-6.54; P = 0.030) and having group sex (33.3%, OR = 3.95; 95% CI 1.55-10.09; P = 0.004). One in five participants (20.1% and 19.5%) did not believe that HIV could be transmitted through insertive or receptive anal sex, respectively. Risk behaviour is high and knowledge of HIV transmission methods was low among MSM in Kuala Lumpur. Future prevention efforts should focus on providing risk reduction education to this community.

Abstract: Five local Malaysian patients with clinical manifestations consistent with lymphatic filariasis were referred to our medical centre between 2003 and 2006. Although no microfilariae (mf) were detected in their nocturnal blood samples, all were diagnosed to have lymphatic filariasis on the basis of clinical findings and positive serology results. PCR on their blood samples revealed that two of the patients were infected with Brugia pahangi, an animal filarial worm hitherto not known to cause human disease in the natural environment. All the patients were successfully treated with anti-filarial drugs: four patients were treated with a combination of diethylcarbamazine (DEC) and albendazole, and one with doxycycline. Four of them were residents of Petaling Jaya, a residential suburbia located 10 km southwest of Kuala Lumpur city, Malaysia. The fifth patient was a frequent visitor of the suburbia. This suburbia has no history or record of B. malayi infection. The most likely vector of the worm was Armigeres subalbatus as extensive entomological surveys within the suburbia revealed only adult females of this mosquito species were infected with B. pahangi larvae. Wild monkeys caught in the suburbia were free from B. pahangi mf, but domestic cats were mf positive. This suggests that infected cats might be the source of the zoonotic infection in the suburbia. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Abstract: Amongst HIV patients with successful virological responses to antiretroviral therapy (ART), poor CD4(+) T-cell recovery is associated with low nadir CD4(+) T-cell counts and persistent immune activation. These factors might be influenced by dendritic cell (DC) function. Interferon-alpha-producing plasmacytoid DC and IL-12-producing myeloid DC were quantified by flow cytometry after stimulation with agonists to TLR7/8 (CL075) or TLR9 (CpG-ODN). These were compared between patients who achieved CD4(+) T-cell counts above or below 200 cells/mu L after 6 months on ART (High vs. Low groups). High Group patients had more DC producing interferon-alpha or IL-12 at Weeks 6 and 12 on ART than Low Group patients. The frequencies of cytokine-producing DC at Week 12 were directly correlated with CD4(+) T-cell counts at baseline and at Week 12. Patients with good recovery of CD4(+) T-cells had robust TLR-mediated interferon-alpha responses by plasmacytoid DC and IL-12 responses by myeloid DC during early ART (1-3 months). (C) 2011 Elsevier Inc. All rights reserved.

Abstract: Of 682 antiretroviral-naïve patients initiating antiretroviral therapy in a prospective, multicenter human immunodeficiency virus type 1 (HIV-1) drug resistance monitoring study involving 8 sites in Hong Kong, Malaysia, and Thailand, the prevalence of patients with ≥1 drug resistance mutation was 13.8%. Primary HIV drug resistance is emerging after rapid scaling-up of antiretroviral therapy use in Asia.

Abstract: Objectives: Chemokines influence the migration of leukocytes to secondary lymphoid tissue and sites of inflammation. In HIV patients, they are implicated in inflammatory complications of antiretroviral therapy (ART), notably Immune Reconstitution Disease (IRD) and Sensory Neuropathy (SN). However most chemokines have not been monitored as patients begin ART or correlated with IRD and SN. Methods: Plasma chemokine levels were assessed longitudinally using commercial ELISAs in 69 patients treated in Kuala Lumpur, Malaysia. Plasma was available at baseline and after 6, 12, 24 and 48 weeks on ART. Chemokine genotypes were assessed using allele-specific fluorescent probes. IRD were diagnosed in 15 patients. 30 patients were screened for SN using the ACTG BPNS tool after six months on ART. SN was detected in 8 patients. Results: Plasma CXCL10 levels decreased on ART compared to baseline (p = 0.002-0.0001), but remain higher than healthy controls (p <= 0.0001). The decline was clearer in patients without IRD. CCL5 levels rose on ART but remained similar to controls. CCL2 levels were higher in patients than controls after week 12. Plasma chemokine levels were not affected by CD4+ T-cell counts or any genotypes tested. Several patients with SN displayed higher CCL5 levels throughout therapy compared to patients without neuropathy. Levels of other chemokines and chemokine genotypes were not associated with SN. Conclusions: Chemokines are differentially affected by ART. CXCL10 and CCL5 may influence IRD and CCL5 warrants further investigation for an effect in SN. These trends are not influenced by chemokine genotypes investigated here.

Abstract: Objectives: Most HIV patients who experience Mycobacterium tuberculosis-associated immune restoration disease (TB IRD) display elevated interferon-gamma (IFN gamma) responses against mycobacterial antigens, but these can occur without an IRD. Recognition of mycobacteria-associated molecular patterns through toll-like receptors (TLRs) on dendritic cells and monocytes induces cytokine production. Here, we investigate TLR-induced responses in IRD. Design: Peripheral blood mononuclear cells (PBMCs) were collected at approximately weeks 0, 6, 12, 24 and 48 after antiretroviral therapy from five patients experiencing TB IRD, nine matched non-IRD patients and 15 healthy controls. Methods: IFNg production by PBMC stimulated with protein purified derivative (PPD) was assessed by ELISpot. TLR2 expression on myeloid dendritic cells (mDCs) and monocytes was assessed by flowcytometry. TNF alpha, IL-12p40 and IL-10 were measured by ELISA in 24-h cultures of PBMC with lipomannan (mycobacteria-derived TLR2 agonist). Results: TLR2 expression on mDC and monocytes was higher in patients than controls at baseline (P<0.005). TLR2 expression decreased to normal levels on mDC by week 12, but remained higher on monocytes at week 24 (P=0.02). At week 24, IRD patients showed higher IFNg responses to PPD (P=0.02), TLR2 expression on monocytes (P=0.006) and lipomannan-induced TNF alpha production (P=0.016) than non-IRD patients. Lipomannan-induced TNF alpha and IL-12p40 responses paralleled TB IRD in the patients with high TLR2 expression. IL-10 levels did not associate with IRD. Conclusion: TLR2-induced pro-inflammatory cytokines by dendritic cells or monocytes may contribute to the pathogenesis of mycobacterial IRD. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Abstract: HIV-1 CRF07_BC and CRF08_BC are closely related circulating recombinant forms (CRFs) with serious public health consequences in China. The temporal and spatial dynamics of these CRI's were determined by estimating their times of divergence, using phylogenetic and Bayesian coalescent methods. Studies of the timelines of CRF07_BC and CRF08_BC trace the expansion of these strains back their origins to Yunnan province. The present study highlights the relevance of incorporating evolutionary and molecular epidemiological analyses into an in-depth understanding of the genesis of HIV epidemic, providing information for determining regional and global public health policies, including future vaccine strategies. Crown Copyright (C) 2009 Published by Elsevier Ltd. All rights reserved.

Abstract: Objectives: Natural killer (NK) cell function was investigated in Malaysian HIV patients beginning antiretroviral therapy (ART) with advanced immunodeficiency. Some patients experienced immune restoration disease (IRD) presenting as exacerbations of pre-existing infections. Whilst most IRD are attributed to interferon-gamma (IFNγ) produced by T-cells, NK cells may also contribute. xD; xD;Methods: Blood leukocytes were collected prospectively from 100 HIV patients over 1 year on ART, plus 36 healthy controls. Eleven patients who experienced an IRD and 14 matched controls were assayed. Cells producing IFNγ were quantitated by ELISpot after stimulation with an NK target (K562 cells) or antigens from pathogens associated with the IRD. NK cell subsets, CD16 and perforin expression were determined by flow cytometry xD; xD;Results: NK cell IFNγ responses were lower in HIV patients at baseline (p<0.001), improved by Week 24 (p<0.01) but remained lower than uninfected controls (p<0.05). Proportions of CD56hi NK cells increased (p<0.01) above controls at Week 24. Perforin expression on these cells was higher than controls at baseline (p<0.01), but declined on ART. Proportions of CD56hl NK cells were similar in patients and controls throughout. IRD patients showed lower CD16 expression on CD56lo NK cells than non-IRD patients before treatment (p<0.05) xD; xD;Conclusions: NK cells profiles were restored on ART, but NK cell IFNγ production remained impaired. Low CD16 expression on CD56lo NK cells may mark a predisposition for an IRD.

Abstract: The published work on HIV in people who use drugs shows that the global burden of HIV infection in this group can he reduced. Concerted action by governments, multilateral organisations. health systems, and individuals could lead to enormous benefits for families, communities, and societies. We review the evidence and identify synergies between biomedical science, public health, and human rights. Cost-effective interventions, including needle and syringe exchange programmes, opioid substitution therapy, and expanded access to HIV treatment and care, are supported on public health and human rights grounds; however, only around 10% of people who use drugs worldwide are being reached. and far too many are imprisoned for minor offences or detained without trial. To change this situation will take commitment, advocacy, and political courage to advance the action agenda. Failure to do so will exacerbate the spread of HIV infection, undermine treatment programmes, and continue to expand prison populations with patients in need of care.

Abstract: Human enterovirus 71 (EV-71) is one of the major etiologic causes of hand, foot, and mouth disease (HFMD) among young children worldwide, with fatal instances of neurological complications becoming increasingly common. Global VP1 capsid sequences (n = 628) sampled over 4 decades were collected and subjected to comprehensive evolutionary analysis using a suite of phylogenetic and population genetic methods. We estimated that the common ancestor of human EV-71 likely emerged around 1941 (95% confidence interval [CI], 1929 to 1952), subsequently diverging into three genogroups: B, C, and the now extinct genogroup A. Genealogical analysis revealed that diverse lineages of genogroup B and C (subgenogroups B1 to B5 and C1 to C5) have each circulated cryptically in the human population for up to 5 years before causing large HFMD outbreaks, indicating the quiescent persistence of EV-71 in human populations. Estimated phylogenies showed a complex pattern of spatial structure within well-sampled subgenogroups, suggesting endemicity with occasional lineage migration among locations, such that past HFMD epidemics are unlikely to be linked to continuous transmission of a single strain of virus. In addition, rises in genetic diversity are correlated with the onset of epidemics, driven in part by the emergence of novel EV-71 subgenogroups. Using subgenogroup C1 as a model, we observe temporal strain replacement through time, and we investigate the evidence for positive selection at VP1 immunogenic sites. We discuss the consequences of the evolutionary dynamics of EV-71 for vaccine design and compare its phylodynamic behavior with that of influenza virus.

