Network-based strategies to combat HCV: Examining social and spatial drivers of transmission among PWID in New Delhi.

People who inject drugs (PWID) account for some of the fastest-growing HCV epidemics globally. While individual risk factors for infection are understood, less is known about network and spatial factors critical for elimination strategies. Two thousand five hundred twelve PWID in New Delhi, India, were recruited (2017-19) through network referrals. Biometrics identified duplicates and cross-network linkages. Participants completed semi-annual surveys and blood tests for HCV antibodies and RNA. Poisson regression and network analyses identified predictors of incident HCV and compared network-based intervention approaches. Baseline HCV antibody prevalence was 65.1%, of whom 79.6% were HCV RNA-positive. We observed 92 HCV seroconversions over 382.25 person-years (incidence: 24.1 per 100 person-years). Of the 92 seroconverters, 67% (62) were directly connected to an RNA-positive participant, and all were within one degree of separation from an RNA-positive participant. Individual-level factors associated with seroconversion included age, sexual activity, and injection behaviours. After adjusting for individual-level factors, seroconversion was significantly associated with number of RNA-positive partners (adjusted incidence rate ratio [AIRR] = 1.30) and injecting at a particular venue (AIRR = 2.53). This association extended to indirect ties, with 17% reduced odds of seroconversion for each degree of separation from the venue (AIRR = 0.83). Network analyses comparing intervention strategies found that targeting venues identified more cases compared to a treat-a-friend approach. We observed a fast-growing HCV epidemic driven by viremia within individuals' immediate networks and indirect social and spatial ties, demonstrating the importance of achieving broad, sustained virologic response and rethinking network-based interventions to include venues.

High prevalence of hepatitis B virus among MSM living with HIV in India.

People living with HIV (PWH) have been shown to bear a higher burden of hepatitis B virus (HBV) due to shared routes and risk factors for transmission. Populations such as men who have sex with men (MSM) are at an increased risk of both being infected with HBV and HIV, that places them at higher risk of hepatocellular carcinoma. Using weighted and adjusted multilevel logistic regression, we characterized the prevalence and correlates of hepatitis B surface antigen (HBsAg) among MSM living with HIV across 12 Indian cities from 2012 to 2013. Overall, the prevalence of HBsAg was 8% (range across cities: 0.5%-19%). Being between the ages of 25-34, and 35-44 increased the odds of having chronic HBV infection compared to MSM 24 years or younger. Daily or seasonal employment and being unemployed increased the odds of HBsAg prevalence compared to those with monthly or weekly wages. Sexual risk behaviours such as having had sex with both men and women in the prior 6 months and history of sex work increased the odds of having HBV. Ever having insertive sex with a man or hijra (assigned male at birth, currently identifies as female/nonbinary) was negatively associated with HBV. Despite the existence of efficacious vaccines, HBV continues to have high prevalence among PWHs. Programmes to increase early screening, vaccinations and HBV literacy are urgently needed. Integrating HBV and HIV programmes for MSM populations could be critical in addressing this dual burden and improving outcomes for both infections.

A Mixture Model for Estimating SARS-CoV-2 Seroprevalence in Chennai, India.

Serological assays used to estimate the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) often rely on manufacturers' cutoffs established on the basis of severe cases. We conducted a household-based serosurvey of 4,677 individuals in Chennai, India, from January to May 2021. Samples were tested for SARS-CoV-2 immunoglobulin G (IgG) antibodies to the spike (S) and nucleocapsid (N) proteins. We calculated seroprevalence, defining seropositivity using manufacturer cutoffs and using a mixture model based on measured IgG level. Using manufacturer cutoffs, there was a 5-fold difference in seroprevalence estimated by each assay. This difference was largely reconciled using the mixture model, with estimated anti-S and anti-N IgG seroprevalence of 64.9% (95% credible interval (CrI): 63.8, 66.0) and 51.5% (95% CrI: 50.2, 52.9), respectively. Age and socioeconomic factors showed inconsistent relationships with anti-S and anti-N IgG seropositivity using manufacturer cutoffs. In the mixture model, age was not associated with seropositivity, and improved household ventilation was associated with lower seropositivity odds. With global vaccine scale-up, the utility of the more stable anti-S IgG assay may be limited due to the inclusion of the S protein in several vaccines. Estimates of SARS-CoV-2 seroprevalence using alternative targets must consider heterogeneity in seroresponse to ensure that seroprevalence is not underestimated and correlates are not misinterpreted.

