Eleven protease mutations have been associated with reduced susceptibility to darunavir. In this study of 87 HIV-1-infected patients experiencing virological failure to second-line regimens containing protease inhibitors boosted with ritonavir (viral load >1,000 HIV RNA copies/ml), we observed a low prevalence (3%) of ≥3 darunavir resistance-associated mutations, indicating that this drug may be a good option for third-line antiretroviral therapy in southern India.
We report a high frequency of drug resistance mutations among patients with unusual insertions or deletions at the β3–β4 hairpin-loop-coding region of HIV-1 subtype C reverse transcriptase, during failure of first-line antiretroviral therapy containing only reverse transcriptase inhibitors in Chennai, India.
Background & objectives:
Sustainability of free antiretroviral therapy (ART) roll out programmes in resource-limited settings is challenging given the need for lifelong therapy and lack of effective vaccine. This study was undertaken to compare treatment outcomes among HIV-infected patients enrolled in a graduated cost-recovery programme of ART delivery in Chennai, India.
Financial status of patients accessing care at a tertiary care centre, YRGCARE, Chennai, was assessed using an economic survey; patients were distributed into tiers 1- 4 requiring them to pay 0, 50, 75 or 100 per cent of their medication costs, respectively. A total of 1754 participants (ART naïve = 244) were enrolled from February 2005-January 2008 with the following distribution: tier 1=371; tier 2=338; tier 3=693; tier 4=352. Linear regression models with generalized estimating equations were used to examine immunological response among patients across the four tiers.
Median age was 34; 73 per cent were male, and the majority were on nevirapine-based regimens. Median follow up was 11.1 months. The mean increase in CD4 cell count within the 1st three months of HAART was 50.3 cells/μl per month in tier 1. Compared to those in tier 1, persons in tiers 2, 3 and 4 had comparable increases (49.7, 57.0, and 50.9 cells/μl per month, respectively). Increases in subsequent periods (3-18 and >18 months) were also comparable across tiers. No differential CD4 gains across tiers were observed when the analysis was restricted to patients initiating ART under the GCR programme.
Interpretation & conclusions:
This ART delivery model was associated with significant CD4 gains with no observable difference by how much patients paid. Importantly, gains were comparable to those in other free rollout programmes. Additional cost-effectiveness analyses and mathematical modelling would be needed to determine whether such a delivery programme is a sustainable alternative to free ART programmes.
ART; cost-recovery programme; HIV; India; treatment outcomes
Analysis of human immunodeficiency virus type 1 pol gene sequences from 107 patients receiving second-line antiretroviral therapy (ART) revealed that a high prevalence of resistance mutations among second-line ART-experienced patients limits the ART-sequencing options, suggesting darunavir as the third-line drug in India.
Background. A cross-sectional study among individuals receiving second-line antiretroviral treatment was conducted to report on the level of detectable viremia and the types of drug resistance mutations among those with detectable human immunodeficiency virus (HIV) type 1 plasma viral loads (PVLs).
Methods. PVLs were measured using Abbott m2000rt real-time polymerase chain reaction, and genotyping was performed with the ViroSeq genotyping system, version 2.0, and ViroSeq analysis software, version 2.8.
Results. Of 107 patient plasma specimens consecutively analyzed, 30 (28%) had undetectable PVLs (<150 copies/mL), and 77 (72%) were viremic with a median PVL of 5450 copies/mL (interquartile range, 169–1 997 967). Sequencing was done for 107 samples with PVLs >2000 copies/mL: 33 patients (73%) had 1 of the protease (PR) inhibitor mutations; 41 (91%) had nucleoside reverse-transcriptase inhibitor (NRTI) mutations; 33 (73%) had non-NRTI (NNRTI) mutations; and 30 (66.7%) had both NRTI and NNRTI mutations. Triple-class resistance to NRTIs, NNRTIs, and PR inhibitors was observed in 24 (53%) patients. Based on the mutational profiles observed, all 45 sequences were susceptible to darunavir and tipranavir, whereas 47% showed resistance to lopinavir, 58% showed resistance to atazanavir, and >60% showed resistance to saquinavir, indinavir, nelfinavir, and fosamprenavir.
Conclusions. The results of the study showed that the majority of patients receiving second-line antiretroviral therapy started to accumulate PR resistance mutations, and the mutation profiles suggest that darunavir might be the drug of choice for third-line regimens in India.
To characterize factors associated with injection cessation, relapse and initiation.
MIDACS is a prospective cohort of injection drug users (IDUs) recruited in 2005–06 with semi-annual follow-up through 2009. Discrete-time survival models were used to characterize predictors of time to first injection cessation and relapse.