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Abstract: HIV-infected drug users have increased age-matched morbidity and mortality compared with HIV-infected people who do not use drugs. Substance-use disorders negatively affect the health of HIV-infected drug users, who also have frequent medical and psychiatric comorbidities that complicate HIV treatment and prevention. Evidence-based treatments are available for the management of substance-use disorders, mental illness, HIV and other infectious complications such as viral hepatitis and tuberculosis, and many non-HIV-associated comorbidities. Tuberculosis co-infection in HIV-infected drug users, including disease caused by drug-resistant strains, is acquired and transmitted as a consequence of inadequate prescription of antiretroviral therapy, poor adherence, and repeated interfaces with congregate settings such as prisons. Medication-assisted therapies provide the strongest evidence for HIV treatment and prevention efforts, yet are often not available where they are needed most. Antiretroviral therapy, when prescribed and adherence is at an optimum, improves health-related outcomes for HIV infection and many of its comorbidities, including tuberculosis, viral hepatitis, and renal and cardiovascular disease. Simultaneous clinical management of multiple comorbidities in HIV-infected drug users might result in complex pharmacokinetic drug interactions that must be adequately addressed Moreover, interventions to improve adherence to treatment, including integration of health services delivery, are needed. Multifaceted, interdisciplinary approaches are urgently needed to achieve parity in health outcomes in HIV-infected drug users

Abstract: Background: The aim of this study was to examine the relationship between trends in CD4 counts (slope) and HIV viral load (VL) after initiation of combination antiretroviral treatment (cART) in Asian patients in The TREAT Asia HIV Observational Database (TAHOD). Methods: Treatment-naive HIV-infected patients who started cART with three or more and had three or more CD4 count and HIV VL tests were included. CD4 count slopes were expressed as changes of cells per microliter per year. Predictors of CD4 count slopes from 6 months after initiation were assessed by random-effects linear regression models. Results: A total of 1676 patients (74% male) were included. The median time on cART was 4.2 years (IQR 2.5-5.8 years). In the final model, CD4 count slope was associated with age, concurrent HIV VL and CD4 count, disease stage, hepatitis B or C co-infection, and time since cART initiation. CD4 count continues to increase with HIV VL up to 20 000 copies/mL during 6-12 months after cART initiation. However, the HIV VL has to be controlled below 5 000, 4 000 and 500 copies/mL for the CD4 count slope to remain above 20 cells/microliter per year during 12-18, 18-24, and beyond 24 months after cART initiation. Conclusions: After cART initiation, CD4 counts continued to increase even when the concurrent HIV VL was detectable. However, HIV VL needed to be controlled at a lower level to maintain a positive CD4 count slope when cART continues. The effect on long-term outcomes through the possible development of HIV drug resistance remains uncertain.

Abstract: The published work on HIV in people who use drugs shows that the global burden of HIV infection in this group can he reduced. Concerted action by governments, multilateral organisations. health systems, and individuals could lead to enormous benefits for families, communities, and societies. We review the evidence and identify synergies between biomedical science, public health, and human rights. Cost-effective interventions, including needle and syringe exchange programmes, opioid substitution therapy, and expanded access to HIV treatment and care, are supported on public health and human rights grounds; however, only around 10% of people who use drugs worldwide are being reached. and far too many are imprisoned for minor offences or detained without trial. To change this situation will take commitment, advocacy, and political courage to advance the action agenda. Failure to do so will exacerbate the spread of HIV infection, undermine treatment programmes, and continue to expand prison populations with patients in need of care.

Abstract: In Malaysia, co-circulation of CRF01_AE and subtype B has resulted in the emergence of the second generation derivative; CRF33_01B in approximately 20% of its HIV-1 infected individuals. Our objective was to identify possible biological advantages that CRF33_01B possesses over its progenitors. Biological and molecular comparisons of CRF33_01B against its parental subtypes clearly show that CRF33_01B replicated better in activated whole peripheral blood mononuclear cells (PBMCs) and CD4+ T-lymphocytes, but not monocyte-derived macrophages (MDMs). Also, its acquired fitness was greater than CRF01_AE but not subtype B. Moreover, CRF33_01B has higher rate of apoptotic cell death and syncytia induction compared to subtype B. These adaptive and survival abilities could have been acquired by CRF33_01B due to the incorporation of subtype B fragments into the gag-RT region of its full-length genome. Our studies confirm the previously held belief that HIV-1 strains may harbor enhanced biological fitness upon recombination. We therefore estimate a possible gradual replacement of the current predominance of CRF01_AE, as well as wider dissemination of CRF33_01B, together with the identification of other new CRF01_AE/B inter-subtype recombinants in Malaysia.

Abstract: HIV-1 CRF07_BC and CRF08_BC are closely related circulating recombinant forms (CRFs) with serious public health consequences in China. The temporal and spatial dynamics of these CRI's were determined by estimating their times of divergence, using phylogenetic and Bayesian coalescent methods. Studies of the timelines of CRF07_BC and CRF08_BC trace the expansion of these strains back their origins to Yunnan province. The present study highlights the relevance of incorporating evolutionary and molecular epidemiological analyses into an in-depth understanding of the genesis of HIV epidemic, providing information for determining regional and global public health policies, including future vaccine strategies. Crown Copyright (C) 2009 Published by Elsevier Ltd. All rights reserved.

Abstract: HIV-infected prisoners face an inordinate number of community re-entry challenges. In 2007, 102 HIV-infected prisoners in Malaysia were surveyed anonymously within six months prior to release to assess the prevalence and correlates of community re-entry challenges. Staying out of prison (60.8%), remaining off drugs (39.2%), finding employment (35.3%) and obtaining HIV care (32.4%) were the re-entry challenges reported most frequently. Global stigma, negative self-image and public attitudes-related stigma were independently associated with challenges to obtaining HIV care. In multivariate analyses, those with previous incarcerations (adjusted odds ratio [AOR], 3.2; 95% confidence interval [CI], 1.4-7.6), higher HIV-related symptoms (AOR, 2.0; 95% CI, 1.0-4.1) and higher public attitudes-related stigma (AOR, 2.5; 95% CI, 1.2-5.1) had a significantly higher likelihood of identifying more re-entry challenges. Targeted interventions, such as effective drug treatment, HIV care and public awareness campaigns, are crucial for stemming the HIV epidemic and improving health outcomes among HIV-infected prisoners in Malaysia.

Abstract: A molecular epidemiological investigation conducted among injecting drug users in eastern Peninsular Malaysia in 2007 identified a cluster of sequences (n = 3) located outside any known HIV-1 genotype. Analyses of near full-length nucleotide sequences of these strains from individuals with no recognizable linkage revealed that they have an identical subtype structure comprised of CRF01_AE and subtype B', distinct from any known circulating recombinant forms (CRFs). This novel CRF, designated CRF48_01B, is closely related to CRF33_01B, previously identified in Kuala Lumpur. Phylogenetic analysis of multiple CRF48_01B genome regions showed that CRF48_01B forms a monophyletic cluster within CRF33_01B, suggesting that this new recombinant is very likely a descendant of CRF33_01B. CRF48_01B thus represents one of the first examples of a "second-generation'' CRF, generated by additional crossover with pre-existing CRFs. Corroborating these results, Bayesian molecular clock analyses indicated that CRF48_01B emerged in similar to 2001, approximately similar to 8 years after the emergence of CRF33_01B.

Abstract: Although drugs are haram and therefore prohibited in Islam, illicit drug use is widespread in many Islamic countries throughout the world. In the last several years increased prevalence of this problem has been observed in many of these countries which has in turn led to increasing injecting drug use driven HIV/AIDS epidemic across the Islamic world. Whilst some countries have recently responded to the threat through the implementation of harm reduction programmes, many others have been slow to respond. In Islam, The Quran and the Prophetic traditions or the Sunnah are the central sources of references for the laws and principles that guide the Muslims' way of life and by which policies and guidelines for responses including that of contemporary social and health problems can be derived. The preservation and protection of the dignity of man, and steering mankind away from harm and destruction are central to the teachings of Islam. When viewed through the Islamic principles of the preservation and protection of the faith, life, intellect, progeny and wealth, harm reduction programmes are permissible and in fact provide a practical solution to a problem that could result in far greater damage to the society at large if left unaddressed.

Abstract:

Abstract: Background: Sensory neuropathy (SN) is common in patients with HIV. Hepatitis C (HCV) coinfection is often cited as an HIV-SN risk factor, but data to support this are lacking. This collaboration aimed to examine the association between HCV serostatus and SN risk among ambulatory HIV-positive patients. Methods: Patients with HIV were assessed in cross-sectional studies in Baltimore, Jakarta, Johannesburg, Kuala Lumpur, Melbourne, and Sydney for SN (defined by both supportive symptoms and signs). HCV seropositivity was assessed as an SN risk using a chi(2) test, followed by logistic regression modeling to correct for treatment exposures and demographics. Results: A total of 837 patients of African, Asian, and Caucasian descent were studied. HCV seroprevalence varied by site (Baltimore n = 104, 61% HCV +; Jakarta 96, 51%; Johannesburg 300, 1%; Kuala Lumpur 97, 10%; Melbourne 206, 16%; Sydney 34, 18%). HCV seropositivity was not associated with increased SN risk at any site, but was associated with reduced SN risk in Melbourne (p = 0.003). On multivariate analyses, the independent associations with SN were increasing age, height, and stavudine exposure. HCV seropositivity was not independently associated with an increased SN risk at any site, but associated independently with reduced SN risk in Baltimore (p = 0.04) and Melbourne (p = 0.06). Conclusions: Hepatitis C (HCV) seropositivity was not associated with increased sensory neuropathy risk among HIV-positive patients at any site. While we were unable to assess HCV RNA or liver damage, the data suggest that HCV coinfection is not a major contributor to HIV-SN. Neurology (R) 2010;74:1538-1542

Abstract: Objective: To examine the association between HIV infection and psychiatric disorders among prisoners, where mental illness, substance abuse, and HIV are disproportionately represented. Design: Cross-sectional study. Methods: Using a sequential randomization scheme, 200 HIV-seropositive and 200 HIV-seronegative prisoners were selected for evaluation of psychiatric illnesses with the Structured Clinical Interview for Diagnostic Statistical Manual of Mental Disorders-IV (SCID-I). Results: The prevalence of mental illness and substance use disorders, particularly opioid dependence, was extremely high. HIV infection was significantly correlated with age, ethnicity, marital status, history of injection drug use, lifetime duration of incarceration, substance abuse, and polysubstance drug use. After controlling for potential confounders, HIV infection was significantly associated with non-substance-induced psychiatric disorders (AOR = 1.92; 95% CI: 1.03-3.59). While prisoners with a triple diagnosis (psychiatric disorders, substance use disorders, and HIV) spent 46.7 more cumulative lifetime months in prison than those with only a psychiatric diagnosis (p<.01), those with a dual diagnosis (psychiatric plus substance use disorders) were comparable to those with one psychiatric diagnosis only. Neither HIV infection nor triple diagnosis was associated with violent offenses. Conclusion: These findings suggest that a public health approach that simultaneously addresses psychiatric illnesses, substance abuse, and HIV infection is needed in both the correctional and the community settings in order to provide adequate care for triply-diagnosed patients and prevent them from returning to prison.

Abstract: Objectives Surrogate markers of HIV disease progression are HIV RNA in plasma viral load (VL) and CD4 cell count (immune function). Despite improved international access to antiretrovirals, surrogate marker diagnostics are not routinely available in resource-limited settings. Therefore, the objective was to assess effects of economic and diagnostic resourcing on patient treatment outcomes. Methods Analyses were based on 2333 patients initiating highly active antiretroviral therapy (HAART) from 2000 onwards. Sites were categorized by World Bank country income criteria (high/low) and annual frequency of VL (>= 3, 1-2 or < 1) or CD4 (>= 3 or < 3) testing. Endpoints were time to AIDS/death and change in CD4 cell count and VL suppression (< 400 HIV-1 RNA copies/mL) at 12 months. Demographics, Centers for Disease Control and Prevention (CDC) classification, baseline VL/CD4 cell counts, hepatitis B/C coinfections and HAART regimen were covariates. Time to AIDS/death was analysed by proportional hazards models. CD4 and VL endpoints were analysed using linear and logistic regression, respectively. Results Increased disease progression was associated with site-reported VL testing less than once per year [hazard ratio (HR)=1.4; P=0.032], severely symptomatic HIV infection (HR=1.4; P=0.003) and hepatitis C virus coinfection (HR=1.8; P=0.011). A total of 1120 patients (48.2%) had change in CD4 cell count data. Smaller increases were associated with older age (P < 0.001) and 'Other' HIV source exposures, including injecting drug use and blood products (P=0.043). A total of 785 patients (33.7%) contributed to the VL suppression analyses. Patients from sites with VL testing less than once per year [odds ratio (OR)=0.30; P < 0.001] and reporting 'Other' HIV exposures experienced reduced suppression (OR=0.28; P < 0.001). Conclusion Low measures of site resourcing were associated with less favourable patient outcomes, including a 35% increase in disease progression in patients from sites with VL testing less than once per year.