Elicitation of potent serum neutralizing antibody responses in rabbits by immunization with an HIV-1 clade C trimeric Env derived from an Indian elite neutralizer.

Evaluating the structure-function relationship of viral envelope (Env) evolution and the development of broadly cross-neutralizing antibodies (bnAbs) in natural infection can inform rational immunogen design. In the present study, we examined the magnitude and specificity of autologous neutralizing antibodies induced in rabbits by a novel HIV-1 clade C Env protein (1PGE-THIVC) vis-à-vis those developed in an elite neutralizer from whom the env sequence was obtained that was used to prepare the soluble Env protein. The novel 1PGE-THIVC Env trimer displayed a native like pre-fusion closed conformation in solution as determined by small angle X-ray scattering (SAXS) and negative stain electron microscopy (EM). This closed spike conformation of 1PGE-THIVC Env trimers was correlated with weak or undetectable binding of non-neutralizing monoclonal antibodies (mAbs) compared to neutralizing mAbs. Furthermore, 1PGE-THIVC SOSIP induced potent neutralizing antibodies in rabbits to autologous virus variants. The autologous neutralizing antibody specificity induced in rabbits by 1PGE-THIVC was mapped to the C3/V4 region (T362/P401) of viral Env. This observation agreed with electron microscopy polyclonal epitope mapping (EMPEM) of the Env trimer complexed with IgG Fab prepared from the immunized rabbit sera. Our study demonstrated neutralization of sequence matched and unmatched autologous viruses by serum antibodies induced in rabbits by 1PGE-THIVC and also highlighted a comparable specificity for the 1PGE-THIVC SOSIP trimer with that seen with polyclonal antibodies elicited in the elite neutralizer by negative-stain electron microscopy polyclonal epitope (ns-EMPEM) mapping.

Changes in HIV care continuum indicators among community-based samples of HIV-infected people who inject drugs and men who have sex with men across 21 cities in India.

Monitoring key populations' progress towards UNAIDS 90-90-90 targets is essential to achieving HIV/AIDS epidemic control. Using serial cross-sectional data, we evaluated changes in HIV care continuum among people who inject drugs(PWID) and men who have sex with men(MSM) in India. Cross-sectional baseline (2012/2013) and follow-up (2016/2017) samples were recruited using respondent-driven sampling across 21 cities. All participants were tested for HIV and RNA measured in HIV-positive participants. Linear regression was used to model temporal site-level changes in continuum indicators in MSM versus PWID. At baseline, we recruited 2,544 HIV-infected PWID and 1,086 HIV-infected MSM. At follow-up, we recruited 2,517 HIV-infected PWID and 1,763 HIV-infected MSM. At baseline, there were no significant differences in continuum indicators between MSM and PWID. At follow-up, compared to PWID, the proportion of MSM reaching each care continuum indicator-awareness of status, receipt of care, ART use, viral suppression-increased by 15-33 percentage points: 78% of MSM versus 49% of PWID were aware of their status (p < 0.01); 56% of MSM versus 32% of PWID were virologically suppressed (p = 0.05). MSM showed marked improvements across the care continuum, whereas PWID lagged and may require additional intervention. Differential improvement in HIV engagement may necessitate population-specific interventions and routine surveillance to facilitate HIV elimination.

Exploring multilevel determinants of co-occurring violence, HIV, mental health and substance use problems.

Multiple factors contribute to co-occurring issues such as violence, HIV, and mental disorders among people who inject drugs (PWID), particularly those residing in limited resource settings. Using an ecological framework, this study explored multilevel determinants of co-occurring violence, HIV, mental health, and substance use issues among PWID. Data were collected via semi-structured in-depth interviews with 31 men and women PWID in India. Findings revealed factors at the community (e.g., stigma), interpersonal (e.g., abusive partners), and individual (e.g., financial stress) levels. Findings highlight the need for prevention and intervention programs addressing factors at multiple ecological levels to reduce comorbidity among PWID.

Spatiotemporal Phylodynamics of Hepatitis C Among People Who Inject Drugs in India.

