Influence of polymorphisms within the CX3CR1 and MDR-1 genes on initial antiretroviral therapy response

OBJECTIVE: Single nucleotide polymorphisms (SNP) in the genes encoding the human CX3CR1 chemokine receptor and the P-glycoprotein multidrug transporter have been associated with accelerated disease progression in untreated individuals and implicated in therapeutic response, respectively. This retrospective study assessed the influence of SNP in the CX3CR1 and MDR-1 genes on initial virological and immunological response in 461 HIV-infected, antiretroviral-naive individuals initiating antiretroviral therapy in British Columbia, Canada. METHODS: CX3CR1 and MDR-1 SNP were determined by PCR amplification of human DNA from plasma, followed by DNA sequencing. Time to virological success [time to HIV plasma viral load (pVL) < or = 500 copies/ml], virological failure (subsequent time to the second of two consecutive pVL > or = 500) and immunological failure (time to the second consecutive CD4 cell count below baseline) were analyzed by Kaplan-Meier methods. RESULTS: Frequencies of CX3CR1 amino acid haplotypes were 249V 280T (0.75), 249I 280M (0.15), and 249I 280T (0.1). Frequencies of MDR-1 nucleotide polymorphisms were 3435C (0.47) and 3435T (0.53). There was no effect detected for SNP in CX3CR1 or MDR-1 on time to virological success, nor of CX3CR1 and MDR-1 SNP on time to virological and immunological failure, respectively ( P > 0.1). There was a trend to earlier virological failure in the MDR-1 3435C/C genotype group ( P = 0.07), and a statistically significant trend to earlier immunological failure in individuals with the CX3CR1 249I polymorphism ( P = 0.02). These remained significant after correcting for baseline age, sex, pVL, CD4 cell count, type of therapy, and adherence ( P < or = 0.05). CONCLUSION: Polymorphisms in MDR-1 and CX3CR1 may be associated with accelerated virological and immunological therapy failure, respectively.     

Natural history of patients with low-level HIV viremia on antiretroviral therapy

Ultrasensitive assays for HIV RNA have identified a significant number of patients with persistent low-level viremia despite antiretroviral therapy. The clinical implications of maintaining antiretroviral therapy during low-level HIV viremia remain unclear. The primary objective of this study was to determine the rate and risk factors for virological increase in subjects with low-level HIV viremia who did not change antiretroviral therapy. Between July 1998 and February 2002, we retrospectively observed 79 HIV-infected adults with low-level HIV viremia (between 50 and 500 copies per milliliter) who had been on a stable antiretroviral regimen for at least 3 months and continued that regimen for at least 3 more months. Virologic increase, defined as HIV RNA levels greater than 1000 copies per milliliter, was observed in 29 of the 79 (37%) subjects. The CD4 cell counts decreased by a median of 1.8 cells/mm(3) per month (interquartile range [IQR], -19.6 to 2.3 cells/mm3) in this group but increased by a median of 0.5 cells/mm3 per month (IQR, -6.3 to 5.8 cells/mm3) in the 50 subjects who did not experience virologic increase. A Kaplan-Meier estimate showed that at 3 years of follow-up, approximately 40% of the observed cohort had not experienced virologic increase. There was a higher rate of virologic increase per log increase in HIV viral load at entry into the cohort (adjusted hazards ratio [HR] 3.7; 95% confidence interval [CI], 1.1 to 12.6). Subjects of white race were also more likely to experience virological increase (adjusted HR 2.6; CI, 1.2 to 5.8). Maintenance of antiretroviral therapy despite low-level HIV viremia provided sustained immunological benefit over a 2-year period in approximately two thirds of our cohort. Higher initial HIV RNA levels and white race were predictors for virologic increase.     