Abstract: Faced with a rising HIV epidemic among injecting drug users, harm reduction policies and programs were introduced in Malaysia in 2005. The positive impact seen since the introduction of these programs comprise the inclusion of the health aspects of illicit drug use in the country's drug policies; better access to antiretroviral therapy for injecting drug users who are HIV infected; reduction in HIV-risk behavior; and greater social benefits, including increased employment. Despite these achievements, tension between law enforcement and public health persists, as harm reduction exists alongside an overall drug policy that is based on abstinence and zero tolerance. Unless there is harmonization of this policy, sustainability and scale-up of harm reduction programs will remain a challenge.

Abstract: Background: To assess the risk and the prognostic significance of tuberculosis (TB) diagnosis in patients from The TREAT Asia HIV Observational Database, a multi-centre prospective cohort of HIV-infected patients receiving HIV care in the Asia-Pacific region. Methods: The risk of TB diagnosis after recruitment was assessed in patients with prospective follow-up. TB diagnosis was fitted as a time-dependent variable in assessing overall survival. Results: At baseline, 22% of patients were diagnosed with TB. TB incidence was 1.98 per 100 person-years during follow up, with predictors including younger age, lower recent CD4 count, duration of antiretroviral treatment, and living in high TB burden countries. Among 3279 patients during 6968 person-years, 142 died (2.04 per 100 person-years). Compared to patients with CDC category A or B illness only, mortality was marginally higher in patients with single Non-TB AIDS defining illness (ADI), or TB only (adjusted HR 1.35, p = 0.173) and highest in patients with multiple non-TB AIDS or both TB and other ADI (adjusted HR 2.21, p < 0.001). Conclusion: The risk of TB diagnosis was associated with increasing immunodeficiency and partly reduced by antiretroviral treatment. The prognosis of developing TB appeared to be similar to that following a diagnosis of other non-TB ADI.

Abstract: Objective: Sensory neuropathy is a common problem in HIV-infected patients and is the dose-limiting toxicity of stavudine. Affordable methods of predicting neuropathy risk are needed to guide prescribing in countries where some use of stavudine remains an economic necessity. We therefore aimed to identify factors predictive of neuropathy risk before antiretroviral use. Methods: A total of 294 patients attending clinics in Melbourne, Kuala Lumpur, and Jakarta were enrolled in a cross-sectional neuropathy screening program in 2006. Neuropathy was defined by the presence of symptoms and signs on the AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen. Demographic, laboratory, and treatment details were considered as possible risk factors for neuropathy. The role of patient demographics in predicting stavudine neuropathy were then assessed in 181 patients who reported that they were free of neuropathy symptoms when first prescribed this drug. Results: The prevalence of neuropathy was 42% in Melbourne (n = 100), 19% in Kuala Lumpur (n = 98), and 34% in Jakarta (n = 96). In addition to treatment exposures, increasing age (p = 0.002) and height (p = 0.001) were independently associated with neuropathy. Age and height cutoffs of >= 170 cm or >= 40 years predicted neuropathy. Among 181 patients who were asymptomatic before stavudine exposure, the risk of neuropathy following stavudine was 20% in younger, shorter patients, compared with 66% in older, taller individuals. Conclusions: Stavudine neuropathy risk increases with patient age and height. Prioritizing older and taller patients for alternative agents would be an inexpensive strategy to reduce neuropathy rates in countries where the burden of HIV disease limits treatment options. Neurology (R) 2009; 73: 315-320

Abstract: Background: Random effects models were used to explore how the shape of CD4 cell count responses after commencing combination antiretroviral therapy (cART) develop over time and, in particular, the role of baseline and follow-up covariates. Methods: Patients in Asia Pacific HIV Observational Database who first commenced cART after January 1, 1997, and who had a baseline CD4 cell count and viral load measure and at least I follow-up measure between 6 and 24 months, were included. CD4 cell counts were determined at every 6-month period after the commencement of cART for up to 6 years. Results: A total of 1638 patients fulfilled the inclusion criteria with a median follow-up time of 58 months. Lower post-cART mean CD4 cell counts were found to be associated with increasing age (P < 0.001), pre-cART hepatitis C coinfection (P = 0.038), prior AIDS (P = 0.019), baseline viral load <= 100,000 copies per milliliter (P < 0.001), and the Asia Pacific region compared with Australia (P = 0.005). A highly significant 3-way interaction between the effects of time, baseline CD4 cell count, and post-cART viral burden (P < 0.0001) was demonstrated. Higher long-term mean CD4 cell counts were associated with lower baseline CD4 cell count and consistently undetectable viral loads. Among patients with consistently detectable viral load, CD4 cell counts seemed to converge for all baseline CD4 levels. Conclusions: Our analyses Suggest that the long-term shape of post-cART CD4 cell count changes depends only on a 3-way interaction between baseline CD4 cell count, viral load response, and time.

Abstract: Despite a good public healthcare infrastructure and greater availability of antiretroviral drugs in Malaysia since 2005, the number of HIV-infected patients receiving treatment remains disproportionately small. Barriers to greater access include a lack of trained human resources to deliver antiretroviral therapy (ART) in a highly individualized and specialized model and, until recently, a lack of treatment for substance abuse in a predominantly injecting drug-use epidemic. However, one of the biggest barriers, and perhaps the most challenging to overcome, is the stigma and discrimination towards HIV-infected people, especially injecting drug users, which prevented many from accessing treatment and care. Increasing and improved access to ART for HIV-infected patients will entail a multipronged strategy that includes the decentralization of clinical care, increased and ongoing training of healthcare workers and support staff, and a comprehensive and intensive effort to reduce stigma and discrimination. Creation of an enabling environment through public education and a well-trained and nonprejudicial healthcare work force, coupled with policy and legal reforms, are essential in ensuring a greater and sustainable access to ART for all.

Abstract: Background: The clinical profile and outcome of nosocomial and non-nosocomial health care-associated native valve endocarditis are not well defined. Objective: To compare the characteristics and outcomes of community-associated and nosocomial and non-nosocomial health care-associated native valve endocarditis. Design: Prospective cohort study. Setting: 61 hospitals in 28 countries. Patients: Patients with definite native valve endocarditis and no history of injection drug use who were enrolled in the ICE-PCS (International Collaboration on Endocarditis Prospective Cohort Study) from June 2000 to August 2005. Measurements: Clinical and echocardiographic findings, microbiology, complications, and mortality. Results: Health care-associated native valve endocarditis was present in 557 (34%) of 1622 patients (303 with nosocomial infection [54%] and 254 with non-nosocomial infection [46%]). Staphylococcus aureus was the most common cause of health care-associated infection (nosocomial, 47%; non-nosocomial, 42%; P = 0.30); a high proportion of patients had methicillin-resistant S. aureus (nosocomial, 57%; non-nosocomial, 41%; P = 0.014). Fewer patients with health care-associated native valve endocarditis had cardiac surgery (41% vs. 51% of community-associated cases; P < 0.001), but more of the former patients died (25% vs. 13%; P < 0.001). Multivariable analysis confirmed greater mortality associated with health care-associated native valve endocarditis (incidence risk ratio, 1.28 [95% CI, 1.02 to 1.59]). Limitations: Patients were treated at hospitals with cardiac surgery programs. The results may not be generalizable to patients receiving care in other types of facilities or to those with prosthetic valves or past injection drug use. Conclusion: More than one third of cases of native valve endocarditis in non-injection drug users involve contact with health care, and non-nosocomial infection is common, especially in the United States. Clinicians should recognize that outpatients with extensive out-of-hospital health care contacts who develop endocarditis have clinical characteristics and outcomes similar to those of patients with nosocomial infection. Primary Funding Source: None.

Abstract: Over the past decade, a number of unique zoonotic and non-zoonotic viruses have emerged in Malaysia. Several of these viruses have resulted in significant morbidity and mortality to those affected and they have imposed a tremendous public health and economic burden on the state. Amongst the most devastating was the outbreak of Nipah virus encephalitis in 1998, which resulted in 109 deaths. The culling of more than a million pigs, identified as the amplifying host, ultimately brought the outbreak under control. A year prior to this, and subsequently again in 2000 and 2003, large outbreaks of hand-foot-and-mouth disease due to enterovirus 71, with rare cases of fatal neurological complications, were reported in young children. Three other new viruses - Tioman virus (1999), Pulau virus (1999), and Melaka virus (2006) - whose origins have all been linked to bats, have been added to the growing list of novel viruses being discovered in Malaysia. The highly pathogenic H5N1 avian influenza has also been detected in Malaysia with outbreaks in poultry in 2004, 2006, and 2007. Fortunately, no human infections were reported. Finally, the HIV/AIDS epidemic has seen the emergence of an HIV-1 recombinant form (CRF33_01B) in HIV-infected individuals from various risk groups, with evidence of ongoing and rapid expansion.

Abstract: HIV is capable of frequent genetic exchange through recombination. Despite the pandemic spread of HIV-1 recombinants, their times of origin are not well understood. We investigate the epidemic history of a HIV-1 circulating recombinant form (CRF) by estimating the time of the recombination event that lead to the emergence of CRF33_01B, a recently described recombinant descended from CRF01_AE and subtype B. The gag, pol and env genes were analyzed using a combined coalescent and relaxed molecular clock model, implemented in a Bayesian Markov chain Monte Carlo framework. Using linked genealogical trees we calculated the time interval between the common ancestor of CRF33_01B and the ancestors it shares with closely related parental lineages. The recombination event that generated CRF33_01B (t(rec)) occurred sometime between 1991 and 1993, suggesting that recombination is common in the early evolutionary history of HIV-1. The proof-of-concept approach provides a new tool for the investigation of HIV molecular epidemiology and evolution. (C) 2009 Elsevier Inc. All rights reserved.

Abstract: Background: Diversion of buprenorphine (BPN) has been described in settings where it is legally prescribed and has resulted in increasing concern. To address this concern, co-formulation of buprenorphine/naloxone (BPN/NLX) replaced buprenorphine alone in Malaysia in December 2006. Methods: To assess the significance of BPN/NLX introduction, 41 BPN/NLX injectors in Kuala Lumpur, Malaysia were recruited using a modified snowball recruitment technique. Results: In January 2007, all subjects had previously injected BPN alone. During the transition from injecting BPN alone to co-formulated BPN/NLX, the mean daily BPN injection dose increased from 1.88 mg (range 1.0-4.0 mg) to 2.49 mg/day (p .001). Overall, 18 (44%) subjects increased their daily amount of injection while 22 (54%) had no change in dose; only one subject reduced the amount of injection. Development of opioid withdrawal symptoms was the primary outcome, however the only symptom that was significantly associated with BPN/NLX dosage was the report of stomach pains (p = .01). In logistic regression analysis, the development of opioid withdrawal symptoms was associated with increased benzodiazepine injection and increased syringe sharing. Conclusion and Scientific Significance: These data suggests that the introduction of BPN/NLX did not reduce injection related risk behaviors such as syringe sharing and was associated with increased benzodiazepine use. Evidence-based approaches to treat BPN injection are urgently needed.

