Showing papers in "AIDS in 2008"

Stigma in the HIV/AIDS epidemic: a review of the literature and recommendations for the way forward.

Abstract: Although stigma is considered a major barrier to effective responses to the HIV/AIDS epidemic, stigma reduction efforts are relegated to the bottom of AIDS programme priorities. The complexity of HIV/AIDS-related stigma is often cited as a primary reason for the limited response to this pervasive ph

Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa.

Abstract: Two-thirds of the world's HIV-infected people live in sub-Saharan Africa, and more than 1.5 million of them die annually. As access to antiretroviral treatment has expanded within the region; early pessimism concerning the delivery of antiretroviral treatment using a large-scale public health approach has, at least in the short term, proved to be broadly unfounded. Immunological and virological responses to ART are similar to responses in patients treated in high-income countries. Despite this, however, early mortality rates in sub-Saharan Africa are very high; between 8 and 26% of patients die in the first year of antiretroviral treatment, with most deaths occurring in the first few months. Patients typically access antiretroviral treatment with advanced symptomatic disease, and mortality is strongly associated with baseline CD4 cell count less than 50 cells/mul and WHO stage 4 disease (AIDS). Although data are limited, leading causes of death appear to be tuberculosis, acute sepsis, cryptococcal meningitis, malignancy and wasting syndrome. Mortality rates are likely to depend not only on the care delivered by antiretroviral treatment programmes, but more fundamentally on how advanced disease is at programme enrollment and the quality of preceding healthcare. In addition to improving delivery of antiretroviral treatment and providing it free of charge to the patient, strategies to reduce mortality must include earlier diagnosis of HIV infection, strengthening of longitudinal HIV care and timely initiation of antiretroviral treatment. Health systems delays in antiretroviral treatment initiation must be minimized, especially in patients who present with advanced immunodeficiency.

Bacterial vaginosis and HIV acquisition: A meta-analysis of published studies

Abstract: Bacterial vaginosis (BV) is the most frequent type of vaginitis in women of reproductive age [1–3]. BV is an imbalance in the ecology of the normal vaginal flora [4] that is characterized by the depletion of lactobacilli [3], and the proliferation of anaerobic bacteria such as Gardnerella vaginalis, Morbilincus species, Prevotella species, Mycoplasma hominis and the recently identified Atopobium vaginae [2, 5–7]. It most often manifests clinically as a vaginal pH of >4.5, the presence of thin whitish homogenous vaginal discharge, the detection of “clue” cells and the presence of an amine odor after the addition of 10 percent potassium hydroxide [8, 9]. BV has been shown to increase the risk of adverse gynecological and obstetrical outcomes such as preterm delivery[10, 11] pelvic inflammatory disease (PID) and upper genital tract infections [12–14]. However, the effect of BV on the risk of HIV infection in women has not been clearly quantified. The magnitude of the association between BV and HIV has varied in epidemiological studies, ranging from the absence of any association[15] to a near four-fold odds of being HIV infected among BV-positive women compared to BV-negative women [16]. BV is estimated to be the most prevalent vaginal infection particularly in countries with high HIV prevalence [2]. If BV is confirmed to increase the risk of HIV infection, the treatment of BV could be a meaningful intervention to prevent HIV acquisition. In a 2001 review of the role of sexually transmitted diseases in HIV acquisition, Rottingen et al estimated that BV was associated with a 40% increase in the risk of HIV based on an analysis of two studies[17]. Obtaining a precise and updated estimate of the strength of the association between BV and HIV from published studies could be useful in predicting the potential impact of the control of BV on HIV incidence rates in a population. This prediction could also be more accurate if factors that modify the strength of the BV and HIV association were identified. This paper aims to systematically review all published studies of the association between BV and HIV infection. Estimates of the association between BV and HIV are presented for both HIV incidence and prevalence studies, and analyzed for potential modification factors, publication bias, and heterogeneity of study results.

Low rates of mother-to-child transmission of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006

Abstract: Aim: In the United Kingdom (UK) and Ireland, avoidance of breastfeeding and alternative combinations of antiretroviral therapy regimen and mode of delivery are recommended according to maternal clinical status. The aim of this analysis was to explore the impact of different strategies to prevent mother-to-child transmission at a population level. Design: Comprehensive national surveillance study. Methods: Pregnancies in diagnosed HIV-infected women in the UK and Ireland are notified to the National Study of HIV in Pregnancy and Childhood; infant infection status is subsequently reported. Factors associated with transmission in this observational study were explored for singleton births between 2000 and 2006. Results: The overall mother-to-child transmission rate was 1.2% (61/5151, 95% confidence interval: 0.9‐1.5%), and 0.8% (40/4864) for women who received at least 14 days of antiretroviral therapy. Transmission rates following combinations recommended in British guidelines were 0.7% (17/2286) for highly active antiretroviral therapy with planned Caesarean section, 0.7% (4/559) for highly active antiretroviral therapy with planned vaginal delivery, and 0% (0/464) for zidovudine monotherapy with planned Caesarean section (P ¼0.150). Longer duration of highly active antiretroviral therapy was associated with reduced transmission after adjusting for viral load, mode of delivery and sex (adjusted odds ratio ¼0.90 per week of highly active antiretroviral therapy, P ¼0.007). Among 2117 infants born to women on highly active antiretroviral therapy with viral load less than 50copies/ml, only three (0.1%) were infected, two with evidence of in-utero transmission. Conclusion: Sustained low HIV transmission rates following different combinations of interventions in this large unselected population are encouraging. Current options for treatment and delivery offered to pregnant women according to British guidelines appear to be effective. 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2008, 22:973‐981

Age-disparate and intergenerational sex in southern Africa: the dynamics of hypervulnerability.