855 IDUs who reported injecting in the six months prior to baseline and had > 1 follow-up visit.
Cessation was defined as the first visit where no injection drug use was reported (prior six months) and relapse as the first visit where drug injection (prior six months) was reported after first cessation.
All participants were male; median age was 35. Over three years, 92.7% reported cessation (incidence rate [IR]: 117 per 100 person-years). Factors positively associated with cessation included daily injection and incarceration and factors negatively associated with cessation included marriage, alcohol and homelessness. Of those who reported cessation, 24% relapsed (IR: 19.7 per 100 person-years). Factors positively associated with relapse included any education, injection in the month prior to baseline, sex with a casual partner, non-injection drug use, incarceration and homelessness. Alcohol was negatively associated with relapse. The primary reasons for cessation were medical conditions (36%) and family pressure (22%). The majority initiated with non-injection drugs, transitioning to injection after a median 4 years.
Injection drug users in Southern India demonstrate a high rate of injection cessation over three years, but relapse is not uncommon. Compensatory increases in alcohol use indicate that cessation of injection does not mean cessation of all substance use. Family pressure, concerns about general health, fear of HIV infection, and a history of non-injection drug use are important correlates of cessation.
natural history; drug use; India; injection drug users; cohort
In HIV-1 subtype C infected populations in south India, we searched for novel mutations associated with failing antiretroviral therapy that included nucleoside reverse transcriptase (RT) inhibitors. HIV-1 RT sequences were generated from treated and untreated groups and each nucleotide position was analysed with appropriate corrections for multiple testing. We found that nonsynonymous mutations at positions 208 and 228 were strongly associated with the presence of thymidine analogue mutations in the treated group, and were not present at all in the naïve group. The role of these substitutions on treatment outcomes and the evolution of drug resistance in HIV-1 subtype-C infected populations warrant further investigation.
HIV-1 Drug Resistance Mutation; HIV-1 Subtype C; HIV in India; Thymidine Analogue Mutation (TAMs); HIV-1 RT mutation at codon 208; 228; HIV Drug Resistance in India
The purpose of this study was to examine whether social network factors predict HIV and Hepatitis C (HCV) serostatus after controlling for individual-level factors at baseline among a cohort of male injection drug users in Chennai, India.
The sample, which was recruited through street outreach, consists of 1,078 males who reported having injected drugs in the last 6 months
The participants reported 3,936 social support and risk network members. HIV and HCV positive serostatus were negatively associated with network member providing emotional support, and positively associated with network member providing material support. In addition, HCV positivity was associated with network member being an active drug user known for more than 10 years and network member being male kin networks, even after adjusting for individual demographic factors and risk behaviors.
These findings suggest that social network factors are significantly linked to HIV and HCV status among IDUs in Southern India and highlight the mixed effects of social capital on health. Future HIV/HCV prevention efforts should incorporate IDU peers to alter drug network injection risk norms. For drug users who have minimal network support, support groups and other informal and formal support mechanisms may help coping with HIV/HCV and cessation of drug use.
Social networks; HIV; Hepatitis C; India; social capital; injection drug users
The authors characterized human immunodeficiency virus (HIV) and hepatitis C virus (HCV) incidence and prospective changes in self-reported risk behavior over 2 years among 1,158 injection drug users (IDUs) recruited in Chennai, India, in 2005–2006. At baseline, HIV prevalence was 25.3%, and HCV prevalence was 54.5%. Seropositive persons with prevalent HIV infection were used to estimate baseline HIV incidence by means of the Calypte HIV-1 BED Incidence EIA (Calypte Biomedical Corporation, Portland, Oregon). Longitudinal HIV and HCV incidence were measured among 865 HIV-negative IDUs and 519 HCV antibody-negative IDUs followed semiannually for 2 years. Participants received pre- and posttest risk reduction counseling at each visit. Estimated HIV incidence at baseline was 2.95 per 100 person-years (95% confidence interval (CI): 1.21, 4.69) by BED assay; observed HIV incidence over 1,262 person-years was 0.48 per 100 person-years (95% CI: 0.17, 1.03). HCV incidence over 645 person-years was 1.71 per 100 person-years (95% CI: 0.85, 3.03). Self-reported risk behaviors declined significantly over time, from 100% of participants reporting drug injection at baseline to 11% at 24 months. In this cohort with high HIV and HCV prevalence at enrollment, the authors observed low incidence and declining self-reported risk behavior over time. While no formal intervention was administered, these findings highlight the potential impact of voluntary counseling and testing in a high-risk cohort.