BACKGROUND AND AIMS: Implementing effective interventions for HCV requires a detailed understanding of local transmission dynamics and geospatial spread. Little is known about HCV phylodynamics, particularly among high-burden populations, such as people who inject drugs (PWID). APPROACH AND RESULTS: We used 483 HCV sequences and detailed individual-level data from PWID across four Indian cities. Bayesian phylogeographic analyses were used to evaluate transmission hotspots and geospatial diffusion of the virus. Phylogenetic cluster analysis was performed to infer epidemiologic links and factors associated with clustering. A total of 492 HIV sequences were used to draw comparisons within the same population and, in the case of coinfections, evaluate molecular evidence for shared transmission pathways. Overall, 139/483 (28.8%) of HCV sequences clustered with a median cluster size of 3 individuals. Genetically linked participants with HCV were significantly younger and more likely to be infected with HCV subtype 3b as well as to live and inject close to one another. Phylogenetic evidence suggests likely ongoing HCV infection/reinfection with limited support for shared HIV/HCV transmission pathways. Phylogeographic analyses trace historic HCV spread back to Northeastern India and show diffusion patterns consistent with drug trafficking routes. CONCLUSIONS: This study characterizes HCV phylodynamics among PWID in a low and middle-income country setting. Heterogeneity and recent genetic linkage of HCV across geographically disparate Indian states suggest that targeted interventions could help prevent reimportation of virus through drug trafficking routes.

Substance use is associated with condomless anal intercourse among men who have sex with men in India: a partner-level analysis.

BACKGROUND: Men who have sex with men (MSM) bear a disproportionately high burden of new HIV infections while lagging behind other populations with respect to engagement across the HIV care continuum. General risk factors for condomless anal intercourse (CAI) among MSM are well studied but there is a paucity of partner-level data, where emerging evidence suggests that much of the variation in condom use occurs. METHODS: MSM were recruited across 10 cities in India using respondent-driven sampling (RDS) from 2016-17. Among the individuals who reported sexual intercourse in the prior 6 months, condom use and partner characteristics of the last 4 partners were captured. Correlates of CAI at the individual and partner level were determined using Poisson regression models using generalized estimating equations and incorporating RDS-II weights, which weights estimates for the participant's network size. RESULTS: Among the 8,086 individuals, 21,723 sexual partnerships were analyzed. The prevalence of CAI was 46.9% and most partners were casual or one-time (70.7%) with partner HIV status reported as unknown in 42.6% of the sexual encounters. In multivariable analyses, partner-level characteristics associated with higher likelihood of CAI included unknown partner HIV status (aPR vs. known HIV negative partner: 1.34; 95% confidence interval (CI): 1.27-1.43) and use of alcohol/ drugs prior to intercourse either sometimes (aPR 1.42; 95% CI: 1.33-1.51) or always (aPR 1.31; 95% CI: 1.23-1.41). At an individual level, any HIV treatment literacy was associated with a lower likelihood of CAI (aPR 0.80; 95% CI: 0.74-0.86). CONCLUSIONS: To reduce HIV transmission among this population of MSM across India, combination interventions are likely needed. Interventions targeting substance use and education as well as initiatives to increase self-testing are urgently needed among MSM in India and have the potential to reduce HIV transmission in this high-risk population. Trial registration ClinicalTrials.gov Identifier: NCT01686750. Date of Registration: September 18, 2012.

Neutralization diversity of HIV-1 Indian subtype C envelopes obtained from cross sectional and followed up individuals against broadly neutralizing monoclonal antibodies having distinct gp120 specificities.