Abstract: This paper reviews the current state of knowledge on age-disparate sexual relationships in the context of the southern African HIV/AIDS hyperepidemic. Disproportionately high HIV infection rates among young women aged 15–24 years have been attributed to their greater involvement in relationships wit

Natural history of hepatitis C virus infection in HIV-infected individuals and the impact of HIV in the era of highly active antiretroviral therapy: a meta-analysis.

Abstract: OBJECTIVES To estimate stage-specific transition probabilities in individuals coinfected with HIV and hepatitis C virus (HCV), to examine the effect of covariates on these rates, and to investigate the effect of HIV on HCV-related cirrhosis in the era of highly active antiretroviral therapy (HAART). DESIGN Systematic review of natural history studies among HCV-infected individuals. METHODS Markov maximum likelihood estimation method was used to estimate stage-specific transition probabilities. A meta-analysis was performed to obtain pooled transition probabilities, and a meta-regression to investigate the impact of covariates on these rates. Risk of cirrhosis between individuals monoinfected with HCV and coinfected with HIV/HCV were compared by HAART status. RESULTS The estimated mean (95% confidence intervals) annual transition probabilities of 3567 individuals coinfected with HIV/HCV (n = 17 studies) were as follows: fibrosis stage (F) F0 --> F1 0.122 (0.098-0.153); F1 --> F2 0.115 (0.095-0.140); F2 --> F3 0.124 (0.097-0.159); and F3 --> F4 0.115 (0.098-0.135) units/year. The prevalence of cirrhosis after 20 and 30 years of HCV infection was 21% (16-28%) and 49% (40-59%), respectively. Longer duration of HCV infection was significantly associated with slower rate of fibrosis progression. The overall rate ratio of cirrhosis between individuals coinfected with HIV/HCV and monoinfected with HCV (n = 27 studies) was 2.1 (1.5-3.0), 2.5 (1.8-3.4) in the non-HAART group, and 1.7 (1.1-2.8) in the HAART group. CONCLUSION The rate of fibrosis progression among individuals coinfected with HIV/HCV appears constant. Our results confirm that chronic hepatitis C outcomes are worse among coinfected individuals. Over the period studied, HAART did not appear to fully correct the adverse effect of HIV infection on HCV prognosis.

Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48.

Abstract: BACKGROUND The present primary analysis of AntiRetroviral Therapy with TMC114 ExaMined In naive Subjects (ARTEMIS) compares the efficacy and safety of once-daily darunavir/ritonavir (DRV/r) with that of lopinavir/ritonavir (LPV/r) in treatment-naive patients. METHODS Patients with HIV-1 RNA at least 5000 copies/ml were stratified by HIV-1 RNA and CD4 cell count in a phase III, open-label trial, and randomized to receive DRV/r 800/100 mg qd or LPV/r 800/200 mg total daily dose (bid or qd) plus fixed-dose tenofovir and emtricitabine for 192 weeks. The primary objective was to demonstrate non-inferiority of DRV/r as compared with LPV/r in HIV-1 RNA less than 50 copies/ml per-protocol time-to-loss of virologic response at 48 weeks. RESULTS Six hundred and eighty-nine patients were randomized and treated; mean baseline HIV-1 RNA: 4.85 log10 copies/ml and median CD4 count: 225 cells/microl. At 48 weeks, 84% of DRV/r and 78% of LPV/r patients achieved HIV-1 RNA less than 50 copies/ml (estimated difference = 5.6 [95% confidence interval -0.1-11]%), demonstrating non-inferiority of DRV/r as compared with LPV/r (P < 0.001; per-protocol time-to-loss of virologic response). Patients with HIV-1 RNA at least 100 000 copies/ml had a significantly higher response rate with DRV/r (79%) versus LPV/r (67%; P < 0.05). Median CD4 cell count increases (non-completer = failure; cells/mul) were 137 for DRV/r and 141 for LPV/r. DRV/r had a lower incidence of possibly treatment-related grade 2-4 gastrointestinal-related adverse events (7 versus 14%) and treatment-related moderate-to-severe diarrhea (4 versus 10%) than LPV/r. Adverse events leading to discontinuation were DRV/r: 3% and LPV/r: 7%. CONCLUSION DRV/r 800/100 mg qd was non-inferior to LPV/r 800/200 mg at 48 weeks, with a more favorable safety profile. Significantly higher response rates were observed with DRV/r in patients with HIV-1 RNA at least 100 000 copies/ml. DRV/r 800/100 mg offers a new effective and well tolerated once-daily, first-line treatment option for treatment-naive patients.

CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection.