Persistent low-level viraemia and virological failure in HIV-1-infected patients treated with highly active antiretroviral therapy

OBJECTIVE: To assess the prognostic significance of persistent low-level viraemia (PLV, defined as persistent plasma viral loads of 51-1000 HIV-1 RNA copies/mL for at least 3 months) in patients who had achieved viral suppression on antiretroviral therapy (ART). METHODS: A retrospective cohort of HIV-infected patients who received ART, were followed-up for > or =12 months, made regular visits to the clinic during which blood tests were performed for an ultrasensitive HIV RNA assay every 3 months, and achieved viral loads <50 copies/mL were evaluated. Virological failure was defined as two consecutive viral load measurements >1000 copies/mL. RESULTS: Of 362 patients, 78 (27.5%) experienced PLV. The demographics of patients with and without PLV were similar. PLV occurred at a mean (+/-standard deviation) of 22.6+/-16.9 months after ART initiation and lasted for 6.4+/-3.4 months. During a median follow-up of 29.5 months, patients with PLV had a higher rate of virological failure (39.7% vs 9.2%; P < 0.001). The median time to failure was 68.4 months [95% confidence interval (CI) 37.0-99.7] for patients with PLV and >72 months for patients without PLV (log rank test, P < 0.001). By Cox regression, patients with PLV had a greater risk of virological failure [hazard ratio (HR) 3.8; 95% CI 2.2-6.4; P < 0.001]. Among patients with PLV, a PLV of >400 copies/mL (HR 3.3; 95% CI 1.5-7.1; P = 0.003) and a history of ART (HR 2.4; 95% CI 1.0-5.7; P = 0.042) predicted virological failure. CONCLUSIONS: PLV is associated with virological failure. Patients with a PLV >400 copies/mL and a history of ART experience are more likely to experience virological failure. Patients with PLV should be considered for treatment optimization and interventional studies.     

Adherence is not a barrier to successful antiretroviral therapy in South Africa

OBJECTIVE: To determine adherence of an indigent African HIV-infected cohort initiating antiretroviral therapy (ART); to identify predictors of incomplete adherence (< 95%) and virologic failure (> 400 HIV RNA copies/ml). DESIGN: Prospective monitoring of adherence in a poor HIV-positive cohort, attending a public sector hospital and receiving ART through phase III studies. METHODS: Adherence to ART was determined over 48 weeks by counting tablet-returns. Logistic regression models including age, WHO HIV stage, home language, socio-economic status, complexity and type of regimen were fitted to determine predictors of incomplete adherence and virologic failure at 48 weeks. RESULTS: 289 patients were recruited between January 1996 and May 2001. Median (mean) adherence of the cohort was 93.5% (87.2%). Three times daily dosing [risk ratio (RR), 3.07; 95% confidence interval (CI), 1.40-6.74], speaking English (RR, 0.41; 95% CI, 0.21-0.80) and age (RR, 0.97; 95% CI, 0.94-0.99) were independent predictors of incomplete adherence. Socio-economic status, sex and HIV stage did not predict adherence. Independent predictors of virologic failure included baseline viral load (RR, 2.57; 95% CI, 1.57-4.22) and three times daily dosing (RR, 2.64; 95% CI, 1.23-5.66), incomplete adherence (RR, 1.92; 95% CI, 1.10-3.57), age (RR, 0.96; 95% CI, 0.92-0.99) and dual nucleoside therapy (RR, 2.69; 95% CI, 1.17-6.15). CONCLUSION: The proportion of individuals achieving viral suppression matched results from the developing world. Speaking the same language as site staff and simplified dosing frequency were beneficial. Socio-economic status had no impact on adherence and should not be used as a limitation to ART access.     

Clinical utility of HIV-1 genotyping and expert advice: the Havana trial.