BACKGROUND: The potential use of the broadly neutralizing monoclonal antibodies (bnAbs) towards prophylaxis and treatment to HIV-1 is currently being explored. While a number of promising bnAbs have been discovered and a few of them have progressed towards clinical development, their extent of neutralization coverage with respect to global HIV-1 variants given the existence of genetically distinct subtypes and recombinants circulating globally is not clearly known. In the present study, we examined the variation in the neutralization susceptibility of pseudoviruses expressing 71 full length primary HIV-1 subtype C envs obtained from limited cross-sectional individuals over different time points against four bnAbs that target gp120 with distinct specificities: VRC01, CAP256-VRC26.25, PGDM1400 and PGT121. RESULTS: We found significant variations in the susceptibility of Indian clade C to these four bnAbs. These variations were found to be distinct to that observed in African subtype C based on the existing datasets and concordant with their sequence diversity. Trend analysis indicated an increasing neutralization resistance observed over time with CAP25-VRC26.25, PGDM1400 and PGT121 when tested on pseudoviruses expressing envs obtained from 1999 to 2016. However, inconsistent trend in neutralization susceptibility was observed, when pseudoviruses expressing envs obtained from three followed up individuals were examined. Finally, through predictive analysis of the 98 Indian subtype C including those assessed in the present study by employing additive model implemented in CombiNAber ( http://www.hiv.lanl.gov ), we observed two possibilities where combinations of three bnAbs (VRC01/CAP56-VRC26.25/PGT121 and PGDM1400/CAP256-VRC26.25/PGT121) could achieve near 100% neutralization coverage. CONCLUSIONS: Our findings not only indicate disparate intra-clade C genetic vis-à-vis neutralization diversities but also warrant the need for more comprehensive study using additional isolates towards comparing inter and intra-clade neutralization diversities which will be necessary for selecting the bnAb combinations suitable for optimal coverage of the region-specific HIV-1 circulating subtypes. Expanding these efforts is imperative for designing efficacious bnAb based intervention strategies for India as well as subtype C in general.

Prevalence and Phylogenetic Characterization of Hepatitis C Virus Among Indian Men Who Have Sex With Men: Limited Evidence for Sexual Transmission.

BACKGROUND: Data from high-income countries suggest increasing hepatitis C virus (HCV) prevalence/incidence among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM), but limited data derive from low-and-middle-income countries. METHODS: We recruited 4994 MSM from 5 states across India using respondent-driven sampling. Logistic regression incorporating respondent-driven sampling weights and machine learning feature selection were used to identify correlates of prevalent HCV, and Bayesian phylogenetic analysis was used to examine genetic clustering. RESULTS: The median age was 25 years, the HIV prevalence was 7.2%, and 49.3% of participants reported recent unprotected anal intercourse. The HCV prevalence was 1.3% (95% confidence interval, 1.0%-1.6%; site range, 0.2%-3.4%) and was 3.1% in HIV-positive versus 1.1% among HIV-negative men. HCV infection was significantly associated with injection drug use (odds ratio, 177.1; 95% confidence interval, 72.7-431.5) and HIV infection (4.34; 1.88-10.05). Machine learning did not uncover any additional epidemiologic signal. Phylogenetic analysis revealed 3 clusters suggestive of linked transmission; each contained ≥1 individual reporting injection drug use. CONCLUSIONS: We observed a low HCV prevalence in this large sample of MSM despite a high prevalence of known risk factors, reflecting either the need for a threshold of HCV for sexual transmission and/or variability in sexual practices across settings.

Psychosocial Barriers to Viral Suppression in a Community-based Sample of Human Immunodeficiency Virus-infected Men Who Have Sex With Men and People Who Inject Drugs in India.

BACKGROUND: Little is known about the impact of psychosocial factors and substance use on viral suppression among human immunodeficiency virus (HIV)-infected key populations in resource-limited settings. Accordingly, we examined the association and interactions between depression, alcohol use, and recreational drug use on viral suppression among men who have sex with men (MSM) and people who inject drugs (PWID) in India. METHODS: MSM and PWID were recruited across India using respondent-driven sampling (RDS). Correlates of viral suppression were determined using Poisson regression models incorporating RDS-II weights. Two-way multiplicative interactions were assessed with separate models of all combinations of the 3 variables of interest using interaction terms; 3-way interactions were evaluated by stratifying 2-way interactions by the third variable. RESULTS: Among 1454 treatment-eligible HIV-infected MSM and 1939 PWID, older age (adjusted prevalence ratio [aPR], 1.14 for MSM; 1.41 for PWID) and higher HIV treatment literacy (aPR, 1.58 for MSM; 3.04 for PWID) were positively associated with viral suppression. Among MSM, there was evidence of a synergistic negative association between severe depression and recreational drug use (aPR, 0.37 [95% confidence interval {CI}, .16-.84]), alcohol dependence and recreational drug use (aPR, 0.45 [95% CI, .20-.99]), and severe depression, alcohol dependence, and recreational drug use (aPR, 0.23 [95% CI, .09-.57]). Among PWID, daily injection (aPR, 0.51 [95% CI, .31-.82]) was the primary barrier to suppression. CONCLUSIONS: Incorporating psychosocial and harm-reduction services into differentiated care models targeting MSM and PWID in low-resource settings is critical to achieving the 90-90-90 HIV/AIDS targets.