Abstract: Background: Reductions in AIDS-related morbidity and mortality following the advent of combination antiretroviral therapy have coincided with relative increases in chronic non-AIDS end-organ diseases among HIV+ patients. Objective: To examine the association of latest CD4+ counts with risk of non-AIDS diseases in a cohort of 1397 patients who initiate antiretroviral therapy. Methods: CD4+ counts and HIV RNA levels along with fatal, and non-fatal, AIDS and non-AIDS diseases (liver, cardiovascular, renal, and cancer) were assessed over a median follow-up of 5 years. Cox proportional regression models were used to study risk associations. Results: A total of 227 patients experienced an AIDS event and 80 patients developed a non-AIDS disease event. Both AIDS and non-AIDS diseases rates (events/100 person-years), respectively, declined with higher latest CD4+ counts: 13.8 and 2.1 with latest CD4+ counts less than 200 cells/microl; 2.0 and 1.7 for counts of 200-350 cells/microl; and 0.7 and 0.7 for counts greater than 350 cells/microl. After adjusting for baseline covariates and the latest HIV RNA level, risk of AIDS and non-AIDS diseases were lowered by 44% (95% confidence interval for hazard ratio 0.50-0.62, P < 0.01) and 14% (95% confidence interval for hazard ratio 0.77-0.96, P = 0.01), respectively, for each 100 cell/microl higher latest CD4+ count. Conclusion: Higher CD4+ counts on antiretroviral therapy are associated with lower rates of non-AIDS diseases and AIDS. These findings expand our understanding of the implications of HIV-related immunodeficiency and motivate randomized studies to evaluate the effects of antiretroviral therapy on a broad set of clinical outcomes at CD4+ counts greater than 350 cells/microl.

Mother-to-child HIV transmission despite antiretroviral therapy in the ANRS French Perinatal Cohort.

Abstract: OBJECTIVE: To identify factors associated with mother-to-child HIV-1 transmission (MTCT) from mothers receiving antenatal antiretroviral therapy. DESIGN: The French Perinatal Cohort (EPF), a multicenter prospective cohort of HIV-infected pregnant women and their children. METHODS: Univariate analysis and logistic regression, with child HIV status as dependent variable, were conducted among 5271 mothers who received antiretroviral therapy during pregnancy, delivered between 1997 and 2004 and did not breastfeed. RESULTS: The MTCT rate was 1.3% [67/5271; 95% confidence interval (CI), 1.0-1.6]. It was as low as 0.4% (5/1338; 95% CI, 0.1-0.9) in term births with maternal HIV-1 RNA level at delivery below 50 copies/ml. MTCT increased with viral load, short duration of antiretroviral therapy, female gender and severe premature delivery: 6.6% before 33 weeks versus 1.2% at 37 weeks or more (P 10 000 copies/ml). Elective cesarean section tended to be inversely associated with MTCT in the overall population, but not in mothers who delivered at term with viral load < 400 copies/ml [odds ratio (OR), 0.83; 95% CI, 0.29-2.39; P = 0.37]. Among them, only duration of antenatal therapy was associated with transmission (OR by week, 0.94; 95% CI, 0.90-0.99; P = 0.03). CONCLUSIONS: Low maternal plasma viral load is the key factor for preventing MTCT. Benefits in terms of MTCT reduction may be expected from early antiretroviral prophylaxis. The potential toxicity of prolonged antiretroviral use in pregnancy should be evaluated.

Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy.

Abstract: Patients with inefficient CD4+ T-cell recovery on virogically suppressive highly active antiretroviral therapy constitute a major clinical hurdle given the threat of HIV/AIDS disease progression. We show heightened circulating lipopolysaccharide associated with plasma enterobacterial DNA and highly activated Ki67+CD4+CD8+ in 24 immunologic-nonresponders (CD4+ T-cell or= 400; HIV-RNA < or = 50). These data provide novel insight into INRs pathogenesis, since they correlate augmented systemic translocation of microbial bioproducts with T-cell hyperactivation.

Systematic review exploring time trends in the association between educational attainment and risk of HIV infection in sub-Saharan Africa

Abstract: Objective: To assess the evidence that the association between educational attainment and risk of HIV infection is changing over time in sub-Saharan Africa. Design and methods: Systematic review of published peer-reviewed articles. Articles were identified that reported original data comparing individually measured educational attainment and HIV status among at least 300 individuals representative of the general population of countries or regions of sub-Saharan Africa. Statistical analyses were required to adjust for potential confounders but not over-adjust for variables on the causal pathway. Results: Approximately 4000 abstracts and 1200 full papers were reviewed. Thirty-six articles were included in the study, containing data on 72 discrete populations from 11countriesbetween1987and2003,representingover200000individuals.Studieson data collected prior to 1996 generally found either no association or the highest risk of HIV infection among the most educated. Studies conducted from 1996 onwards were more likely to find a lower risk of HIV infection among the most educated. Where data over time were available, HIV prevalence fell more consistently among highly educated groups than among less educated groups, in whom HIV prevalence sometimes rose while overall population prevalence was falling. In several populations, associations suggesting greater HIV risk in the more educated at earlier time points were replaced by weaker associations later. Discussion: HIV infections appear to be shifting towards higher prevalence among the least educated in sub-Saharan Africa, reversing previous patterns. Policy responses that ensure HIV-prevention measures reach all strata of society and increase education levels are urgently needed. 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2008, 22:403‐414

Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients.