OBJECTIVE: To determine whether HIV-1 genotyping and expert advice add additional short-term virologic benefit in guiding antiretroviral changes in HIV+ drug-experienced patients. DESIGN: A two factorial (genotyping and expert advice), randomized, open label, multi-center trial. The patients were stratified according to the number of treatment failures. PATIENTS AND METHODS: HIV-1 infected patients on stable antiretroviral therapy who presented virological failure were included into the study. Genotypic testing was performed by using TrueGene HIV Genotyping kit and the results were interpreted by a software package (RetroGram, version 1.0). An expert advisory committee suggested the new therapeutic approach based on clinical information alone or on clinical information plus HIV-1 genotyping results. Plasma HIV-1 RNA load, CD4+ cell count and adverse events were recorded at baseline and every 12 weeks. RESULTS: A total of 326 patients were included. The baseline CD4+ cell count and plasma HIV-1 RNA were 387 (+/- 224) x 10(6) cells/l and 4 (+/- 1) log(10) respectively. The proportion of patients with plasma HIV-1 RNA < 400 copies/ml at 24 weeks differed between genotyping and no genotyping arms (48.5 and 36.2%, P < 0.05). Factors associated with a higher probability of plasma HIV-1 RNA < 400 copies/ml were HIV-1 genotyping [odds ratio (OR), 1.7; 95% confidence interval (CI), 1.1-2.8; P = 0.016] and the expert advice in patients failing to a second-line antiretroviral therapy (OR, 3.2; 95% CI, 1.2-8.3; P = 0.016). CONCLUSIONS: HIV-1 genotyping interpreted by a software package improves the virological outcome when it is added to the clinical information as a basis for decisions on changing antiretroviral therapy. The expert advice also showed virologic benefit in the second failure group.     

Impact of GB virus type C infection on mother-to-child HIV transmission in the Women and Infants Transmission Study Cohort

BACKGROUND: GB virus type C (GBV-C) viraemia is associated with a beneficial outcome in HIV-infected individuals in several though not all studies. GBV-C viraemia was examined in a matched case-control study of 133 HIV-infected pregnant women who transmitted HIV to their infants ('cases') and 266 non-transmitting controls. METHODS: HIV-infected children and controls were pair-matched for high-risk delivery, race and year of delivery. GBV-C status was determined in maternal plasma samples obtained at or within 3 months of delivery. RESULTS: Pregnant women with GBV-C viraemia (11% of those studied) had lower HIV RNA levels (P=0.01) and higher CD4 percentages (P=0.0006) [corrected] than women without GBV-C. A trend towards decreased mother-to-child transmission in the multivariate analysis was observed among GBV-C viraemic women delivering after highly active antiretroviral therapy (HAART) became available [odds ratio (OR) 0.30, 95% confidence interval (CI) 0.08-1.05; P=0.06], but not in women delivering prior to the widespread use of HAART. CONCLUSIONS: GBV-C viraemia was associated with a beneficial effect on CD4 percentage and HIV RNA level in these pregnant women, and was also associated with a trend towards reduced risk of mother-to-child HIV transmission among women after HAART became available. Further studies with larger or multiple cohorts are necessary to assess possible benefits in this population.     

Reduced mother-to-child transmission of HIV associated with infant but not maternal GB virus C infection

BACKGROUND: Prolonged coinfection with GB virus C (GBV-C) has been associated with improved survival in human immunodeficiency virus (HIV)-infected adults. We investigated whether maternal or infant GBV-C infection was associated with mother-to-child transmission (MTCT) of HIV-1 infection. METHODS: The study population included 1364 HIV-infected pregnant women enrolled in 3 studies of MTCT of HIV in Bangkok, Thailand (the studies were conducted from 1992-1994, 1996-1997, and 1999-2004, respectively). We tested plasma collected from pregnant women at delivery for GBV-C RNA, GBV-C antibody, and GBV-C viral genotype. If GBV-C RNA was detected in the maternal samples, the 4- or 6-month infant sample was tested for GBV-C RNA. The rates of MTCT of HIV among GBV-C-infected women and infants were compared with the rates among women and infants without GBV-C infection. RESULTS: The prevalence of GBV-C RNA in maternal samples was 19%. Of 245 women who were GBV-C RNA positive, 101 (41%) transmitted GBV-C to their infants. Of 101 infants who were GBV-C RNA positive, 2 (2%) were infected with HIV, compared with 162 (13%) of 1232 infants who were GBV-C RNA negative (odds ratio [OR] adjusted for study, 0.13 [95% confidence interval {CI}, 0.03-0.54]). This association remained after adjustment for maternal HIV viral load, receipt of antiretroviral prophylaxis, CD4(+) count, and other covariates. MTCT of HIV was not associated with the presence of GBV-C RNA (adjusted OR [aOR], 0.94 [95% CI, 0.62-1.42]) or GBV-C antibody (aOR, 0.90 [95% CI, 0.54-1.50]) in maternal samples. CONCLUSIONS: Reduced MTCT of HIV was significantly associated with infant acquisition of GBV-C but not with maternal GBV-C infection. The mechanism for this association remains unknown.     