cohort studies; hepacivirus; HIV; India; risk-taking; substance abuse, intravenous
Use of a combination of CD4 counts and HIV viral load testing in the management of antiretroviral therapy (ART) provides higher prognostic estimation of the risk of disease progression than does the use of either test alone. The standard methods to monitor HIV infection are flow cytometry based for CD4+ T cell count and molecular assays to quantify plasma viral load of HIV. Commercial assays have been routinely used in developed countries to monitor ART. However, these assays require expensive equipment and reagents, well trained operators, and established laboratory infrastructure. These requirements restrict their use in resource-limited settings where people are most afflicted with the HIV-1 epidemic. With the advent of low-cost and/or low-tech alternatives, the possibility of implementing CD4 count and viral load testing in the management of ART in resource-limited settings is increasing. However, an appropriate validation should have been done before putting them to use for patient testing.
CD4 count; HIV monitoring; low-cost assays; plasma viral load; resource-limited settings
Over the past 30 years, several interventions have been identified to prevent HIV transmission from HIV-infected persons to uninfected persons in discordant relationships. Yet, transmissions continue to occur. Interventions such as voluntary counselling and testing, condom promotion and risk reduction counselling are very effective in preventing transmission among serodiscordant couples but are underutilized in India despite their widespread availability. New interventions such as pre-risk exposure prophylaxis and universal antiretroviral therapy (irrespective of CD4 count) have been newly identified but face several challenges that impede their widespread implementation in India. Discordant couples in India also face certain unique socio-cultural issues such as marital and fertility pressure. We briefly review the various interventions (existing and novel) available for persons in discordant relationships in India and socio-cultural issues faced by these individuals and make recommendations to maximize their implementation.
ART; CD4 counts; HIV- pre-risk exposure prophylaxis; risk reduction counselling; serodiscordant couples
The purpose of this study was to examine the relationship between perceived drug use stigma, acquiescence response bias, and HIV injection risk behaviors among current injection drug users in Chennai, India.
The sample consists of 851 males in Chennai, India who reported having injected drugs in the last month and were recruited through street outreach.
Results indicate a strong and consistent positive association between drug use stigma and HIV injection drug use risk behaviors. This association held across the injection behaviors of frequency of sharing needles, cookers, cotton filters, rinse water, prefilled syringes and common drug solutions, even after controlling for acquiescence response bias, frequency of injection, and HIV/HCV serostatus.
These findings suggest that future HIV prevention and harm reduction programs for injection drug users and service providers should address drug use stigma.
stigma; HIV; HCV; acquiescence response bias; risk behavior; India; injection drug use
It is estimated that there are up to 1.1 million injection drug users (IDUs) in India; the majority are likely married. We characterize HIV, hepatitis B (HBV) and hepatitis C (HCV) prevalence and the risk environment of a sample of spouses of IDUs.
A cohort of 1158 IDUs (99% male) was recruited in Chennai, India from 2005-06. A convenience sample of 400 spouses of the male IDUs in this cohort was recruited in 2009. A risk assessment questionnaire was administered and a blood sample collected. Logistic regression was used to identify factors associated with prevalent HIV.
Median age was 31 years; thirteen percent were widowed and 7% were not currently living with their spouse. Only 4 (1%) reported ever injecting drugs; Twenty-two percent and 25% reported ever using non-injection drugs and alcohol, respectively. The majority had one lifetime sexual partner and 37 (9%) reporting exchanging sex. Only 7% always used condoms with their regular partner. HIV, HBV and HCV prevalence were 2.5%, 3.8% and 0.5%, respectively; among spouses of HIV+ IDUs (n = 78), HIV prevalence was 10.3%. The strongest predictor of HIV was spousal HIV status (OR: 17.9; p < 0.001). Fifty-six percent of women had ever experienced intimate partner violence; Eight-six percent reported sexual violence.
Our finding of a 10-fold higher HIV prevalence among spouses of IDUs compared with general population women indicates their vulnerability; prevalence is likely to increase given the context of low condom use and frequent sexual violence. Prevention efforts directed at IDUs should also include programs for spouses.
Background & Objectives:
We characterized HCV antibody prevalence, viral persistence, genotype and liver disease prevalence among IDUs in Chennai, India as the study of the association of HIV with each of these states is important and there are no data available.
Between 2005-2006, 1158 IDUs were recruited and followed semi-annually. All were tested for HCV antibodies at baseline; a random sample of 400 antibody positives (200 HIV-positive and 200 HIV-negative) were tested for HCV RNA; 13 of these were sequenced. Assessment of asparate amino transferase (AST)-to-platelet ratio index (APRI) was done on 557 IDUs. Prevalence ratios of each outcome were examined.