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

Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study.

Abstract: The objective was to determine the incidence clinical manifestations risk factors and outcome of immune reconstitution inflammatory syndrome (IRIS) in South Africa. The design used was a prospective surveillance cohort and nested case-control study in a large University hospital-based antiretroviral therapy (ART) clinic. A total of 423 ART-naive HIV-infected South African patients were followed for signs and symptoms IRIS during the first 6 months of ART. We also performed a nested case-control study with controls matched to IRIS cases on ART duration. During the first 6 months of ART 44 (10.4%) patients experienced IRIS for an overall incidence rate of 25.1 cases per 100 patient-years. Diagnoses included tuberculosis (18/44 41%) abscess formation and suppurative folliculitis (8/44 18.2%) varicella zoster (6/44 13.6%) herpes simplex (4/44 9.1%) cryptococcal meningitis (3/44 6.8%) molluscum contagiosum (3/44 6.8%) and Kaposis sarcoma (2/44 4.5%). Median IRIS onset was 48 days (interquartile range 29-99) from ART initiation. In comparison with controls IRIS cases had significantly lower CD4 cell counts at baseline (79 versus 142 cells/microl; P = 0.02) and at IRIS diagnosis (183 versus 263 cells/microl; P = 0.05) but similar virological and immunological response to ART. In multivariable analyses higher baseline CD4 cell count was protective of developing IRIS (HR 0.72 per 50 cells/microl increase). Most IRIS cases were mild with ART discontinued in three (6.8%) patients corticosteroids administered to four (9.1%) patients and hospitalization required in 12 (27.3%) patients. Two deaths were attributable to IRIS. IRIS may affect 10% of patients initiating ART in Africa particularly those with advanced immunosuppression but severe life-threatening IRIS is uncommon. (authors)

A combined microfinance and training intervention can reduce HIV risk behaviour in young female participants

Abstract: Objective: To assess effects of a combined microfinance and training intervention on HIV risk behavior among young female participants in rural South Africa. Design: Secondary analysis of quantitative and qualitative data from a cluster randomized trial, the Intervention with Microfinance for AIDS and Gender Equity study. Methods: Eight villages were pair-matched and randomly allocated to receive the intervention. At baseline and after 2 years, HIV risk behavior was assessed among female participants aged 14‐35 years. Their responses were compared with women of the same age and poverty group from control villages. Intervention effects were calculated using adjusted risk ratios employing village level summaries. Qualitative data collected during thestudyexploredparticipants’responsestotheinterventionincludingHIVriskbehavior. Results: After 2 years of follow-up, when compared with controls, young participants had higher levels of HIV-related communication (adjusted risk ratio 1.46, 95% confidence interval 1.01‐2.12), were more likely to have accessed voluntary counseling and testing (adjusted risk ratio 1.64, 95% confidence interval 1.06‐2.56), and less likely to have had unprotected sex at last intercourse with a nonspousal partner (adjusted risk ratio 0.76, 95% confidence interval 0.60‐0.96). Qualitative data suggest a greater acceptance of intrahousehold communication about HIV and sexuality. Although women noted challenges associated with acceptance of condoms by men, increased confidence and skills associated with participation in the intervention supported their introduction in sexual relationships. Conclusions: In addition to impacts on economic well being, women’s empowerment and intimate partner violence, interventions addressing the economic and social vulnerability of women may contribute to reductions in HIV risk behavior. 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2008, 22:1659‐1665

The role of HIV in serious diseases other than AIDS.

Abstract: IntroductionNow that we are over 10 years into the HAART era in resource-rich countries the major clinical impact of this therapy on reduced AIDS events and AIDS deaths has been well described [1] and in the past few years the focus has turned to describing and understanding what residual clinical d

Immune activation and AIDS pathogenesis.

Abstract: The mechanisms by which HIV induces the immune dysfunction clinically defined as AIDS have been a subject of intense study since the discovery of the virus in the early 1980s. Initial virological analysis demonstrated low levels of virus replication in infected patients, suggesting that the virus alone was incapable of inducing AIDS and that additional factors must also play a role in determining the HIV-associated immunologic dysfunction. This concept has recently been emphasized from a statistical perspective by the observation that while the level of HIV replication is significantly correlated with the risk of disease progression [1], this parameter only predicts a minor part of the variation in the rate of progression among infected patients [2]. In the mid 1990s, improvements in the techniques available to detect HIV demonstrated that virus replication was active throughout the course of the disease [3,4]. In addition, the observation that inhibition of viral replication with antiretroviral drugs substantially attenuates disease progression established very clearly that virus replication is responsible for pathogenicity. What remains poorly defined, however, is the mechanistic linkage between virus replication and the onset of AIDS.

Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy.