Acquisition of GB Virus Type C and Lower Mortality in Patients With Advanced HIV Disease

Background.?GB virus type C (GBV-C) is transmitted by sexual or parenteral exposure and is prevalent among patients receiving blood products. GBV-C is associated with lower human immunodeficiency virus (HIV) RNA and better survival among HIV-infected patients. Open questions are the presence and the direction of any causal relationship between GBV-C infection and HIV disease markers in the context of highly active antiretroviral therapy (HAART). Methods.?We used a limited access database obtained from the National Heart, Lung, and Blood Institute's Viral Activation Transfusion Study (VATS), a randomized controlled trial of leukoreduced vs nonleukoreduced transfusions to HIV-infected transfusion-naive patients. Blood samples from 489 subjects were tested for GBV-C markers. Cox regression models and inverse probability of treatment weights were used to examine the association between GBV-C coinfection and mortality in the VATS cohort. Results.?We found a significant reduction in mortality among GBV-C coinfected VATS subjects, after adjusting for HAART status, HIV RNA level, and CD4 cell count at baseline. Acquisition of GBV-C RNA (n?=?39) was associated with lower mortality in 294 subjects who were GBV-C negative at baseline, adjusting for baseline covariates (hazard ratio?=?0.22, 95% confidence interval [CI]: .08-.58) and in models in which weights were used to control for time-updated covariates (odds ratio?=?0.21, 95% CI: .08-.60). Conclusions.?GBV-C viremia is associated with lower mortality, and GBV-C acquisition via transfusion is associated with a significant reduction in mortality in HIV-infected individuals, controlling for HIV disease markers. These findings provide the first evidence that incident GBV-C infection alters mortality in HIV-infected patients.     

The effect of baseline CD4 cell count and HIV-1 viral load on the efficacy and safety of nevirapine or efavirenz-based first-line HAART

BACKGROUND: A substantial number of patients start their first-line antiretroviral therapy at an advanced stage of an HIV-1 infection. Potential differences between specific drug regimens in antiviral efficacy and safety in these patients are of major importance. METHODS: A post-hoc analysis within the randomized controlled 2NN trial comparing efficacy between regimes containing nevirapine (NVP), efavirenz (EFV), or both, in addition to stavudine and lamivudine. Primary outcome: risk of virologic failure in different strata of baseline CD4 T-lymphocyte counts and plasma HIV-1 RNA concentrations (pVL). Virologic failure: never reaching a pVL < 400 copies/ml, or a rebound to two consecutive values > 400 copies/ml. RESULTS: The risk of virologic failure was increased at very low CD4 counts (< 25 x 10(6) cells/l) compared to CD4 counts > 200 x 10(6) cells/l [hazard ratio (HR), 1.28; 95% confidence interval (CI), 0.93-1.77]. The same was seen for a pVL > or = 100,000 copies/ml compared to a lower pVL (HR, 1.20; CI, 0.96-1.50). There were no statistically significant differences between NVP and EFV in risk of virologic failure within any of the CD4 or pVL strata, although EFV performed slightly better in the low CD4 stratum. The incidence of rash in the NVP group was significantly higher in female patients with higher CD4 cell counts, while adverse events in the EFV group were not associated with CD4 cell count. CONCLUSIONS: Initial antiretroviral therapy including NVP or EFV is effective in patients with an advanced HIV-1 infection. A high baseline CD4 cell count is associated with the occurrence of rash in female patients using NVP.     