Median age was 35 yr; 99 per cent were male. HCV antibody prevalence was 55 per cent and was associated with older age, being unmarried, longer injection history, tattoo and injecting at a dealer’s place. Of the 400 HCV antibody positive IDUs, 281 (70.3%) had persistent infection which was less common among hepatitis B-infected persons but not associated with HIV. Of the 13 samples sequenced, 11 (85%) were HCV genotype 3a. Fibrosis prevalence according to APRI was: HIV/HCV-uninfected, 4 per cent; HIV mono-infected, 3 per cent; HCV mono-infected, 11 per cent; HIV/HCV co-infected, 12 per cent (P<0.001). In addition to being associated with HCV and HIV/HCV, fibrosis prevalence was higher among those drinking alcohol frequently; daily marijuana use was protective.
Interpretation & Conclusions:
Our findings show that IDUs in Chennai have high HCV prevalence and associated disease burden. The burden will increase as access to antiretroviral therapy improves particularly given the high prevalence of HIV, HCV and alcohol use.
APRI; HCV genotype; hepatitis C virus; HIV; injection drug users; liver disease
We characterize the demographics, injection practices and risk behaviours of 1158 injection drug users (IDUs) in Chennai, the capital of Tamil Nadu in southern India who were recruited in 2005–2006 by community outreach. The median age was 35 years; the majority of IDUs were male, of Tamil ethnicity and married, earning less than USD 75 per month. Most (76%) had injected in the prior month. The median age at first injection was 25 years; the most common drug injected was heroin (80%) followed by buprenorphine. High risk behaviours were common and included needle sharing, unsafe disposal and inappropriate cleaning of needles as well as limited condom use. IDUs in India need to be educated on harm reduction and safe-injection practices; Pharmacies could serve as potential venues for HIV prevention interventions among IDUs in India as most IDUs obtain their needles from pharmacies without prescription.
Injection drug use; India; risk behaviour; HIV
Commercial HIV-1 genotypic resistance assays are very expensive, particularly for use in resource-constrained settings like India. Hence a cost effective in-house assay for drug resistance was validated against the standard ViroSeq™ HIV-1 Genotyping System 2.0 (Celera Diagnostics, CA, USA). A total of 50 samples were used for this evaluation (21 proficiency panels and 29 clinical isolates). Known resistance positions within HIV-1 protease (PR) region (1–99 codons) and HIV-1 reverse-transcriptase (RT) region (1–240 codons) were included. The results were analysed for each codon as follows: (i) concordant; (ii) partially concordant; (iii) indeterminate and (iv) discordant. A total of 2750 codons (55 codons per patient sample × 50 samples) associated with drug resistance (1050 PR and 1700 RT) were analysed. For PR, 99% of the codon results were concordant and 1% were partially concordant. For RT, 99% of the codon results were concordant, 0.9% were partially concordant and 0.1% were discordant. No indeterminate results were observed and the results were reproducible. Overall, the in-house assay provided comparable results to those of US FDA approved ViroSeq™, which costs about a half of the commercial assay ($ 100 vs. $ 230), making it suitable for resource-limited settings.
ViroSeq™ HIV-1 genotyping; In-house HIV-1 drug resistance assay; Concordance; Mixtures; Indeterminate rate; HIV-1 genotyping evaluation
HIV/AIDS in India disproportionately affects women, not by their own risks, but by those of their partners, generally their spouses. We address two marginalized populations at elevated risk of acquiring HIV: women who are married to men who also have sex with men (MSM) and wives of injection drug users (IDUs).
We used a combination of focus groups (qualitative) and structured surveys (quantitative) to identify the risks that high-risk men pose to their low-risk wives and/or sexual partners. Married MSM were identified using respondent-driven recruitment in Tamil Nadu, India, and were interviewed by trainer assessors. A sample of wives of injection drug users in Chennai were recruited from men enrolled in a cohort study of the epidemiology of drug use among IDUs in Chennai, and completed a face-to-face survey. Focus groups were held with all groups of study participants, and the outcomes transcribed and analyzed for major themes on family, HIV and issues related to stigma, discrimination and disclosure.
Using mixed-methods research, married MSM are shown to not disclose their sexual practices to their wives, whether due to internalized homophobia, fear of stigma and discrimination, personal embarrassment or changing sexual mores. Married MSM in India largely follow the prevailing norm of marriage to the opposite sex and having a child to satisfy social pressures. Male IDUs cannot hide their drug use as easily as married MSM, but they also avoid disclosure. The majority of their wives learn of their drug-using behaviour only after they are married, making them generally helpless to protect themselves. Fear of poverty and negative influences on children were the major impacts associated with continuing drug use.