Abstract: Background: The clinical profile and outcome of nosocomial and non-nosocomial health care-associated native valve endocarditis are not well defined. Objective: To compare the characteristics and outcomes of community-associated and nosocomial and non-nosocomial health care-associated native valve endocarditis. Design: Prospective cohort study. Setting: 61 hospitals in 28 countries. Patients: Patients with definite native valve endocarditis and no history of injection drug use who were enrolled in the ICE-PCS (International Collaboration on Endocarditis Prospective Cohort Study) from June 2000 to August 2005. Measurements: Clinical and echocardiographic findings, microbiology, complications, and mortality. Results: Health care-associated native valve endocarditis was present in 557 (34%) of 1622 patients (303 with nosocomial infection [54%] and 254 with non-nosocomial infection [46%]). Staphylococcus aureus was the most common cause of health care-associated infection (nosocomial, 47%; non-nosocomial, 42%; P = 0.30); a high proportion of patients had methicillin-resistant S. aureus (nosocomial, 57%; non-nosocomial, 41%; P = 0.014). Fewer patients with health care-associated native valve endocarditis had cardiac surgery (41% vs. 51% of community-associated cases; P < 0.001), but more of the former patients died (25% vs. 13%; P < 0.001). Multivariable analysis confirmed greater mortality associated with health care-associated native valve endocarditis (incidence risk ratio, 1.28 [95% CI, 1.02 to 1.59]). Limitations: Patients were treated at hospitals with cardiac surgery programs. The results may not be generalizable to patients receiving care in other types of facilities or to those with prosthetic valves or past injection drug use. Conclusion: More than one third of cases of native valve endocarditis in non-injection drug users involve contact with health care, and non-nosocomial infection is common, especially in the United States. Clinicians should recognize that outpatients with extensive out-of-hospital health care contacts who develop endocarditis have clinical characteristics and outcomes similar to those of patients with nosocomial infection. Primary Funding Source: None.

Abstract: Background: To assess the risk and the prognostic significance of tuberculosis (TB) diagnosis in patients from The TREAT Asia HIV Observational Database, a multi-centre prospective cohort of HIV-infected patients receiving HIV care in the Asia-Pacific region. Methods: The risk of TB diagnosis after recruitment was assessed in patients with prospective follow-up. TB diagnosis was fitted as a time-dependent variable in assessing overall survival. Results: At baseline, 22% of patients were diagnosed with TB. TB incidence was 1.98 per 100 person-years during follow up, with predictors including younger age, lower recent CD4 count, duration of antiretroviral treatment, and living in high TB burden countries. Among 3279 patients during 6968 person-years, 142 died (2.04 per 100 person-years). Compared to patients with CDC category A or B illness only, mortality was marginally higher in patients with single Non-TB AIDS defining illness (ADI), or TB only (adjusted HR 1.35, p = 0.173) and highest in patients with multiple non-TB AIDS or both TB and other ADI (adjusted HR 2.21, p < 0.001). Conclusion: The risk of TB diagnosis was associated with increasing immunodeficiency and partly reduced by antiretroviral treatment. The prognosis of developing TB appeared to be similar to that following a diagnosis of other non-TB ADI.

Abstract: Objective. The aim of our study was to develop, on the basis of simple clinical data, predictive short-term risk equations for AIDS or death in Asian patients infected with human immunodeficiency virus (HIV) who were included in the TREAT Asia HIV Observational Database. Methods. Inclusion criteria were highly active antiretroviral therapy initiation and completion of required laboratory tests. Predictors of short-term AIDS or death were assessed using Poisson regression. Three different models were developed: a clinical model, a CD4 cell count model, and a CD4 cell count and HIV RNA level model. We separated patients into low-risk, high-risk, and very high-risk groups according to the key risk factors identified. Results. In the clinical model, patients with severe anemia or a body mass index (BMI; calculated as the weight in kilograms divided by the square of the height in meters) <= 18 were at very high risk, and patients who were aged ! 40 years or were male and had mild anemia were at high risk. In the CD4 cell count model, patients with a CD4 cell count <50 cells/mu L, severe anemia, or a BMI <= 18 were at very high risk, and patients who had a CD4 cell count of 51-200 cells/mu L, were aged ! 40 years, or were male and had mild anemia were at high risk. In the CD4 cell count and HIV RNA level model, patients with a CD4 cell count <50 cells/mu L, a detectable viral load, severe anemia, or a BMI similar to 18 were at very high risk, and patients with a CD4 cell count of 51-200 cells/mu L and mild anemia were at high risk. The incidence of new AIDS or death in the clinical model was 1.3, 4.9, and 15.6 events per 100 person-years in the low-risk, high-risk, and very high-risk groups, respectively. In the CD4 cell count model the respective incidences were 0.9, 2.7, and 16.02 events per 100 person-years; in the CD4 cell count and HIV RNA level model, the respective incidences were 0.8, 1.8, and 6.2 events per 100 person-years. Conclusions. These models are simple enough for widespread use in busy clinics and should allow clinicians to identify patients who are at high risk of AIDS or death in Asia and the Pacific region and in resource-poor settings.

Abstract: A growing number of emerging HIV-1 recombinants classified as circulating recombinant forms (CRFs) have been identified in Southeast Asia in recent years, establishing a molecular diversity of increasing complexity in the region. Here, we constructed a replication-competent HIV-1 clone for CRF33_01B (designated p05MYKL045.1), a newly identified recombinant comprised of CRF01_AE and subtype B. p05MYKL045.1 was reconstituted by cloning of the near full-length HIV-1 sequence from a newly-diagnosed individual presumably infected heterosexually in Kuala Lumpur, Malaysia. The chimeric clone, which contains the 59 LTR (long terminal repeat) region of p93JP-NH1 (a previously isolated CRF01_AE infectious clone), showed robust viral replication in the human peripheral blood mononuclear cells. This clone demonstrated robust viral propagation and profound syncytium formation in CD4(+), CXCR4-expressing human glioma NP-2 cells, indicating that p05MYKL045.1 is a CXCR4-using virus. Viral propagation, however, was not detected in various human T cell lines including MT-2, M8166, Sup-T1, H9, Jurkat, Molt-4 and PM1.p05MYKL045.1 appears to proliferate only in restricted host range, suggesting that unknown viral and/or cellular host factors may play a role in viral infectivity and replication in human T cell lines. Availability of a CRF33_01B molecular clone will be useful in facilitating the development of vaccine candidates that match the HIV-1 strains circulating in Southeast Asia.

Abstract: Diversion of buprenorphine has been described in settings where it is legally prescribed and has become an increasing concern in Malaysia; it resulted in banning of buprenorphine in Singapore where unsubstantiated case reports suggested that buprenorphine injection was associated with particularly poor outcomes. We therefore conducted a case series of qualitative interviews with buprenorphine injectors in Kuala Lumpur, Malaysia to examine further the issues surrounding buprenorphine injection as well as the abuse of midazolam in combination with buprenorphine. Interviews with 19 men do not suggest significant adverse health consequences from buprenorphine injection alone and injectors have adapted diverted buprenorphine as a treatment modality. A subset of these injectors, however, combined buprenorphine and midazolam for euphoric effects with resultant symptoms of a possible pharmacological interaction. Prospective cohort studies, rather than hospital-derived samples, are needed to better understand the safety of buprenorphine injection.

Abstract: Background: A total of 8.3 million HIV-positive people live in the Asia-Pacific region. The burden of HIV-associated neurocognitive impairment and symptomatic sensory neuropathy in this region is unknown. Methods: Between July 2005 and March 2006, we undertook a cross-sectional study at 10 sentinel sites within eight Asia-Pacific countries to determine the prevalence of moderate to severe HIV-related neurocognitive impairment and symptomatic sensory neuropathy. We clinically assessed and administered sensitive neuropsychological and peripheral neuropathy screening tools to 658 patients infected with HIV. Univariate and logistic regression analyses were applied to the data. Results: The results showed that 76 patients (11.7%) (95% CI 9.3-14.2) were significantly neurocognitively impaired, 235 patients (36.4%) (95% CI 32.7-40.2) were depressed, and 126 patients (19.7%) (95% CI 16.6-22.8) had either definite or probable symptomatic sensory neuropathy; 63% of this last group had exposure to stavudine, didanosine, or zalcitabine. Several potential confounders including depression (OR 1.49, 95% CI 0.88-2.51, p = 0.11) and prior CNS AIDS illness (OR 1.28, 95% CI 0.50-2.89, p = 0.54) were not significantly associated with neurocognitive impairment. Conclusions: A total of 12% of patients had moderate to severe HIV-related neurocognitive impairment, 20% of patients had symptomatic sensory neuropathy, and 36% of patients had evidence of depression. This study provides a broad regional estimate of the burden of HIV-related neurologic disease and depression in the Asia-Pacific region.

Abstract: The Asian HIV epidemic appears to be complex, characterized by the prevalence of multiple subtypes and circulating recombinant forms with gradual replacement of pure HIV-1 subtypes in several geographical regions. The main objectives of the present study are to identify and analyse the full-length viral genomes of three unique recombinant forms (URFs); the HIV-1 isolates 07MYKLD47, 07MYKLD48 and 07MYKLD49 from Malaysia. Long-range polymerase chain reaction (PCR) amplification of seven overlapping reading frames was used to derive near full-length HIV-1 genomes. Detailed phylogenetic and bootscanning analyses were performed to determine phylogenetic associations and subtypic assignments. We further confirmed the mosaic composition of these CRF01_AE/B inter-subtype recombinant forms, which are composed of B-subtype fragment(s) in the backbone of CRF01_AE. Both 07MYKLD47 and 07MYKLD48 have an insertion of B subtype (880 bp and 532 bp) in the gag-pol and gp41-env gene regions, respectively. Whereas the isolate 07MYKLD49 has three B-subtype fragments inserted in different gene region along the genome; one each in the gag-pol (1862 bp) and pol-vif (1935 bp) regions, and a short B-subtype insertion (541 bp) in the 5' LTR-gag region. This highlights the public health relevance of newly emerging second generation HIV-1 recombinant forms and their dispersal, along with their rapid and continuous evolution in the region.

Abstract: The published work on HIV in people who use drugs shows that the global burden of HIV infection in this group can be reduced. Concerted action by governments, multilateral organisations, health systems, and individuals could lead to enormous benefits for families, communities, and societies. We review the evidence and identify synergies between biomedical science, public health, and human rights. Cost-effective interventions, including needle and syringe exchange programmes, opioid substitution therapy, and expanded access to HIV treatment and care, are supported on public health and human rights grounds; however, only around 10% of people who use drugs worldwide are being reached, and far too many are imprisoned for minor offences or detained without trial. To change this situation will take commitment, advocacy, and political courage to advance the action agenda. Failure to do so will exacerbate the spread of HIV infection, undermine treatment programmes, and continue to expand prison populations with patients in need of care.