Antibody avidity-based approach to estimate population-level incidence of hepatitis C.

BACKGROUND & AIMS: Accurate HCV incidence estimates are critical for monitoring progress towards HCV elimination goals, including an 80% reduction in HCV incidence by 2030. Moreover, incidence estimates can help guide prevention and treatment programming, particularly in the context of the US opioid epidemic. METHODS: An inexpensive, Genedia-based HCV IgG antibody avidity assay was evaluated as a platform to estimate cross-sectional, population-level primary HCV incidence using 1,840 HCV antibody and RNA-positive samples from 875 individuals enrolled in 5 cohort studies in the US and India. Using samples collected <2 years following HCV seroconversion, the mean duration of recent infection (MDRI) was calculated by fitting a maximum likelihood binomial regression model to the probability of appearing recent. Among samples collected ≥2 years post-HCV seroconversion, an individual-level false recent ratio (FRR) was calculated by estimating the probability of appearing recent using an exact binomial test. Factors associated with falsely appearing recent among samples collected ≥2 years post seroconversion were determined by Poisson regression with generalized estimating equations and robust variance estimators. RESULTS: An avidity index cut-off of <40% resulted in an MDRI of 113 days (95% CI 84-146), and FRRs of 0.4% (95% CI 0.0-1.2), 4.6% (95% CI 2.2-8.3), and 9.5% (95% CI 3.6-19.6) among individuals who were HIV-uninfected, HIV-infected, and HIV-infected with a CD4 count <200/µl, respectively. No variation was seen between HCV genotypes 1 and 3. In hypothetical scenarios of high-risk settings, a sample size of <1,000 individuals could reliably estimate primary HCV incidence. CONCLUSIONS: This cross-sectional approach can estimate primary HCV incidence for the most common genotypes. This tool can serve as a valuable resource for program and policy planners seeking to monitor and reduce HCV burden. LAY SUMMARY: Determining the rate of new hepatitis C virus (HCV) infections in a population is critical to monitoring progress toward HCV elimination and to appropriately guide control efforts. However, since HCV infections are most often initially asymptomatic, it is difficult to estimate the rate of new HCV infections without following HCV-uninfected people over time and repeatedly testing them for HCV infection. Here, we present a novel, resource-efficient method to estimate the rate of new HCV infections in a population using data from a single timepoint.

Integrating HCV testing with HIV programs improves hepatitis C outcomes in people who inject drugs: A cluster-randomized trial.

BACKGROUND & AIMS: There have been calls to integrate HCV testing into existing services, including harm reduction and HIV prevention and treatment, but there are few empirical trials to date. We evaluated the impact of integrating HCV testing/education into integrated care centers (ICCs) delivering HIV services to people who inject drugs (PWID) across India, using a cluster-randomized trial. METHODS: We compared ICCs with usual care in the PWID stratum (12 sites) of a 22-site cluster-randomized trial. In 6 sites, ICCs delivering HIV testing, harm reduction, other preventive services and linkage to HIV treatment were scaled from opioid agonist therapy centers and operated for 2 years. On-site rapid HCV antibody testing was integrated after 1 year. To assess impact, we conducted baseline and evaluation surveys using respondent-driven sampling (RDS) across the 12 sites (n = 11,993 recruited at baseline; n = 11,721 recruited at evaluation). The primary outcome was population-level self-reported HCV testing history. RESULTS: At evaluation, HCV antibody prevalence ranged from 7.2-76.6%. Across 6 ICCs, 5,263 ICC clients underwent HCV testing, of whom 2,278 were newly diagnosed. At evaluation, PWID in ICC clusters were 4-fold more likely to report being tested for HCV than in usual care clusters, adjusting for baseline testing (adjusted prevalence ratio [aPR] 3.69; 95% CI 1.34-10.2). PWID in ICC clusters were also 7-fold more likely to be aware of their HCV status (aPR 7.11; 95% CI 1.14-44.3) and significantly more likely to initiate treatment (aPR 9.86; 95% CI 1.52-63.8). CONCLUSIONS: We provide among the first empirical data supporting the integration of HCV testing into HIV/harm reduction services. To achieve elimination targets, programs will need to scale-up such venues to deliver comprehensive HCV services. CLINICALTRIALS. GOV IDENTIFIER: NCT01686750. LAY SUMMARY: Delivering hepatitis C virus (HCV) testing to people who inject drugs (PWID) in places where they also have access to HIV prevention and treatment services is an effective way to improve uptake of HCV testing among communities of PWID. To achieve the World Health Organization's ambitious elimination targets, integrated programs will need to be scaled up to deliver comprehensive HCV services.