We propose a research and prevention agenda to address the HIV risks encountered by families of high-risk men in the Indian and other low- and middle-income country contexts.
Injection drug users (IDUs) have estimated mortality rates over 10 times higher than the general population; much of this excess mortality is HIV associated. Few mortality estimates among IDUs from developing countries, including India, exist.
IDUs (1158) were recruited in Chennai from April 2005 to May 2006; 293 were HIV positive. Information on deaths and causes was obtained through outreach workers and family/network members. Mortality rates and standardized mortality ratios were calculated; multivariate Poisson regression was used to identify predictors of mortality.
We observed 85 deaths over 1998 person-years (p-y) of follow-up [incidence rate (IR) 4.25 per 100 p-y; 95% confidence interval (CI) 3.41, 5.23]. The overall standardized mortality ratio was 11.1; for HIV-positive IDUs, the standardized mortality ratio was 23.9. Mortality risk among HIV-positive IDUs (IR 8.88 per 100 p-y) was nearly three times that of negative IDUs (IR 3.03 per 100 p-y) and increased with declining immune status (CD4 cells > 350: 5.44 per 100 p-y vs. CD4 cells ≤ 200: 34.5 per 100 p-y). This association persisted after adjustment for potential confounders. The leading causes of mortality in both HIV negative and positive IDUs were overdose (n = 22), AIDS (n = 14), tuberculosis (n = 8) and accident/trauma (n = 9).
Substantial mortality was observed in this cohort with the highest rates among HIV-positive IDUs with CD4 cells less than 350. Although in these 2 years, non-AIDS deaths outnumbered AIDS-related deaths, the relative contribution of AIDS-associated mortality is likely to increase with advancing HIV disease progression. These data reinforce the need for interventions to reduce the harms associated with drug use and increase HAART access among IDUs in Chennai.
HIV; India; injection drug users; mortality; overdose
To estimate the prevalence of HIV and hepatitis C virus (HCV) and hepatitis B virus (HBV) co-infection as well as current risk behaviors among HIV positive and negative injection drug users (IDUs) in Chennai, India.
Cross-sectional analysis of a convenience sample of 912 IDUs recruited between March 2004 and April 2005. Specimens were tested for HIV, HBV and HCV. Adjusted prevalence ratios (PR) were estimated using Poisson regression with robust variance estimates.
The prevalence of HIV, HBsAg and anti-HCV were 29.8%, 11.1% and 62.1%, respectively. Among HIV-infected IDUs, prevalence of co-infection with anti-HCV and HBsAg/anti-HCV were 86% and 9.2%, respectively. In multivariate analysis, injecting at a dealer’s place (PR: 1.57) and duration of injection drug use ≥ 11 years (PR: 3.02) were positively associated with prevalent HIV infection. Contrastingly, alcohol consumption ≥ 1/week (PR: 0.55) was negatively associated with HIV. HIV positive IDUs were as or more likely compared to HIV negative IDUs to report recent high-risk injection-related behaviors.
There is a high burden of HIV, HCV and HBV among IDUs that needs to be addressed by improving access to therapies for these infections; further, preventive measures are urgently needed to prevent further spread of HIV, HBV and HCV in this vulnerable population.
Diagnosis of human immunodeficiency virus (HIV) infection is important for patient management and prevention of new infections. The number of test kits available for the detection of HIV antibodies is unprecedented. In order to identify appropriate test kits, we evaluated a variety of commercial kits manufactured abroad as well as in India. The plasma and serum specimens (n = 264) were collected from individuals attending the Voluntary Counseling and Testing Centre at the YRG Centre for AIDS and Education. The specimens were used to evaluate six commercially available HIV test kits: Enzaids HIV 1+2, HIV-CheX, Murex HIV-1.2.0, Genscreen HIV 1/2 version 2, Vironostika HIV Uni-Form II Ag/Ab, and CombAids RS Advantage. High sensitivities and specificities (≥99%) were observed for the Enzaids, Murex, Vironostika, and CombAids assays. HIV-CheX showed the highest number of false-positive and false-negative results. The Genscreen test also gave many false positives. The study indicated that the Enzaids, Murex, and Vironostika enzyme-linked immunosorbent assay kits and the CombAids RS Advantage rapid assay could be used to achieve acceptable results for the detection of HIV antibodies. A combination of two tests is recommended to optimize the efficiency of HIV antibody testing algorithms, especially when evaluation with an HIV Western blot confirmatory test is not possible.