Abstract: Objective: To describe the cases of anal cancer that appeared in the French Hospital Database on HIV between 1992 and 2004 and to study risk factors of anal cancer. Methods: We examined the incidence rates of anal cancer between 1992 and 2004 and the risk associated among 86322 HIV-infected patients included in the French Hospital Database on HIV. Results: We identified 132 cases of anal cancer, including 124 cases in men (94%), of whom 75% had sex with men. Median age at diagnosis was 42.8 years (interquartile range: 36.9-49.4). At diagnosis, 103 patients (78%) were receiving combination antiretroviral therapy for a median of 37.1 months (interquartile range: 4.5-59.8). Median survival after anal cancer diagnosis was 5 years. The respective overall incidence rates of anal cancer per 100000 person-years between 1992 and March 1996, April 1996 to 1998 and between 1999 and 2004 were 11 (95% confidence interval, 4-17), 18 (95% confidence interval, 10-27) and 40 (95% confidence interval, 32-47). The risk of anal cancer was higher among men who have sex with men. After adjustment for age at inclusion in the study, as well as gender, the HIV transmission group, the nadir CD4 cell count and AIDS status, the incidence was higher in the years 1999-2004 than in between 1992 to March 1996 (hazard ratio, 2.5; 95% confidence interval, 1.2-5.3), with no change in the years 1999-2004. Conclusion: The incidence of anal cancer has increased among HIV-infected patients in France since 1996. Although an ascertainment bias cannot be excluded, data indicate that combination antiretroviral therapy does not prevent anal cancer in these patients. This supports the urgent need for developing anal cancer screening programs for HIV-infected men who have sex with men.

Low CD4+ T cell count as a major atherosclerosis risk factor in HIV-infected women and men

Abstract: Recent studies among HIV-infected populations have linked use of combination antiretroviral therapy with increased risk of cardiovascular disease (CVD) events [1-4] and subclinical atherosclerosis [5-7]. Among HIV-infected individuals, low CD4+ T-cell count has also been identified as a vascular risk factor [5]. However, the data have not been consistent as other studies have not confirmed the reported associations of antiretroviral use [8-11] or low CD4+ T-cell count [2] with clinical or subclinical CVD. Several potential mechanisms have been described that may link HIV disease and its treatment with increased risk of vascular disease. Individuals with untreated HIV infection have decreased levels of high-density lipoprotein cholesterol (HDL-C) and increased levels of triglycerides [12-14], which are adverse risk factors for vascular disease. On the other hand, persons with untreated HIV infection also have reductions in low-density lipoprotein cholesterol (LDL-C) and total cholesterol, which may be favorable characteristics with regard to atherosclerotic risk [12-14]. Initiation of antiretroviral therapy tends to normalize lipid parameters (total cholesterol, LDL-C and triglycerides, but not HDL-C) [14]. Some therapies, notably protease inhibitors (PI), may have adverse effects on LDL-C and triglyceride levels, blood pressure, and risk of diabetes [15-19]. Use of nucleoside analogs has been associated with body fat changes, insulin resistance and diabetes [20-22]. Circulating markers of inflammation such as C-reactive protein (CRP) may be elevated among individuals with HIV infection, especially during progression to AIDS [23]. The purpose of the present investigation was to assess the association of HIV infection, HIV disease parameters (including CD4+ T-cell counts, HIV viral load, and AIDS) and antiretroviral medication use with subclinical vascular disease. We report the results from two studies, conducted in parallel, within the Women's Interagency HIV Study (WIHS) and the Multicenter AIDS Cohort Study (MACS). WIHS and MACS are population-based US cohort studies that offer several important strengths, including large sample size, inclusion of HIV-uninfected persons who were recruited from the same at-risk populations as the HIV-infected individuals, and extensive longitudinal, protocol-driven data collection on clinical, behavioral, and demographic variables. The present report describes data from the baseline phase of a WIHS-MACS Carotid Ultrasound Substudy, which features standardized image acquisition and measurement of carotid artery intima-media thickness, a quantitative measure of atherosclerosis burden.

Evaluation of the WHO criteria for antiretroviral treatment failure among adults in South Africa.

Abstract: OBJECTIVE:: To assess the performance of WHO clinical and CD4 cell count criteria for antiretroviral treatment (ART) failure among HIV-infected adults in a workplace HIV care programme in South Africa. DESIGN:: Cohort study. METHODS:: We included initially ART-naive participants who remained on first-line therapy and had an evaluable HIV viral load result at the 12-month visit. WHO-defined clinical and CD4 cell count criteria for ART failure were compared against a gold standard of virological failure. RESULTS:: Among 324 individuals (97.5% men, median age 40.2, median starting CD4 cell count and viral load 154 cells/mul and 47 503 copies/ml, respectively), 33 (10.2%) had definite or probable virological failure at 12 months, compared with 19 (6.0%) and 40 (12.5%) with WHO-defined CD4 and clinical failure, respectively. CD4 criteria had a sensitivity of 21.2% and a specificity of 95.8% in detecting virological failure, and clinical criteria had sensitivity of 15.2% and specificity of 88.1%. The positive predictive value of CD4 and clinical criteria in detecting virological failure were 36.8 and 12.8%, respectively. Exclusion of weight loss or tuberculosis failed to improve the performance of clinical criteria. CONCLUSION:: WHO clinical and CD4 criteria have poor sensitivity and specificity in detecting virological failure. The low specificities and positive predictive values mean that individuals with adequate virological suppression risk being incorrectly classified as having treatment failure and unnecessarily switched to second-line therapy. Virological failure should be confirmed before switching to second-line therapy.

HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies.

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

A new strategy to understand how HIV infects women: identification of a window of vulnerability during the menstrual cycle.

Abstract: Although 85% of new HIV cases are due to sexual transmission from men to women little attention is being paid to the immune system in the female reproductive tract (FRT) and to how it meets the conflicting challenges of protecting from pathogens and permitting procreation. As a new approach we have tried to envision how HIV evades FRT mucosal immune protection and have been led to the unexpected conclusion that in a normal menstrual cycle there is a window of vulnerability (7-10 days following ovulation) in which the potential for viral infectivity in the FRT is enhanced. During that period aspects of the innate humoral and cell-mediated immune systems are suppressed by sex hormones to optimize conditions for procreation. Suppression occurs in the upper (Fallopian tubes uterus endocervix) and lower (ectocervix and vagina) FRT and coincides with the recruitment of potentially infectable cells and upregulation of coreceptors essential for viral uptake. Implications of these findings are that the entire FRT is a potential target for HIV infection immune cells and antibodies in blood are not surrogate markers for immune protection in the FRT and immune protection against HIV will require an understanding of the hormone-induced regulation of humoral cellmediated and innate immune systems throughout the FRT. (excerpt)

Education and vulnerability: the role of schools in protecting young women and girls from HIV in southern Africa.

Abstract: Education has a potentially important role to play in tackling the spread of HIV, but is there evidence that this potential is realized? This analysis combines the results of previous literature reviews and updates them with the findings of recent randomized controlled trials and a discussion of possible mechanisms for the effect of schooling on vulnerability to HIV infection. There is a growing body of evidence that keeping girls in school reduces their risk of contracting HIV. The relationship between educational attainment and HIV has changed over time, with educational attainment now more likely to be associated with a lower risk of HIV infection than earlier in the epidemic. Educational attainment cannot, however, be isolated from other socioeconomic factors as the cause of HIV risk reduction. The findings of this analysis suggest that the equitable expansion of primary and secondary schooling for girls in southern Africa will help reduce their vulnerability to HIV. Evidence of ineffective HIV prevention education in schools underlines the need for careful evidence-based programme design. Despite the challenges, recent provisional evidence suggests that highly targeted programmes promoting realistic options for young adults may lead to safer sexual behaviour. Targeted education programmes have also been successful in changing students' attitudes to people living with HIV and AIDS, which is associated with testing and treatment decisions. This reduction in stigma may be crucial in encouraging the uptake of voluntary counselling and testing, a central strategy in the control of the epidemic. Expansions of carefully designed and evaluated school-based HIV prevention programmes can help to reduce stigma and have the potential to promote safe sexual behaviour.

Antiretroviral drugs and liver injury

Abstract: Antiretroviral drug-related liver injury (ARLI) is a common cause of morbidity, mortality and treatment discontinuation in HIV-infected patients [1]. Prevention and management of ARLI have emerged as major issues among HIV-infected patients in the era of HAART [2]. Virtually every licensed antiretroviral medication has been associated with liver enzyme elevations, although certain drugs may cause liver injury more frequently than others. In addition, certain comorbidities, such as chronic hepatitis B (HBV) or hepatitis C (HCV) infection, may predispose patients to ARLI [3]. Several major mechanisms of ARLI have been described, including metabolic host-mediated injury, hypersensitivity reactions, mitochondrial toxicity, and immune reconstitution phenomena. The management of ARLI should be based on its clinical severity and underlying pathogenic mechanism. Herein, we propose use of a universal standard for defining liver injury to enable comparisons between future studies. Novel mechanisms for hepatotoxicity are also discussed along with preventive measures to avoid the onset of ARLI.

Response to combination antiretroviral therapy: variation by age

Abstract: Objective: To provide information on responses to combination antiretroviral therapy in children, adolescents and older HIV-infected persons.Design and setting: Multicohort collaboration of 33 European cohorts.Subjects: Forty-nine thousand nine hundred and twenty-one anti retroviral-naive individuals starting combination antiretroviral therapy from 1998 to 2006.Outcome measures: Time from combination antiretroviral therapy initiation to HIV RNA less than 50copies/ml (virological response), CD4 increase of more than 100cells/mu l (immunological response) and new AIDS/death were analysed using survival methods. Ten age strata were chosen: less than 2, 2-5, 6-12, 13-17, 18-29, 30-39 (reference group), 40-49, 50-54, 55-59 and 60 years or older; those aged 6 years or more were included in multivariable analyses.Results: The four youngest age groups had 223, 184, 219 and 201 individuals and the three oldest age groups had 2693, 1656 and 1613 individuals. Precombination antiretroviral therapy CD4 cell counts were highest in young children and declined with age. By 12 months, 53.7% (95% confidence interval: 53.2-54.1%) and 59.2% (58.7-59.6%) had experienced a virological and immunological response. The probability of virological response was lower in those aged 6-12 (adjusted hazard ratio: 0.87) and 13-17 (0.78) years, but was higher in those aged 50-54 (1.24), 55-59 (1.24) and at least 60 (1.18) years. The probability of immunological response was higher in children and younger adults and reduced in those 60 years or older. Those aged 55-59 and 60 years or older had poorer clinical outcomes after adjusting for the latest CD4 cell count.Conclusion: Better virological responses but poorer immunological responses in older individuals, together with low precombination antiretroviral therapy CD4 cell counts, may place this group at increased clinical risk. The poorer virological responses in children may increase the likelihood of emergence of resistance.

