HIV-1 coreceptor usage and CXCR4-specific viral load predict clinical disease progression during combination antiretroviral therapy

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

CD4+ T-cell count increase in HIV-1-infected patients with suppressed viral load within 1 year after start of antiretroviral therapy

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

Contribution of 20 single nucleotide polymorphisms of 13 genes to dyslipidemia associated with antiretroviral therapy

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

Hypogonadism in HIV-1-infected men is common and does not resolve during antiretroviral therapy

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

Plasma leptin levels in men are not related to the development of lipoatrophy during antiretroviral therapy

OBJECTIVES: To assess the correlations between the hormone leptin and lipoatrophy in HIV-positive, treatment-naive patients on combination antiretroviral therapy (cART). DESIGN: Case-control study nested in a multicentre cohort of HIV-infected adults. Cases were patients that developed lipoatrophy and controls those who did not. PATIENTS AND METHODS: Clinical parameters and plasma leptin determinations were studied in 97 HIV-1-infected, treatment-naive Caucasian men (10 cases and 87 controls) on an unchanged and virologically successful drug regimen with a zidovudine/lamivudine backbone at baseline and after 2 years of cART. The association of plasma leptin levels and the development of lipoatrophy was investigated. RESULTS: Two years of cART was not associated with a change in plasma leptin levels. Plasma leptin levels remained sensible to changes in body mass index. There was no difference in leptin levels between patients who developed lipoatrophy and controls, neither before nor after cART. The only predictor of development of lipoatrophy was a higher age (P = 0.02). CONCLUSIONS: Leptin as measured in plasma is unlikely to play a major role in the genesis of lipoatrophy.

Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia

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

Characteristics, determinants, and clinical relevance of CD4 T cell recovery to <500 cells/microL in HIV type 1-infected individuals receiving potent antiretroviral therapy

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

Modeling the influence of APOC3, APOE, and TNF polymorphisms on the risk of antiretroviral therapy-associated lipid disorders

BACKGROUND: Single-nucleotide polymorphisms in genes involved in lipoprotein and adipocyte metabolism may explain why dyslipidemia and lipoatrophy occur in some but not all antiretroviral therapy (ART)-treated individuals. METHODS: We evaluated the contribution of APOC3 -482C-->T, -455T-->C, and 3238C-->G; epsilon 2 and epsilon 4 alleles of APOE; and TNF -238G-->A to dyslipidemia and lipoatrophy by longitudinally modeling >2600 lipid determinations and 2328 lipoatrophy assessments in 329 ART-treated patients during a median follow-up period of 3.4 years. RESULTS: In human immunodeficiency virus (HIV)-infected individuals, the effects of variant alleles of APOE on plasma cholesterol and triglyceride levels and of APOC3 on plasma triglyceride levels were comparable to those reported in the general population. However, when treated with ritonavir, individuals with unfavorable genotypes of APOC3 and [corrected] APOE were at risk of extreme hypertriglyceridemia. They had median plasma triglyceride levels of 7.33 mmol/L, compared with 3.08 mmol/L in the absence of ART. The net effect of the APOE*APOC3*ritonavir interaction was an increase in plasma triglyceride levels of 2.23 mmol/L. No association between TNF -238G-->A and lipoatrophy was observed. CONCLUSIONS: Variant alleles of APOE and APOC3 contribute to an unfavorable lipid profile in patients with HIV. Interactions between genotypes and ART can lead to severe hyperlipidemia. Genetic analysis may identify patients at high risk for severe ritonavir-associated hypertriglyceridemia.

Body fat changes among antiretroviral-naive patients on PI- and NNRTI-based HAART in the Swiss HIV cohort study