Abstract: Human immunodeficiency virus type 1 (HIV-1) CRF08_BC and CRF07_BC are two major recombinants descended from subtypes B ' and C. Despite their massive epidemic impact in China, their migration patterns and divergence times remain unknown. Phylogenetic and population genetic analyses were performed on 228 HIV-1 sequences representing CRF08_BC, CRF07_BC, and subtype C strains from different locations across China, India, and Myanmar. Genome-specific rates of evolution and divergence times were estimated using a Bayesian Markov chain Monte Carlo framework under various evolutionary models. CRF08_BC originated in 1990.3 (95% credible region [CR], 1988.6 to 1991.9) in Yunnan province before spreading to Guangxi (south) and Liaoning (northeast) around 1995. Inside Guangxi region, the eastward expansion of CRF08_BC continued from Baise city (west) to Binyang (central) between 1997 and 1998 and later spread into Pingxiang around 1999 in the south, mainly through injecting drug users. Additionally, CRF07_BC diverged from its common ancestor in 1993.3 (95% CR, 1991.2 to 1995.2) before crossing the border into southern Taiwan in late 1990s. Phylogenetic analysis indicates that both CRF08_BC and CRF07_BC can trace their origins to Yunnan. The parental Indian subtype C lineage likely entered China around 1981.2 (95% CR, 1976.7 to 1985.9). Using a multiple unlinked locus model, we also showed that the dates of divergence calculated in this study may not be significantly affected by intrasubtype recombination among different lineages. This is the first phylodynamic study depicting the spatiotemporal dynamics of HIV/AIDS in East Asia.

Abstract: The HIV-1 epidemic among injecting drug users (IDU) in Taiwan is caused primarily by CRF07_BC infections. Evolutionary analyses, which utilize outgroup reference strains from northwestern China (Xinjiang), reveal that CRF07_BC was introduced into southern Taiwan in 1998-2001 and spread to central-northern Taiwan in 2001-2003, causing the largest HIV/AIDS epidemic in Taiwan. The separate introduction of CRF07_BC into Xinjiang occurred in 1992-1995. This study illustrates the temporal dynamics of CRF07_BC spread among IDU across east Asia.

Abstract: Objectives A proportion of HIV patients beginning antiretroviral therapy (ART) develop immune restoration disease (IRD). Immunological characteristics of IRD were investigated in a cohort of HIV patients beginning therapy in Kuala Lumpur, Malaysia. Methods Peripheral blood mononuclear cells were collected at weeks 0, 6, 12, 24 and 48 of ART from five patients experiencing IRD [two with cryptococcal and three with Mycobacterium tuberculosis (Mtb) disease], eight non-IRD controls who had begun ART with CD4 T-cell counts of < 100 cells/mu L and 17 healthy controls. Leukocytes producing interferon-gamma (IFN gamma) were quantified by enzyme-linked immunospot assay after stimulation with purified protein derivative (PPD), early secretory antigenic target-6 (ESAT-6), Cryptococcus neoformans or Cytomegalovirus antigens. Plasma immunoglobulin (IgG) antibodies reactive with these antigens were assessed by enzyme-linked immunosorbent assay. Proportions of activated (HLA-DRhi) and regulatory (CD25 CD127(lo) and CTLA-4(+)) CD4 T-cells were quantified by flow cytometry. Results Plasma HIV RNA declined and CD4 T-cell counts rose within 8-27 weeks on ART. Mtb IRD patients displayed elevated IFN gamma responses and/or plasma IgG to PPD, but none responded to ESAT-6. Cryptococcal IRD occurred in patients with low baseline CD4 T-cell counts and involved clear IFN gamma and antibody responses to cryptococcal antigen. Proportions of activated and regulatory CD4 T-cells declined on ART, but remained higher in patients than in healthy controls. At the time of IRD, proportions of activated CD4 T-cells and regulatory CD4 T-cells were generally elevated relative to other patients. Conclusions Cryptococcal and Mtb IRD generally coincide with peaks in the proportion of activated T-cells, pathogen-specific IFN gamma responses and reactive plasma IgG. IRD does not reflect a paucity of regulatory CD4 T-cells.

Abstract: Background: A total of 8.3 million HIV-positive people live in the Asia-Pacific region. The burden of HIV-associated neurocognitive impairment and symptomatic sensory neuropathy in this region is unknown. Methods: Between July 2005 and March 2006, we undertook a cross-sectional study at 10 sentinel sites within eight Asia-Pacific countries to determine the prevalence of moderate to severe HIV-related neurocognitive impairment and symptomatic sensory neuropathy. We clinically assessed and administered sensitive neuropsychological and peripheral neuropathy screening tools to 658 patients infected with HIV. Univariate and logistic regression analyses were applied to the data. Results: The results showed that 76 patients (11.7%) (95% CI 9.3-14.2) were significantly neurocognitively impaired, 235 patients (36.4%) (95% CI 32.7-40.2) were depressed, and 126 patients (19.7%) (95% CI 16.6-22.8) had either definite or probable symptomatic sensory neuropathy; 63% of this last group had exposure to stavudine, didanosine, or zalcitabine. Several potential confounders including depression (OR 1.49, 95% CI 0.88-2.51, p = 0.11) and prior CNS AIDS illness (OR 1.28, 95% CI 0.50-2.89, p = 0.54) were not significantly associated with neurocognitive impairment. Conclusions: A total of 12% of patients had moderate to severe HIV-related neurocognitive impairment, 20% of patients had symptomatic sensory neuropathy, and 36% of patients had evidence of depression. This study provides a broad regional estimate of the burden of HIV-related neurologic disease and depression in the Asia-Pacific region.

Abstract: Human immunodeficiency virus type 1 (HIV-1) CRF08_BC and CRF07_BC are two major recombinants descended from subtypes B ' and C. Despite their massive epidemic impact in China, their migration patterns and divergence times remain unknown. Phylogenetic and population genetic analyses were performed on 228 HIV-1 sequences representing CRF08_BC, CRF07_BC, and subtype C strains from different locations across China, India, and Myanmar. Genome-specific rates of evolution and divergence times were estimated using a Bayesian Markov chain Monte Carlo framework under various evolutionary models. CRF08_BC originated in 1990.3 (95% credible region [CR], 1988.6 to 1991.9) in Yunnan province before spreading to Guangxi (south) and Liaoning (northeast) around 1995. Inside Guangxi region, the eastward expansion of CRF08_BC continued from Baise city (west) to Binyang (central) between 1997 and 1998 and later spread into Pingxiang around 1999 in the south, mainly through injecting drug users. Additionally, CRF07_BC diverged from its common ancestor in 1993.3 (95% CR, 1991.2 to 1995.2) before crossing the border into southern Taiwan in late 1990s. Phylogenetic analysis indicates that both CRF08_BC and CRF07_BC can trace their origins to Yunnan. The parental Indian subtype C lineage likely entered China around 1981.2 (95% CR, 1976.7 to 1985.9). Using a multiple unlinked locus model, we also showed that the dates of divergence calculated in this study may not be significantly affected by intrasubtype recombination among different lineages. This is the first phylodynamic study depicting the spatiotemporal dynamics of HIV/AIDS in East Asia.

Abstract: The HIV protease-reverse transcriptase (PR-RT) (1047 bp), gp120-env (891 bp) and gp41-env (547 bp) regions from the plasma of 115 HIV-1-infected patients in Kuala Lumpur (KL), Malaysia were sequenced. Detailed phylogenetic and bootscanning analyses were performed to determine the mosaic structure of the HIV-1 strains and their recombination breakpoint(s). Among the 50 patient samples in which all three regions could be amplified, the HIV-1 CRF0 1_AE subtype (46%) was predominant followed by subtypes B (10%) and B' (6%). A total of 9/50 (18%) patients were infected with a CR-F01_AE/B inter-subtype recombinant, displaying a recombinant form (RF) PR-RT, CPF01__AE(gp120-env) and CRF01_AE(gp41-evn). This RF was derived from the Thai variants of CRF01_AE and B' subtype, with two distinct B' subtype segments in the backbone of CRF01_AE, similar to the newly identified CRF33-01 B. In addition, one sample demonstrated a close structural relationship with the new CRF33_01B in the PR-RT region but displayed B' segment in part of the env region (RFPR-RT, CRF01_AE/B'(gp120-env)) and B'(gp41-env)) indicating continuing evolution of CRF33_01B. The remaining 18% of samples were identified as unique recombinant forms (URFs). (c) 2007 Elsevier Inc. All rights reserved.

Abstract: A new HIV-1 circulating recombinant form (CRF), CRF33_01B, has been identified in Malaysia. Concurrently we found a unique recombinant form (URF), that is, the HIV-1 isolate 06MYKLD46, in Kuala Lumpur, Malaysia. It is composed of B or a Thai variant of the B subtype (B') and CRF01_AE. Here, we determined the near full-length genome of the isolate 06MYKLD46 and performed detailed phylogenetic and bootscanning analyses to characterize its mosaic composition and to further confirm the subtype assignments. Although the majority of the 06MYKLD46 genome is CRF01_AE, we found three short fragments of B or B' subtype inserted along the genome. These B or B' subtype regions were 716 and 335 bp, respectively, in the protease-reverse transcriptase (PR-RT) region, similar to those found in CRF33_01B, as well as an extra 590 bp in the env gene region. Thus we suggest that 06MYKLD46 is a possible second-generation HIV-1 recombinant derived from CRF33_01B.

Abstract: Background The antiretroviral treatment (ART) combination of stavudine, lamivudine and nevirapine (d4T/3TC/NVP) is the most frequently used initial regimen in many Asian countries. There are few data on the outcome of this treatment in clinic cohorts in this region. Methods We selected patients from the TREAT Asia HIV Observational Database (TAHOD) who started their first ART regimen with d4T/3TC/NVP. Treatment change was defined as cessation of therapy or the addition or change of one or more drugs. Clinical failure was defined as diagnosis with an AIDS-defining illness, or death while on d4T/3TC/NVP treatment. Results The rate of treatment change among TAHOD patients starting d4T/3TC/NVP as their first antiretroviral treatment was 22.3 per 100 person-years, with lower baseline haemoglobin (i.e. anaemia) associated with slower rate of treatment change. The rate of clinical failure while on d4T/3TC/NVP treatment was 7.3 per 100 person-years, with baseline CD4 cell count significantly associated with clinical failure. After d4T/3TC/NVP was stopped, nearly 40% of patients did not restart any treatment and, of those who changed to other treatment, the majority changed to zidovudine (ZDV)/3TC/NVP and less than 3% of patients changed to a protease inhibitor (PI)-containing regimen. The rates of disease progression on the second-line regimen were similar to those on the first-line regimen. Conclusion These real-life data provide an insight into clinical practice in Asia and the Pacific region. d4T/3TC/NVP is maintained longer than other first-line regimens and change is mainly as a result of adverse effects rather than clinical failure. There is a need to develop affordable second-line antiretroviral treatment options for patients with HIV infection in developing countries.

Abstract: Objective: To examine the relationships between blood CD4 natural regulatory T (T-reg) cells, plasma HIV RNA level, CD4 T-cell count and immune activation in untreated HIV-infected patients and immunodeficient patients beginning antiretroviral therapy (ART), using a novel phenotype to define Treg cells (CD25CD127(lo)CD4). Data were compared with established T-reg cell markers (FoxP3, CTLA-4 and GITR). Methods: Twenty-nine untreated HIV-infected patients with CD4 T-cell counts of < 300 or > 400/mu l were compared in a cross-sectional study and 12 patients beginning combination ART with < 100 CD4 T cells/mu l were followed for 1 year on therapy. Three- and four-colour flow cytometry was used to quantitate proportions of Treg cells. Results: In control donors and patients with high CD4 T-cell counts, 28-89% (median 60%) of CD25CD127(lo)CD4 cells were FoxP3, but < 10% expressed GITR or CTLA-4. Immunodeficient patients also had CD4-negative lymphocytes with the phenotype FoxP3CD127(lo). Proportions of CD25CD127(lo) cells and activated (HLA-DRhi) cells in the CD4 T-cell population were increased in patients with low CD4 T cell counts. The proportion of CD25CD127(lo)CD4 T cells correlated positively with plasma HIV RNA level and CD4 T-cell activation, but inversely with CD4 T-cell count. Longitudinal studies of 12 patients receiving ART in two distinct cohorts (Western Australia and Malaysia) showed that the proportion of CD25CD127(lo)CD4 cells decreased slightly over time, but remained above levels seen in non-HIV controls. Conclusions: Proportions of circulating T cells with a regulatory cell phenotype increase with HIV-associated immune activation and remain high after I year on ART. (c) 2007 Lippincott Williams & Wilkins.