Crack cocaine, disease progression, and mortality in a multicenter cohort of HIV-1 positive women

Abstract: Recent research suggests that cocaine may directly affect the pathobiology of HIV by causing immune alterations in different lymphocytes such as helper T cells (CD4), suppressor/cytotoxic T cells (CD8), and natural killer (NK) cells.1 Studies show that cocaine interferes with the body’s ability to defend against infection by inhibiting the effector functions of neutrophils and macrophages, and by suppressing cytokine production, decreasing operation of important immune responses.2 Cocaine also enhances the replication of HIV in vitro.3 Cells from chronic cocaine users more readily support HIV replication and development of AIDS-defining opportunistic infections than cells from nonusers, suggesting a direct role for cocaine in the acquisition and progression of AIDS.2 Recently, cocaine has been shown to cause membrane permeability facilitating endothelial transmigration of infected dendritic cells across the blood brain barrier to the central nervous system.4 There is also evidence of cocaine-mediated alteration of immune responses and host resistance due to disturbances in the balance of Th1 pro-inflammatory versus Th2 anti-inflammatory cytokines and lipid bioeffectors.3 Epidemiologic research confirms that crack users are at high risk for HIV infection and progression.5-6 In a prospective study of HIV-seropositive drug users, crack use was significantly associated with progression to AIDS.7 A study of HIV-positive current and former drug users found that active cocaine use was the strongest predictor of failure to maintain viral suppression; 13% of active users maintained suppression vs. 46% of non-users.8 In a prospective cohort study, compared with nonusers and former users, active cocaine and heroin users experienced smaller median reductions in HIV-1 RNA and smaller median increases in CD4 from baseline, controlling for antiretroviral exposure, adherence, and socio-demographic factors.9 Compared to nonusers, the risk of AIDS-related opportunistic conditions was greater for persistent users and intermittent users during periods of active use, with no difference during periods of abstinence.10 Mixed results characterize studies of drug users in exclusively female U.S. cohorts. In a multi-center cohort of HIV-positive women, injection drug use was not associated with progression to AIDS.11 Another large multi-site cohort study found that hard drug use (i.e., cocaine, heroin, methadone, or injecting drugs) was significantly associated with AIDS-defining illnesses, but not with change in CD4, HIV-RNA, or mortality.12 In a third multi-site cohort of HIV+ women, non-injection drug use was associated with time to AIDS-defining event but not with AIDS-related mortality.13 While suggestive, these studies and others focusing on injection drug use do not uniformly demonstrate a link between illicit drug use and HIV-1 disease progression.14-17 Possible reasons include: diverse definitions of illness progression; failure to differentiate between active and nonactive users; and lack of distinction between mortality due to AIDS versus non-AIDS causes.17 Other reasons include lack of controls for highly active antiretroviral therapy (HAART) use and adherence, and inadequate follow-up periods. We addressed all of these issues by examining patterns of crack use and their association with four distinct measures of HIV/AIDS disease progression in a multi-center cohort over an eight-and-one-half-year period during the HAART era.

Reduced bone mineral density in HIV-infected patients: prevalence and associated factors.

Abstract: Background There is a high prevalence of bone demineralization among HIV-infected patients but mechanisms of alteration of bone turnover are still unclear and it is thought to be multifactorial. Methods A cross-sectional survey of 492 HIV-infected patients within the Aquitaine cohort estimated the prevalence of osteoporosis/osteopenia and investigated associated factors. Bone mineral density of total body, lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry. Multivariable analyses of the association with HIV disease status, treatment and anthropometric parameters were stratified according to gender. Results Median age was 43 years (interquartile range, 38-50); 73% were male; 19.7% patients had reached AIDS, 93.1% were treated with HAART; and 28.5% had lipodystrophy. Based on World Health Organization criteria, osteopenia was diagnosed in 54.6% of men [95% confidence interval (CI), 49.4-59.7) and 51.1% of women (95% CI, 42.6-59.6) and osteoporosis in 33.7% of men (95% CI, 28.8-38.6) and 8.3% of women (95% CI, 3.6-13.9). Using a polytomous logistic regression, older age, homosexual transmission group, low body mass index and low HIV plasma viral load were associated with the diagnosis of bone abnormalities in men, whereas older age and low CD4 lymphocyte count nadir were independently associated with osteoporosis/osteopenia in women. The use of HAART was not related to osteoporosis after adjustment (P = 0.58). Conclusions This cohort-based survey showed a high prevalence of osteopenia and osteoporosis of multifactorial origin. Mechanisms and consequences of these bone disorders need to be investigated.

Declines in risk behaviour and sexually transmitted infection prevalence following a community-led HIV preventive intervention among female sex workers in Mysore, India.