Factors associated with clinical and virological failure in patients receiving a triple therapy including a protease inhibitor

OBJECTIVE: To determine the predictors of virological and clinical failure in patients receiving a protease inhibitor as part of triple therapy. METHODS: From the French Hospital Database on HIV, 1402 protease inhibitor-naive patients starting a highly active antiretroviral therapy regimen with ritonavir, saquinavir-hard gel capsule (hgc) or indinavir between July 1996 and March 1997, and with measured HIV RNA at baseline and at 12 months, were studied for progression to a new AIDS-defining event (ADE) or death. Virological failure was defined as plasma HIV RNA > 1000 copies/ml at 12 months. Multivariate analyses were performed using Cox models for clinical outcomes and logistic regression for virological outcomes. RESULTS: During a median follow-up of 14.1 months, 94 (6.7%) patients experienced an ADE or died. At 12 months, 700 patients (49.9%) had virological failure. In the multivariate analysis, baseline CD4 cell count and viral load were found to be independent predictors of both virological and clinical failure. Neither the type of the first protease inhibitor taken nor previous antiretroviral therapy experience was associated with risk of clinical progression. For virological failure, the use of saquinavir-hgc was associated with a significant 1.96-fold increase in risk compared with indinavir; pre-treated patients were at higher risk than antiretroviral therapy-naive patients. CONCLUSION: In this study with large samples of patients, the use of saquinavir-hgc was associated with higher risk of virological failure at 12 months than were ritonavir and indinavir; no differences between protease inhibitors were found for clinical progression. As biases cannot be excluded, a longer duration of follow-up will be necessary to answer the question of whether the results are really discrepant or simply reflect the delay between virological failure and clinical manifestations.     

The role of targeted viral load testing in diagnosing virological failure in children on antiretroviral therapy with immunological failure

Objectives To determine the improvement in positive predictive value of immunological failure criteria for identifying virological failure in HIV‐infected children on antiretroviral therapy (ART) when a single targeted viral load measurement is performed in children identified as having immunological failure. Methods Analysis of data from children (<16 years at ART initiation) at South African ART sites at which CD4 count/per cent and HIV‐RNA monitoring are performed 6‐monthly. Immunological failure was defined according to both WHO 2010 and United States Department of Health and Human Services (DHHS) 2008 criteria. Confirmed virological failure was defined as HIV‐RNA >5000 copies/ml on two consecutive occasions <365 days apart in a child on ART for ≥18 months. Results Among 2798 children on ART for ≥18 months [median (IQR) age 50 (21–84) months at ART initiation], the cumulative probability of confirmed virological failure by 42 months on ART was 6.3%. Using targeted viral load after meeting DHHS immunological failure criteria rather than DHHS immunological failure criteria alone increased positive predictive value from 28% to 82%. Targeted viral load improved the positive predictive value of WHO 2010 criteria for identifying confirmed virological failure from 49% to 82%. Conclusion The addition of a single viral load measurement in children identified as failing immunologically will prevent most switches to second‐line treatment in virologically suppressed children.     

Factors associated with virological response in HIV-infected patients failing antiretroviral therapy: a prospective cohort study

OBJECTIVES: To assess the antiviral response to optimized therapy following genotypic resistance testing and to identify factors associated with virological response in HIV-1-infected patients failing antiretroviral therapy. METHODS: A prospective cohort study was conducted in 344 HIV-1-infected patients who underwent genotypic resistance testing because of virological failure. Virological response was defined as a plasma HIV RNA level below 200 HIV-1 RNA copies/mL or a drop of plasma viral load from baseline of more than 1 log10. A multivariate logistic regression analysis was performed to identify factors associated with virological response. RESULTS: The median age of the patients was 40 years, with a male to female ratio of 4:1. Fifty-one per cent of patients had received the three major classes of antiretrovirals and the median duration of previous antiretroviral therapy was 4.6 years. At baseline, the median plasma HIV RNA level was 4.4 log10 copies/mL and the median CD4 cell count was 274 cells/microL. At 3 months, 55% of patients (188 of 344) had a virological response, which was sustained at 6 months (53%). Predictors of virological response were exposure to two or fewer protease inhibitors [odds ratio (OR) 1.8; P=0.046], and use in optimized therapy of a new class of antiretrovirals (OR 2.9; P=0.006), of more than two new drugs (OR 3.0; P<0.0001), of abacavir (OR 1.9; P=0.03), or of lopinavir/ritonavir (OR 3.7; P=0.0002). CONCLUSIONS: A high proportion of patients achieved a short-term virological response in this cohort study. Patients with the least experience of protease inhibitor treatment and in whom a new class of antiretroviral, more than two new drugs, abacavir or lopinavir/ritonavir was used in optimized therapy had the best virological outcome.     