Abstract: Injection drug use (IDU) plays a critical role in the HIV epidemic in several countries throughout the world. In these countries, injection drug users are at significant risk for both HIV and tuberculosis, and active IDU negatively impacts treatment access, adherence and retention. Comprehensive strategies are therefore needed to effectively deliver preventive, diagnostic and curative services to these complex patient populations. We propose that developing co-located integrated care delivery systems should become the focus of national programmes as they continue to scale-up access to antiretroviral medications for drug users. Existing data suggest that such a programme will expand services for each of these diseases; increase detection of tuberculosis (TB) and HIV; improve medication adherence; increase entry into substance use treatment; decrease the likelihood of adverse drug events; and improve the effectiveness of prevention interventions. Key aspects of integration programmes include: co-location of services convenient to the patient; provision of effective substance use treatment, including pharmacotherapies; cross-training of generalist and specialist care providers; and provision of enhanced monitoring of drug-drug interactions and adverse side effects. Central to implementing this agenda will be fostering the political will to fund infrastructure and service delivery, expanding street-level outreach to IDUs, and training community health workers capable of cost effectively delivering these services. (C) 2007 Elsevier B.V. All rights reserved.

Abstract: Harm reduction, including needle exchange and opioid substitution therapy, has been demonstrated to reduce high-risk behavior and HIV infection among injection drug users. An increasing number of countries in the Middle East, North Africa, and Asia, including those with Muslim majorities, have experienced or are at risk for HIV epidemics initiated by burgeoning injection drug use. Although use of intoxicants is expressly forbidden within Islam, the local culture impacts the interpretation of Islamic law and influences the response to drug misuse, whether punitive or therapeutic. Harm reduction programming has received varying acceptance within this global region, which may be reflected by national trends in HIV prevalence. The purpose of this paper is to examine cultural and religious response to injecting drug use and associated HIV prevalence trends in Malaysia and Iran, with possible application of lessons learned to an emerging situation in Afghanistan.

Abstract: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus which causes fever, rash, and arthralgia. In the past, life-threatening complications were very rarely reported. However, during the recent worldwide outbreaks, there have been several reports of unusually severe complications and deaths. Malaysia is experiencing a nationwide outbreak of CHIKV, with over 10 000 patients affected since April 2008. We report the first case of culture-confirmed CHIKV-associated death in Malaysia, in a patient with fever, rash, acute exacerbation of pre-existing heart failure, rhabdomyolysis, and multiple organ failure. CHIKV infections may cause atypical, severe or fatal presentations.

Abstract: In Malaysia the response to illicit drug use has been largely punitive with the current goal of the Malaysian government being to achieve a drug-free society by 2015. This paper outlines the results of a desk-based situation assessment conducted over a 3-week period in 2004. Additional events, examined in 2005, were also included to describe more recent policy developments and examine how these came about. Despite punitive drug policy there has been a substantial rise in the number of drug users in the country. Over two-thirds of HIV/AIDS cases are among injecting drug users (IDUs) and there has been an exponential rise in the number of cases reported. Further, data suggest high risk drug use practices are widespread. Harm reduction initiatives have only recently been introduced in Malaysia. The successful piloting of substitution therapies, in particular methadone and buprenorphine, is cause for genuine hope for the rapid development of such interventions. In 2005 the government announced it will allow methadone maintenance programmes to operate beyond the pilot phase and needle and syringe exchange programmes will be established to serve the needs of IDUs. (C) 2007 Elsevier B.V All rights reserved.

Abstract: To assess the prevalence of major drug resistance mutations in antiretroviral (ARV)-treated patients with detectable viral load (VL) in Kuala Lumpur, Malaysia, genotypic resistance testing was performed among treated human immunodeficiency virus type 1 (HIV-1) patients attending the University Malaya Medical Center between July 2003 and November 2004. The reverse transcriptase (RT) and protease genes from 36 plasma samples with detectable VL were examined for major mutations associated with ARV resistance as reported by the International AIDS Society-USA Drug Resistance Mutations Group. The prevalence of patients with at least one major mutation conferring drug resistance to nucleoside RT inhibitors (NRTIs), non-NRTIs (NNRTIs) or protease inhibitors (PIs) was 77.8%. In the RT gene, the frequency of mutations associated with NRTIs and NNRTIs resistance was 52.8 and 63.9%, respectively, with M184V and K103N mutations being selected most frequently by these drugs. A patient with Q151M mutation complex was also detected. Twenty-two percent of the patients had mutations associated with PIs. The following pattern of prevalence of ARV-resistant HIV-1 variants was observed: NNRTI-resistant > NRTI-resistant > PI-resistant. The prevalence of major drug resistance mutations among ARV-treated patients with detectable VL is high in Kuala Lumpur. Genotypic drug resistance testing is therefore important for monitoring patients experiencing ARV regimen failure.

Abstract: To assess the prevalence of mutations associated with drug resistance in antiretroviral-naive patients in Kuala Lumpur, Malaysia, genotypic resistance testing was conducted among drug-naive HIV-1 patients attending the University Malaya Medical Center (UMMC) between July 2003 and June 2004. Reverse transcriptase (RT) and protease genes of plasma virions were sequenced from 100 individuals. The majority of the patients were recently diagnosed. Codons 20-255 of the RT and 1-96 of the protease gene were examined for major and minor mutations associated with antiretroviral resistance reported by the International AIDS Society-USA (IAS-USA) Drug Resistance Mutations Group. The prevalence of patients with at least one major mutation conferring drug resistance was 1%, with only one patient having a Y181C amino acid substitution in the RT gene that confers high- level resistance to nevirapine and delavirdine. Minor mutations were detected in high prevalence in the protease gene. Amino acid substitutions I13V, E35D, and M36I were associated with CRF01_ AE while L63P, V77I, and I93L were associated with subtype B. Baseline prevalence of major mutations associated with resistance to antiretroviral drugs was low among antiretroviral- naive HIV-1 patients, suggesting that routine drug resistance testing may be unnecessary for all individuals newly diagnosed with HIV or all patients beginning antiretroviral therapy.

Abstract: To assess the prevalence of mutations associated with drug resistance in antiretroviral-naive patients in Kuala Lumpur, Malaysia, genotypic resistance testing was conducted among drug-naive HIV-1 patients attending the University Malaya Medical Center (UMMC) between July 2003 and June 2004. Reverse transcriptase (RT) and protease genes of plasma virions were sequenced from 100 individuals. The majority of the patients were recently diagnosed. Codons 20–255 of the RT and 1–96 of the protease gene were examined for major and minor mutations associated with antiretroviral resistance reported by the International AIDS Society- USA (IAS-USA) Drug Resistance Mutations Group. The prevalence of patients with at least one major mutation conferring drug resistance was 1%, with only one patient having a Y181C amino acid substitution in the RT gene that confers high-level resistance to nevirapine and delavirdine. Minor mutations were detected in high prevalence in the protease gene. Amino acid substitutions I13V, E35D, and M36I were associated with CRF01_AE while L63P, V77I, and I93L were associated with subtype B. Baseline prevalence of major mutations associated with resistance to antiretroviral drugs was low among antiretroviral-naive HIV-1 patients, suggesting that routine drug resistance testing may be unnecessary for all individuals newly diagnosed with HIV or all patients beginning antiretroviral therapy.

Abstract: A molecular epidemiological investigation was conducted among various risk populations (n = 184) in Kuala Lumpur, Malaysia, in 2003 to 2005, on the basis of nucleotide sequences of protease and reverse transcriptase regions. In addition to circulating HIV-1 strains, including CRF01_AE (57.1%), subtype B (20.1%), and subtype C (0.5%), we detected a candidate with a new circulating recombinant form (CRF). We determined four near-full-length nucleotide sequences with identical subtype structure from epidemiologically unlinked individuals of different risk and ethnic groups. In this chimera, two short subtype B segments were inserted into the gag-RT region in a backbone of CRF01_AE. The recombinant structure was distinct from previously identified CRF15_01B in Thailand. In agreement with the current HIV nomenclature system, this constitutes a novel CRF (CRF33_01B). The overall prevalence of CRF33_01B is 19.0% (35/184). Although the prevalence of CRF33_01B is particularly high among injecting drug users (42.0%, 21/50), it is also detected in a substantial proportion of homo-/bisexual males (18.8%, 3/16) and heterosexuals (9.8%, 9/92). Moreover, unique recombinant forms composed of CRF01_AE and subtype B that have a significant structural relationship with CRF33_01B were detected in 1.6% (3/184) of study subjects, suggesting an ongoing recombination process in Malaysia. This new CRF seems to be bridging viral transmission between different risk populations in this country.

Abstract: A molecular epidemiological investigation was conducted among various risk populations (n = 184) in Kuala Lumpur, Malaysia, in 2003 to 2005, on the basis of nucleotide sequences of protease and reverse transcriptase regions. In addition to circulating HIV-1 strains, including CRF01_AE (57.1%), subtype B (20.1%), and subtype C (0.5%), we detected a candidate with a new circulating recombinant form (CRF). We determined four near-full-length nucleotide sequences with identical subtype structure from epidemiologically unlinked individuals of different risk and ethnic groups. In this chimera, two short subtype B segments were inserted into the gag-RT region in a backbone of CRF01_AE. The recombinant structure was distinct from previously identified CRF15_01B in Thailand. In agreement with the current HIV nomenclature system, this constitutes a novel CRF (CRF33_01B). The overall prevalence of CRF33_01B is 19.0% (35/184). Although the prevalence of CRF33_01B is particularly high among injecting drug users (42.0%, 21/50), it is also detected in a substantial proportion of homo-/bisexual males (18.8%, 3/16) and heterosexuals (9.8%, 9/92). Moreover, unique recombinant forms composed of CRF01_AE and subtype B that have a significant structural relationship with CRF33_01B were detected in 1.6% (3/184) of study subjects, suggesting an ongoing recombination process in Malaysia. This new CRF seems to be bridging viral transmission between different risk populations in this country.

Abstract:

Abstract: Background: Neisseria meningitidis (N. meningitidis) remains the leading worldwide cause of acute bacterial meningitis and fatal sepsis in healthy individuals. Materials and Methods: A total of 12 cases of N. meningitidis from patients with invasive meningococcal infections in University of Malaya Medical Centre, Kuala Lumpur during,the years 1987-2004 were reviewed together with details of age, sex, disease, risk factors treatment and outcome of these patients. Results: Their ages ranged from 10 months to 64 years (median age 29.75 years). The male to female ratio was 1.42:1. Fever, neck stiffness, headache, vomiting and confusion were predominant symptoms. Upper respiratory tract viral infection and Haij pilgrimage were directly associated with invasive meningococcal disease. Penicillin or ceftriaxone or both in some cases were administered as empirical therapy. All isolates were sensitive to penicillin, ceftriaxone, chloramphenicol and rifampicin. The case fatality ratio was 1:4. One Hajj pilgrim died despite having received polyvalent meningococcal vaccine. Amongst the survivors, two patients had neurological deficit, hearing loss and arthritis. Conclusion: Early antimicrobial therapy has been shown to reduce these adverse outcomes. Clinicians need to be alerted to the presence of the disease in the community and the disease should be made notifiable within 24 hours of detection both for early treatment of cases and to facilitate contact tracing, institution of prophylactic treatment and prevention of secondary cases.