Abstract: Objective: To investigate the impact on sexual behaviour and sexually transmitted infections (STI) of a comprehensive community-led intervention programme for reducing sexual risk among female sex workers (FSW) in Mysore, India. The key programme components were: community mobilization and peer-mediated outreach; increasing access to and utilization of sexual health services; and enhancing the enabling environment to support programme activities. Methods: Two cross-sectional surveys among random samples of FSW were conducted 30 months apart, in 2004 and 2006. Results: Of over 1000 women who sell sex in Mysore city, 429 participated in the survey at baseline and 425 at follow-up. The median age was 30 years, median duration in sex work 4 years, and the majority were street based (88%). Striking increases in condom use were seen between baseline and follow-up surveys: condom use at last sex with occasional clients was 65% versus 90%, P < 0001; with repeat clients 53% versus 66%, P < 0.001; and with regular partners 7% versus 30%., P < 0.001. STI prevalence declined from baseline to follow-up: syphilis 25% versus 12%, P < 0.001; trichomonas infection 33% versus 14%, P < 0.001; chlamydial infection 11% versus 5%, P = 0.001; gonorrhoea 50% versus 2%, P = 0.03. HIV prevalence remained stable (26% versus 24%), and detuned assay testing suggested a decline in recent HIV infections. Conclusion: This comprehensive HIV preventive intervention empowering FSW has resulted in striking increases in reported condom use and a concomitant reduction in the prevalence Of Curable STI. This model should be replicated in similar urban settings across India.

Rapid scaling-up of antiretroviral therapy in 10,000 adults in Côte d'Ivoire: 2-year outcomes and determinants.

Abstract: The objective was to assess the rates and determinants of mortality loss to follow-up and immunological failure in a nongovernmental organization-implemented program of access to antiretroviral treatment in Cote dIvoire. In each new treatment center professionals were trained in HIV care and a computerized data system was implemented. Individual patient and program level determinants of survival loss to follow-up and immunological failure were assessed by multivariate analysis. Between May 2004 and February 2007 10 211 patients started antiretroviral treatment in 19 clinics (median preantiretroviral treatment CD4 cell count 123 cells/ml; initial regimen zidovudine-lamivudine-efavirenz 20%; stavudine-lamivudine-efavirenz 22%; stavudine-lamivudine-nevirapine 52%). At 18 months on antiretroviral treatment the median gain in CD4 cell count was +202 cells/microl the probability of death was 0.15 and the probability of being loss to follow-up was 0.21. In addition to the commonly reported determinants of impaired outcomes (low CD4 cell count low BMI low hemoglobin advanced clinical stage old age and poor adherence) two factors were also shown to independently jeopardize prognosis: male sex (men vs. women: hazard ratio = 1.52 for death 1.27 for loss to follow-up 1.31 for immunological failure); and attending a recently opened clinic (inexperienced vs. experienced centers: hazard ratio = 1.40 for death 1.58 for loss to follow-up). None of the three outcomes was associated with the drug regimen. In this rapidly scaling-up program survival and immune reconstitution were good; women and patients followed up in centers with longer experience had better outcomes; outcomes were similar in zidovudine/stavudine-based regimens and in efavirenz/nevirapine-based regimens. Decreasing the rate of loss to follow-up should now be the top priority in antiretroviral treatment rollout. (authors)

Long-term immunologic response to antiretroviral therapy in low-income countries: a collaborative analysis of prospective studies.

Abstract: BACKGROUND: Few data are available on the long-term immunologic response to antiretroviral therapy (ART) in resource-limited settings, where ART is being rapidly scaled up using a public health approach, with a limited repertoire of drugs. OBJECTIVES: To describe immunologic response to ART among ART patients in a network of cohorts from sub-Saharan Africa, Latin America, and Asia. STUDY POPULATION/METHODS: Treatment-naive patients aged 15 and older from 27 treatment programs were eligible. Multilevel, linear mixed models were used to assess associations between predictor variables and CD4 cell count trajectories following ART initiation. RESULTS: Of 29 175 patients initiating ART, 8933 (31%) were excluded due to insufficient follow-up time and early lost to follow-up or death. The remaining 19 967 patients contributed 39 200 person-years on ART and 71 067 CD4 cell count measurements. The median baseline CD4 cell count was 114 cells/microl, with 35% having less than 100 cells/microl. Substantial intersite variation in baseline CD4 cell count was observed (range 61-181 cells/microl). Women had higher median baseline CD4 cell counts than men (121 vs. 104 cells/microl). The median CD4 cell count increased from 114 cells/microl at ART initiation to 230 [interquartile range (IQR) 144-338] at 6 months, 263 (IQR 175-376) at 1 year, 336 (IQR 224-472) at 2 years, 372 (IQR 242-537) at 3 years, 377 (IQR 221-561) at 4 years, and 395 (IQR 240-592) at 5 years. In multivariable models, baseline CD4 cell count was the most important determinant of subsequent CD4 cell count trajectories. CONCLUSION: These data demonstrate robust and sustained CD4 response to ART among patients remaining on therapy. Public health and programmatic interventions leading to earlier HIV diagnosis and initiation of ART could substantially improve patient outcomes in resource-limited settings.