Benefit of viral load testing for confirmation of immunological failure in HIV patients treated in rural Malawi

Objective Viral load testing is used in the HIV programme of Chiradzulu, Malawi, to confirm the diagnosis of immunological failure to prevent unnecessary switching to second‐line therapy. Our objective was to quantify the benefit of this strategy for management of treatment failure in a large decentralized HIV programme in Africa. Methods Retrospective analysis of monitoring data from adults treated with first‐line antiretroviral regimens for >1 year and meeting the WHO immunological failure criteria in an HIV programme in rural Malawi. The positive predictive value of using immunological failure criteria to diagnose virological failure (viral load >5000 copies/ml) was estimated. Results Of the 227 patients with immunological failure (185 confirmed with a repeat CD4 measurement), 155 (68.2%) had confirmatory viral load testing. Forty‐four (28.4%) had viral load >5000 copies/ml and 57 (36.8%) >1000 copies/ml. Positive predictive value was 28.4% (95% CI 21.4–36.2%). Repeat CD4 count testing showed that 41% of patients initially diagnosed with immunological failure did no longer meet failure criteria. Conclusions Our results support the need for confirming all cases of immunological failure with viral load testing before switching to second‐line ART to optimize the use of resources in developing countries.     

Superior virological response to boosted protease inhibitor-based highly active antiretroviral therapy in an observational treatment programme

Background

The use of boosted protease inhibitor (PI)‐based antiretroviral therapy has become increasingly recommended in international HIV treatment consensus guidelines based on the results of randomized clinical trials. However, the impact of this new treatment strategy has not yet been evaluated in community‐treated cohorts.

Methods

We evaluated baseline characteristics and plasma HIV RNA responses to unboosted and boosted PI‐based highly active antiretroviral therapy (HAART) among antiretroviral‐naïve HIV‐infected patients in British Columbia, Canada who initiated HAART between August 1997 and September 2003 and who were followed until September 2004. We evaluated time to HIV‐1 RNA suppression (<500 HIV‐1 RNA copies/mL) and HIV‐1 RNA rebound (≥500 copies/mL), while stratifying patients into those that received boosted and unboosted PI‐based HAART as the initial regimen, using Kaplan–Meier methods and Cox proportional hazards regression.

Results

During the study period, 682 patients initiated therapy with unboosted PI and 320 individuals initiated HAART with a boosted PI. Those who initiated therapy with a boosted PI were more likely to have a CD4 cell count <200 cells/μL and to have a plasma HIV RNA>100 000 copies/mL, and to have AIDS at baseline (all P<0.001). However, when we examined virological response rates, those who initiated HAART with a boosted PI achieved more rapid virological suppression [relative hazard 1.26, 95% confidence interval (CI) 1.06–1.51, P=0.010].

Conclusions

Patients prescribed boosted PIs achieved superior virological response rates despite baseline factors that have been associated with inferior virological responses to HAART. Despite the inherent limitations of observational studies which require this study be interpreted with caution, these findings support the use of boosted PIs for initial HAART therapy.

     