Abstract: Antimicrobial resistance to the extended-spectrum cephalosporins is increasingly reported worldwide. In the local setting, nosocomial infections with multi-resistant Gram-negative bacilli are not uncommon and are a growing concern. However, there is limited data on the carriage rates of such organisms in the local setting. In May 2001, a prospective study was carried out to determine the enteric carriage rates of ceftazidime-resistant Gram negative bacilli (CAZ-R GNB) among residents of nursing homes and from in-patients of the geriatric and adult haematology wards of University Malaya Medical Centre. Ceftazidime-resistant Gram-negative bacilli (CAZ-R GNB) were detected in 25 samples (30%), out of which 6 were from nursing home residents, 5 from geriatric in-patients and 14 from the haematology unit. A total of 28 CAZ-R GNB were isolated and Escherichia coli (10) and Klebsiella pneumoniae (7) were the predominant organisms. Resistance to ceftazidime in E. coli and Klebsiella was mediated by extended-spectrum beta-lactamases (ESBLs). Although the majority of the CAZ-R GNB were from patients in the haematology ward, the six nursing home residents with CAZ-R GNB were enteric carriers of ESBL-producing coliforms. Prior exposure to antibiotics was associated with carriage of ESBL organisms and to a lesser extent, the presence of urinary catheters.

Abstract: Objectives: To investigate the molecular epidemiology of HIV-1 and to screen for the emergence of intersubtype recombinants in Kuala Lumpur, Malaysia. Design: A molecular epidemiology study was conducted among HIV-1 seropositive patients attending the University Malaya Medical Center (UMMC) from July 2003 to June 2004. Methods: Protease (PR) and reverse transcriptase (RT) gene sequences were derived from drug resistance genotyping assay of 100 newly diagnosed or antiretroviral-naive patients. These were phylogenetically analysed to determine the subtypes and recombination breakpoint analyses were performed on intersubtype recombinants to estimate the recombination breakpoint(s). Results: CRF01_AE predominated in Kuala Lumpur with 65% in both PR and RT genes. B subtype was detected at 14% and 12% in PR and RT genes, respectively. C subtype was present at 1% in both genes. Overall, the concordance of PR and RT genes in discriminating subtypes/circulating recombinant forms (CRF) was high at 96%. In this study, novel CRF01_AE/B intersubtype recombinants were detected at high prevalence (22%), including those isolates with subtype discordance. Thai variants of CRF01_AE and B subtype were involved in the genesis of these unique recombinant forms (URF). Interestingly, 19 CRF01_AE/B intersubtype recombinant isolates shared similar recombination breakpoints in both PR and RT genes. Several distinct URF were also identified. Conclusion: PR and RT genes can be utilized for subtype/CRF assessment with high degree of agreement, allowing concurrent surveillance of circulating HIV-1 subtypes with antiretroviral drug resistance genotyping tests. The emergence of highly identical CRF01_AE/B intersubtype recombinants suggests the possibility of the appearance of a new circulating recombinant form in Kuala Lumpur. (c) 2005 Lippincott Williams C Wilkins.

Abstract: It has been approximately two decades since the first case of the Acquired Immunodeficiency Syndrome was reported in Malaysia. Following a small increase in the number of new reported cases of HIV infection and AIDS in the few ensuing years, a rapid explosion of the epidemic took place in the mid 1990s with 4000 and latterly close to 7000 new HIV infections reported annually. The cumulative total reported HIV cases to September 2004 was 61486, with 8955 AIDS cases. The number of deaths due to AIDS to date has totalled a staggering 6665 cases.

Abstract: Background: Relatively little is known regarding HIV disease natural history and response to antiretroviral treatments among Asian people infected with HIV The Therapeutics Research, Education, and AIDS Training in Asia (TREAT Asia) HIV Observational Database (TAHOD) is a recently established collaborative observational cohort study that aims to assess HIV disease natural history in treated and untreated patients in the Asia-Pacific region. Methods: Observational data are collected on HIV-infected patients from 11 sites in the Asia-Pacific region. Data are centrally aggregated for analyses, with the first baseline and retrospective data transferred in September 2003. Retrospective data were analyzed to assess the response to highly active antiretroviral treatment (HAART) over a 6-month period in terms of changes in CD4 count and proportions of patients achieving an undetectable HIV viral load (<400 copies/mL). Results: By the end of May 2004, 1887 patients had been recruited to the TAHOD. Seventy-two percent of patients were male, with median age 36 years. Seventy-eight percent of patients reported HIV infection through heterosexual contact. Forty-three percent of patients had a previous AIDS diagnosis, of whom 55% had tuberculosis. The mean 6-month CD4 count increase was 115 cells/muL (SD = 127) after starting triple-combination therapy. Smaller CD4 count increases were associated with a higher CD4 count before starting treatment, prior treatment with monotherapy or double therapy, and treatment with a HAART regimen containing a nucleoside reverse transcriptase inhibitor (NRTI) and/or protease inhibitor (PI) but without a non-nucleoside reverse transcriptase inhibitor (NNRTI). Five hundred and ninety-eight patients started HAART and had a viral load assessment at 6 months, with 69% attaining an undetectable viral load. Older patients, patients not exposed to HIV through heterosexual contact, and patients treated with HAART containing NRTIs and NNRTIs but without PIs were found to be more likely to achieve an undetectable level. Conclusion: Analyses of retrospective data in the TAHOD suggest that the overall response to HAART in Asian populations is similar to that seen in Western countries.

Abstract: Cryptococcus neoformans is a yeast like fungus, which is commonly found in bird droppings, especially pigeons. Most cases of cryptococcal infections occur in immunocompromised patients or in those who are on long term immunosuppressant therapies. Cryptococcal infection usually presents as a meningoencephalitis or a pulmonary infection. Skin; bone and genital infections are very rare. We report the second case of vaginal cryptococcossis to be reported in English literature and the first to be imaged with CT and MRI.

Abstract: BACKGROUND AND OBJECTIVE: Most reports of nosocomial infection (NI) prevalence have come from developed countries with established infection control programs. In developing countries, infection control is often not as well established due to lack of staff and resources. We examined the rate of NI in our institution. METHODS: A point-prevalence study. of NI and antibiotic prescribing was conducted. On July 16 and 17, 2001, all inpatients were surveyed for NI, risk factors, pathogens isolated, and antibiotics prescribed and their indication. NIs were diagnosed according to CDC criteria. Cost of antibiotic acquisition was calculated by treatment indication. SETTING: Tertiary-care referral center in Malaysia. PATIENTS: All inpatients during the time of the study. RESULTS: Five hundred thirty-eight patients were surveyed. Seventy-five had 103 NIs for a prevalence of 13.9%. The most common NIs were urinary tract infections (12.2%), pneumonia (21.4%), laboratory-confirmed bloodstream infections (12.2%), deep surgical wound infections (11.2%), and clinical sepsis (22.4%). Pseudomonas aeruginosa, MRSA, and MSSA were the most common pathogens. Two hundred thirty-seven patients were taking 347 courses of antibiotics, for an overall prevalence of antibiotic use of 44%. NI treatment accounted for 36% of antibiotic courses prescribed but 47% of antibiotic cost. Cost of antibiotic acquisition for NI treatment was estimated to be approximately 2 million per year (Malaysian dollars). CONCLUSION: Whereas the rate of NI is relatively high at our center compared with rates from previous reports, antibiotic use is among the highest reported in any study of this kind. Further research into this high rate of antibiotic use is urgently required.

Abstract: Earlier studies in the 1990s indicate that human immunodeficiency virus type 1 (HIV-1) subtype B has been the predominant subtype among injecting drug users (IDUs) in Malaysia. More recent studies performed between 2003 and 2004, however, show a high prevalence of unique CRF01_AE/B intersubtype recombinants among IDUs. To determine the subtype distribution among IDUs in Kuala Lumpur prior to the emergence of CRF01_AE/B intersubtype recombinants, the gag-pol or the reverse transcriptase gene was sequenced from IDUs who were diagnosed as HIV positive between 1993 and 2002. Subtype B was present at 50.0% followed by CRF01_AE/B recombinant at 41.7%, with more CRF01_AE/B recombinants detected between 2000 and 2002. All CRF01_AE/B recombinants shared similar recombination patterns. Interestingly, we found that this potential new candidate of circulating recombinant form (CRF) could have emerged as early as the mid-1990s. The results showed evidence of changing HIV-1 molecular epidemiology toward the predominance of CRF01_AE/B intersubtype recombinants among IDUs in Kuala Lumpur.

Abstract: Kostmann's syndrome is a rare congenital disorder of neutrophil production due to impairment of myeloid differentiation in the bone marrow, with the neutrophil count being characteristically less than 500 x 10(3) cells/l (normal: 2-7 X 10(9)/l). Severe persistent neutropenia results in an increased susceptibility to frequent bacterial infections. The condition can be treated with recombinant human granulocyte colony-stimulating factor (G-CSF). Although several articles have addressed the clinicopathological and haematological aspects of this disorder, little or no information has been available concerning the radiological findings in this disorder. This report summarizes the clinical features, radiological findings and management of a patient with Kostmann's syndrome. (c) 2005 Elsevier Inc. All rights reserved.

Abstract: A total of 685 clinical Streptococcus pneumoniae isolates from patients with pneumococcal diseases were collected from 14 centers in 11 Asian countries from January 2000 to June 2001. The in vitro susceptibilities of the isolates to 14 antimicrobial agents were determined by the broth microdilution test. Among the isolates tested, 483 (52.4%) were not susceptible to penicillin, 23% were intermediate, and 29.4% were penicillin resistant (MICs greater than or equal to 2 mg/liter). Isolates from Vietnam showed the highest prevalence of penicillin resistance (71.4%), followed by those from Korea (54.8%), Hong Kong (43.2%), and Taiwan (38.6%). The penicillin MICs at which 90% of isolates are inhibited (MIC(90)s) were 4 mg/liter among isolates from Vietnam, Hong Kong, Korea, and Taiwan. The prevalence of erythromycin resistance was also very high in Vietnam (92.1%), Taiwan (86%), Korea (80.6%), Hong Kong (76.8%), and China (73.9%). The MIC(90)s of erythromycin were >32 mg/liter among isolates from Korea, Vietnam, China, Taiwan, Singapore, Malaysia, and Hong Kong. Isolates from Hong Kong showed the highest rate of ciprofloxacin resistance (11.8%), followed by isolates from Sri Lanka (9.5%), the Philippines (9.1%), and Korea (6.5%). Multilocus sequence typing showed that the spread of the Taiwan(19F) clone and the Spain(23F) clone could be one of the major reasons for the rapid increases in antimicrobial resistance among S. pneumoniae isolates in Asia. Data from the multinational surveillance study clearly documented distinctive increases in the prevalence rates and the levels of antimicrobial resistance among S. pneumoniae isolates in many Asian countries, which are among the highest in the world published to date.