BACKGROUND: Body fat changes are common in patients with HIV. For patients on protease inhibitor (PI)-based highly active antiretroviral therapy (HAART), these changes have been associated with increasing exposure to therapy in general and to stavudine in particular. Our objective is to show whether such associations are more or less likely for patients on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART. METHODS: We included all antiretroviral-naive patients in the Swiss HIV Cohort Study starting HAART after April 2000 who had had body weight, CD4 cell count and plasma HIV RNA measured between 6 months before and 3 months after starting HAART, and at least one assessment of body fat changes after starting HAART. At visits scheduled every 6 months, fat loss or fat gain is reported by agreement between patient and physician. We estimate the association between reported body fat changes and both time on therapy and time on stavudine, using conditional logistical regression. RESULTS: Body fat changes were reported for 85 (9%) out of 925 patients at their first assessment; a further 165 had only one assessment. Of the remaining 675 patients, body fat changes were reported for 156 patients at a rate of 13.2 changes per 100 patient-years. Body fat changes are more likely with increasing age [odds ratio (OR) 1.18 (1.00-1.38) per 10 years], with increasing BMI [OR 1.06 (1.01-1.11)] and in those with a lower baseline CD4 cell count [OR 0.91 (0.83-1.01) per 100 cells/microl]. There is only weak evidence that body fat changes are more likely with increasing time on HAART [OR 1.16 (0.93-1.46)]. After adjusting for time on HAART, fat loss is more likely with increasing stavudine use [OR 1.70 (1.34-2.15)]. There is no evidence of an association between reported fat changes and time on NNRTI therapy relative to PI therapy in those patients who used either one therapy or the other [OR 0.98 (0.56-1.63)]. CONCLUSION: Fat loss is more likely to be reported with increasing exposure to stavudine. We find no evidence of major differences between PI and NNRTI therapy in the risk of reported body fat changes.

[Antiretroviral therapy and pregnancy]

Whereas the perinatal transmission rate with untreated HIV positive women is around 30%, the results of Pediatric AIDS Clinical Trials Group in 1994 showed a reduction by nearly 70% with Zidovudin chemoprophylaxis. The transmission rate can even be reduced to under 2%, if a cesarean section before onset of labour and before premature rupture of membranes is done in addition. An individualized, optimal antiretroviral combination therapy, ideally introduced in the second trimenon (in special cases even already in the first trimenon), is of great importance. As a further strategy of prevention of perinatal transmission, intravenous Zidovudin chemoprophylaxis should be given in addition to the mother during labour and to the newborn during the first six weeks of life. Besides very few exceptions, long-term data after intrauterine administration of antiretroviral therapy do not show any teratogen or other long term consequences to date. The situation in developing countries is very critical with still high transmission rates because of the lack of antiretroviral therapy due to logistical reasons and costs and the need of breastfeeding. For these reasons, more and more feasible short protocols are developed with at least fifty percent reduction of neonatal transmission rates.

Effect of atazanavir versus other protease inhibitor-containing antiretroviral therapy on endothelial function in HIV-infected persons: randomised controlled trial

OBJECTIVE: Impaired endothelial function was demonstrated in HIV-infected persons on protease inhibitor (PI)-containing antiretroviral therapy, probably due to altered lipid metabolism. Atazanavir is a PI causing less atherogenic lipoprotein changes. This study determined whether endothelial function improves after switching from other PI to atazanavir. DESIGN: Randomised, observer-blind, treatment-controlled trial. SETTING: Three university-based outpatient clinics. PATIENTS: 39 HIV-infected persons with suppressed viral replication on PI-containing regimens and fasting low-density lipoprotein (LDL)-cholesterol greater than 3 mmol/l. INTERVENTION: Patients were randomly assigned to continue the current PI or change to unboosted atazanavir. MAIN OUTCOME MEASURES: Endpoints at week 24 were endothelial function assessed by flow-mediated dilation (FMD) of the brachial artery, lipid profiles and serum inflammation and oxidative stress parameters. RESULTS: Baseline characteristics and mean FMD values of the two treatment groups were comparable (3.9% (SD 1.8) on atazanavir versus 4.0% (SD 1.5) in controls). After 24 weeks' treatment, FMD decreased to 3.3% (SD 1.4) and 3.4% (SD 1.7), respectively (all p = ns). Total cholesterol improved in both groups (p<0.0001 and p = 0.01, respectively) but changes were more pronounced on atazanavir (p = 0.05, changes between groups). High-density lipoprotein and triglyceride levels improved on atazanavir (p = 0.03 and p = 0.003, respectively) but not in controls. Serum inflammatory and oxidative stress parameters did not change; oxidised LDL improved significantly in the atazanavir group. CONCLUSIONS: The switch from another PI to atazanavir in treatment-experienced patients did not result in improvement of endothelial function despite significantly improved serum lipids. Atherogenic lipid profiles and direct effects of antiretroviral drugs on the endothelium may affect vascular function. Trial registration number: NCT00447070.

Electronic medical record systems, data quality and loss to follow-up: survey of antiretroviral therapy programmes in resource-limited settings

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

Early loss of HIV-infected patients on potent antiretroviral therapy programmes in lower-income countries

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

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

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.

Does short-term virologic failure translate to clinical events in antiretroviral-naïve patients initiating antiretroviral therapy in clinical practice?

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