Advanced liver fibrosis in HIV/HCV-coinfected patients on antiretroviral therapy

HIV infection is believed to adversely affect the progression of hepatitis C virus (HCV)-related liver disease. However, information regarding HIV and HCV coinfection in the era of highly active antiretroviral therapy (HAART) is scarce. A cross-sectional study in 75 HCV/HIV-coinfected patients (most of them on HAART) and 75 HCV-monoinfected patients paired by age, sex, and date of liver biopsy analyzed the association of HIV infection with advanced liver fibrosis (Knodell fibrosis stages 3 + 4). The median CD4 cell count in HIV-coinfected patients was 546 cells/microl; 78.7% had an HIV-1 viral load <1000 copies/ml and 88% were on antiretroviral therapy. The percentage of patients harboring genotype 4 and with a higher HCV viral load was greater in the HIV-coinfected group. HCV/HIV-coinfected patients had more advanced liver fibrosis (Knodell fibrosis stages 3 + 4) than HCV-monoinfected patients (46.7% vs. 12%, p < 0.0001). In the univariate analysis, the factors associated with advanced liver disease were male sex (OR: 2.7, 95% CI: 1.05-7.1), history of injecting drug use (OR: 4.6, 95% CI: 2.0-10.2), HIV infection (OR: 6.4, 95% CI: 2.7-14.7), and previous exposure to therapy with protease inhibitors (OR: 3.0, 95% CI:1.4-6.3). In the multivariate analysis; only male sex (OR: 3.17, 95% CI: 1.152-8.773) and HIV infection (OR: 6.85, 95% CI: 2.93-16.005) were associated with advanced liver fibrosis. HIV infection is associated with advanced liver fibrosis. HIV/HCV-coinfected individuals on HAART are at risk of developing end-stage liver disease despite virological success and immunological reconstitution.     

Homelessness as a structural barrier to effective antiretroviral therapy among HIV-seropositive illicit drug users in a Canadian setting

Despite the advent of effective antiretroviral therapy (ART), HIV-seropositive injection drug users (IDU) continue to suffer from elevated levels of morbidity and mortality. Evidence is needed to identify social- and structural-level barriers to effective ART. We investigated the impact of homelessness on plasma HIV RNA response among illicit drug users initiating ART in a setting with free and universal access to HIV care. We accessed data from a long-running prospective cohort of community-recruited IDU linked to comprehensive HIV clinical monitoring and ART dispensation records. Using Cox proportional hazards with recurrent events modeling, we estimated the independent effect of homelessness on time to plasma HIV viral load suppression. Between May 1996 and September 2009, 247 antiretroviral na?ve individuals initiated ART and contributed 1755 person-years of follow-up. Among these individuals, the incidence density of plasma HIV RNA suppression less than 500 copies/mm(3) was 56.7 (95% confidence interval [CI]: 46.9-66.0) per 100 person-years. In unadjusted analyses, homelessness was strongly associated with lower rates suppression (hazard ratio = 0.56, 95% CI: 0.40-0.78, p = 0.001), however, after adjustment for adherence this association was no longer significant (adjusted hazard ratio = 0.79, 95% CI: 0.56-1.11, p = 0.177). Homelessness poses a significant structural barrier to effective HIV treatment. However, since this relationship appears to be mediated by lower levels of ART adherence, interventions to improve adherence among members of this vulnerable population are needed.     

Early HIV viral load determination after initiating first‐line antiretroviral therapy for indentifying patients with high risk of developing virological failure: data from a cohort study in a resource‐limited setting

Objectives To evaluate the performance of a single determination of HIV viral load (VL) 6–12 months after starting antiretroviral therapy (ART) for identifying patients who will subsequently develop virological failure. Methods We selected HIV‐infected patients with at least two VL determinations after 6 months of ART from an HIV cohort study in India. Patients were divided in two groups depending on whether the first VL was below (Group 1) or above (Group 2) 1000 copies/ml. Cut‐off for virological failure was defined according to World Health Organization recommendation (>5000 copies/ml). Results The study included 584 patients and 560.1 person‐years of follow‐up. Of all virological failures, 83% were diagnosed at the first VL determination. The cumulative incidence of virological failure after 1 and 2 years since the first VL was 0.9% [95% confidence interval (CI), 0.3–2.7] and 1.7% (95% CI, 0.6–5), respectively, for Group 1, and 58.2% (95% CI, 47–69.7) and 63.1% (95% CI, 49.8–76.4), respectively, for Group 2. Compared with Group 1, patients from Group 2 had a hazard ratio for virological failure of 78.3 (95% CI, 27.8–220.2). Conclusions A single VL determination after 6 months of ART was able to identify patients with high risk of virological failure.