Abstract: The region had barely recovered from the impact of the Severe Acute Respiratory Syndrome (SARS) epidemic in 2003 when another potentially devastating outbreak, namely the H5N1 strain of avian influenza affected poultry industries in eight Asian countries and caused human disease and fatalities in Vietnam and Thailand. Lessons leamt from the SARS outbreak may possibly have played a role in averting these recent human H5N 1 infections into a much larger problem

Abstract: To evaluate the clinical outcomes of pneumococcal pneumonia caused by antibiotic-resistant strains in Asian countries, we performed a prospective observational study of 233 cases of adult pneumococcal pneumonia in 9 Asian countries from January 2000 to June 2001. Among 233 isolates, 128 (55%) were not susceptible to penicillin (25.3% were intermediately susceptible, and 29.6% were resistant). Clinical severity of pneumococcal pneumonia was not significantly different between antibiotic-resistant and antibiotic-susceptible groups. Mortality rates among patients with pneumococcal pneumonia caused by penicillin-, cephalosporin-, or macrolide-resistant strains were not higher than those with antibiotic-susceptible pneumococcal pneumonia. Bacteremia and mechanical ventilation were significant risk factors for death, but any kind of antibiotic resistance was not associated with increased mortality due to pneumococcal pneumonia. Outcome of pneumococcal pneumonia was not significantly affected by drug resistance, and current antimicrobial regimens are mostly effective in the treatment of pneumococcal pneumonia, despite the widespread emergence of in vitro resistance.

Abstract: Seventeen clinical isolates of Streptococcus pneumoniae showing reduced susceptibility to ciprofloxacin (MIC : 4 mug/ml) collected from eight different Asian countries were analyzed by antimicrobial susceptibility, serotyping, pulsed-field gel electrophoresis (PFGE), and DNA sequencing of the quinolone resistance-determining regions (QRDRs) in gyrA, gyrB, parC, and parE. All isolates but one showed more than one amino acid alteration in QRDRs of four responsible genes. Ile460 --> Val in parE was the most common mutation. Data suggest that Lys137 --> Asn in parC may be a primary step in the development of high-level and multiple FQ resistance. An additional mutation of Ser81 --> Phe in gyrA resulted in high-level resistance to ciprofloxacin, levofloxacin, and gatifloxacin, whereas Ser79 --> Phe in parC may exert an important role in the development of moxifloxacin resistance. Two novel amino acid changes in gyrB, Ala390 --> Val and Asn423 --> Thr, were found. Data from PFGE suggest an introduction and local spread of multiple resistant Spain(23)F-1 clone in Hong Kong, but isolates from other Asian countries were not related to this clone.

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Abstract: We report a case of an invasive infection with non-sporulating Chrysosporium species in a patient who was treated with chemotherapy for relapsed acute lymphoblastic leukemia. This patient presented with a persistent lobar pneumonia, skin lesions, and possible involvement of the central nervous system. The patient responded to treatment with amphotericin B and oral itraconazole.

Abstract: A cross-sectional study was carried out in University of Malaya Medical Centre, Kuala Lumpur. Blood samples from 100 HIV-infected patients and 203 Healthy Blood Donors (HBD) were collected and anti- antibodies were detected by using conventional ELISA. The seroprevalence of toxoplasmosis in HIV/AIDS and Healthy Blood Donors were found to be 21% and 28.1% respectively. There was no significant association between the seroprevalence of toxoplasmosis and various possible risk factors i.e. contact with cat, consumption of undercooked meat and history of blood transfusion in both groups. No significant differences between seroprevalence in HIV/AIDS and Health Blood Donors in association with presence of single or multiple risk factors were found. The mean CD4 count among HIV/AIDS patients in this study was 202.23 cell/cumm. There was no significant association between CD4 count and seropositivity for antibodies in HIV/AIDS patients.

Abstract: OBJECTIVES: To determine the occupational risk of Mycobacterium tuberculosis infection among healthcare workers (HCWs) and to examine the utility of tuberculin skin testing in a developing country with a high prevalence of bacille Calmette-Guerin vaccination. DESIGN: Tuberculin skin test (TST) survey. SETTING: A tertiary-care referral center and a teaching hospital in Kuala Lumpur, Malaysia. PARTICIPANTS: HCWs from medical, surgical, and orthopedic wards. INTERVENTION: Tuberculin purified protein derivative RT-23 (State Serum Institute, Copenhagen, Denmark) was used for the TST (Mantoux method). RESULTS: One hundred thirty-seven (52.1%) and 69 (26.2%) of the HCWs tested had indurations of 10 mm or greater and 15 min or greater, respectively. Medical ward HCWs were at significantly higher risk of a positive TST reaction than were surgical or orthopedic ward HCWs (odds ratio, 2.18; 95% confidence interval, 1.33 to 3.57; P = .002 for TST positivity at 10 mm or greater) (odds ratio, 2.61; 95% confidence interval, 1.44 to 4.70; P = .002 for TST positivity at 15 mm or greater). A previous TST was a significant risk factor for a positive TST reaction at either 10 mm or greater or 15 min or greater, but a duration of employment of more than 1 year and being a nurse were only significantly associated with a positive TST reaction at a cut-off point of 15 min or greater. CONCLUSIONS: HCWs at the University of Malaya Medical Centre had an increased risk for M. tuberculosis infection that was significantly associated with the level of occupational tuberculosis exposure. A TST cut-off point of 15 min or greater may correlate better with M. tuberculosis infection than a cut-off point of 10 min or greater in settings with a high prevalence of bacille Calmette-Guerin vaccination.

Abstract: Objectives: To study the excretion of Nipah virus in the upper respiratory secretions and urine of infected patients in relation to other clinical features. Methods: Isolation of Nipah virus from the respiratory secretions and urine was made in Vero cells and identified by indirect immunofluorescence assay using anti-Hendra specific hyperimmune mouse ascitic fluid and FITC-conjugated goat anti-mouse IgG. Results: During the peak outbreak of Nipah virus encephalitis in Malaysia, Nipah virus was isolated from the upper respiratory secretions and urine in eight of 20 patients who were virologically and/or serologically confirmed to be infected with the virus, From these eight patients, Nipah virus was isolated from sire throat swab specimens, three urine specimens and only one nasal swab specimen. The positive virus isolation rate was related to the collection of these specimens during the early phase of the illness (P = 0.068). The presence of serum anti-Nipah specific IgM appeared to reduce the chance of isolating the virus (P = 0.049). There was no significant difference in the isolation rate with respect to the age, gender, ethnic group and clinical features associated with grave prognosis and mortality outcome of the patients. Conclusion: This study shows that it is possible to be infected from secretions of infected patients, but epidemiological survey on close contacts so far did not suggest that human-to-human transmission is common. (C) 2001 The British Infection Society.

Abstract: Nipah virus, a newly identified paramyxovirus caused a severe outbreak of encephalitis in Malaysia with high fatalities. We report an open-label trial of ribavirin in 140 patients, with 54 patients who were managed prior to the availability of ribavirin or refused treatment as control. There were 45 deaths (32%) in the ribavirin arm; 29 deaths (54%) occurred in the control arm. This represents a 36% reduction in mortality (p = 0.011). There was no associated serious side effect. This study suggests that ribavirin is able to reduce the mortality of acute Nipah encephalitis.

Abstract: During the outbreak of Nipah virus encephalitis in Malaysia, stored cerebrospinal fluid (CSF) samples from 84 patients (27 fatal and 57 nonfatal cases) were cultured for the virus. The virus was isolated from 17 fatal cases and I nonfatal case. There were significant associations between CSF virus isolation and mortality as well as clinical features associated with poor prognosis. In addition, there was a positive linear correlation of CSF virus isolation with age. There was no significant association between CSF virus isolation and the character of the CSF, presence of Nipah-specific antibody in the serum or CSF, duration of illness before collection of samples, or sex or ethnicity of the patients. This study suggests that high vital replication in the central nervous system may be an important factor for high mortality.

Abstract: Background: Between September 1998 and June 1999, there was an outbreak of severe viral encephalitis due to Nipah virus, a newly discovered paramyxovirus, in Malaysia. Methods: We studied the clinical features of the patients with Nipah virus encephalitis who were admitted to a medical center in Kuala Lumpur. The case definition was based on epidemiologic, clinical, cerebrospinal fluid, and neuroimaging findings. Results: Ninety-four patients with Nipah virus infection were seen from February to June 1999 (mean age, 37 years; ratio of male patients to female patients, 4.5 to 1). Ninety-three percent had had direct contact with pigs, usually in the two weeks before the onset of illness, suggesting that there was direct viral transmission from pigs to humans and a short incubation period. The main presenting features were fever, headache, dizziness, and vomiting. Fifty-two patients (55 percent) had a reduced level of consciousness and prominent brain-stem dysfunction. Distinctive clinical signs included segmental myoclonus, areflexia and hypotonia, hypertension, and tachycardia and thus suggest the involvement of the brain stem and the upper cervical spinal cord. The initial cerebrospinal fluid findings were abnormal in 75 percent of patients. Antibodies against Hendra virus were detected in serum or cerebrospinal fluid in 76 percent of 83 patients tested. Thirty patients (32 percent) died after rapid deterioration in their condition. An abnormal doll's-eye reflex and tachycardia were factors associated with a poor prognosis. Death was probably due to severe brain-stem involvement. Neurologic relapse occurred after initially mild disease in three patients. Fifty patients (53 percent) recovered fully, and 14 (15 percent) had persistent neurologic deficits. Conclusions: Nipah virus causes a severe, rapidly progressive encephalitis with a high mortality rate and features that suggest involvement of the brain stem. The infection is associated with recent contact with pigs. (N Engl J Med 2000;342:1229-35.) (C) 2000, Massachusetts Medical Society.

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Abstract: Background Between February and April, 1999, an outbreak of viral encephalitis occurred among pig-farmers in Malaysia. We report findings for the first three patients who died. Methods Samples of tissue were taken at necropsy. Blood and cerebrospinal-fluid (CSF) samples taken before death were cultured for viruses, and tested for antibodies to viruses. Findings The three pig-farmers presented with fever, headache, and altered level of consciousness. Myoclonus was present in two patients. There were signs of brainstem dysfunction with hypertension and tachycardia. Rapid deterioration led to irreversible hypotension and death. A virus causing syncytial formation of vero cells was cultured from the CSF of two patients after 5 days; the virus stained positively with antibodies against Hendra virus by indirect immunofluorescence, IgM capture ELISA showed that all three patients had IgM antibodies in CSF against Hendra viral antigens. Necropsy showed widespread microinfarction in the central nervous system and other organs resulting from vasculitis-induced thrombosis. There was no clinical evidence of pulmonary involvement. Inclusion bodies likely to be of viral origin were noted in neurons near vasculitic blood vessels. Interpretation The causative agent was a previously undescribed paramyxovirus related to the Hendra virus. Close contact with infected pigs may be the source of the viral transmission. Clinically and epidemiologically the infection is distinct from infection by the Hendra virus. We propose that this Hendra-like virus was the cause of the outbreak of encephalitis in Malaysia.

Abstract: Osteomyelitis of the skull is a rare disease. We describe two cases due to Salmonella typhimurium and review 10 previously reported cases of salmonella osteomyelitis of the skull. This infection is frequently complicated by extradural abscess, which may be asymptomatic. Diagnostic imaging by means of computed tomographic scanning with contrast or gadolinium-enhanced magnetic resonance imaging should be performed to detect this complication. A good outcome can be expected with a combination of surgery and antibiotic therapy.