Broad neutralization response in a subset of HIV-1 subtype C-infected viraemic non-progressors from southern India.

Broadly neutralizing antibodies (bnAbs) have been considered to be potent therapeutic tools and potential vaccine candidates to enable protection against various clades of human immunodeficiency virus (HIV). The generation of bnAbs has been associated with enhanced exposure to antigen, high viral load and low CD4+ T cell counts, among other factors. However, only limited data are available on the generation of bnAbs in viraemic non-progressors that demonstrate moderate to high viraemia. Further, since HIV-1 subtype C viruses account for more than 50 % of global HIV infections, the identification of bnAbs with novel specificities is crucial to enable the development of potent tools to aid in HIV therapy and prevention. In the present study, we analysed and compared the neutralization potential of responses in 70 plasma samples isolated from ART-naïve HIV-1 subtype C-infected individuals with various disease progression profiles against a panel of 30 pseudoviruses. Among the seven samples that exhibited a neutralization breadth of ≥70 %, four were identified as 'elite neutralizers', and three of these were from viraemic non-progressors while the fourth was from a typical progressor. Analysis of the neutralization specificities revealed that none of the four elite neutralizers were reactive to epitopes in the membrane proximal external region (MPER), CD4-binding site and V1V2 or V3 glycan. However, two of the four elite neutralizers exhibited enhanced sensitivity towards viruses lacking N332 glycan, indicating high neutralization potency. Overall, our findings indicate that the identification of potent neutralization responses with distinct epitope specificities is possible from the as yet unexplored Indian population, which has a high prevalence of HIV-1 subtype C infection.

Alcohol use, expectancies and HIV-related sexual risk: a cross-sectional survey of male migrant workers in South India.

Male migrant workers (MMWs) in India are vulnerable to developing alcohol-related problems and engaging in unprotected sex, putting them at risk of HIV. Research has shown that alcohol-related expectancies mediate vulnerability to alcoholism. We examined which expectancies were associated with sexual risk and drinking. We surveyed 1085 heterosexual MMWs in two South Indian municipalities, assessing expectancies, sex under the influence, and unprotected sex with female sex workers (FSW) and casual female partners in the prior 30 days. Men more strongly endorsed positive than negative expectancies (t = 53.59, p < .01). In multivariate logistic regression, the expectancy of having more fun helped drive the combination of alcohol and unprotected sex with FSW partners (OR = 1.22, p < .05), whereas the expectancy of better sex helped drive a similar combination with casual partners (OR = 1.24, p < .01). Men concerned about alcohol-induced deficits were less likely to drink with FSW partners (OR = 0.81, p < .01), but more likely to have unprotected sex with them (OR = 1.78, p < .01). To reduce risk, MMWs would benefit from combination prevention approaches that use behavioral strategies to address drinking norms and awareness of risk, while using biomedical strategies to reduce viral transmission when risk does occur.

Perspectives on Sexual Identity Formation, Identity Practices, and Identity Transitions Among Men Who Have Sex With Men in India.

Men who have sex with men (MSM) remain at high risk for HIV infection. Culturally specific sexual identities, encompassing sexual roles, behavior, and appearance, may shape MSM's experiences of stigmatization and discrimination, and affect their vulnerability to HIV. This multi-site qualitative study (n = 363) encompassing 31 focus group discussions (FGDs) and 121 in-depth interviews (IDIs) across 15 sites in India investigated sexual identity formation, identity practices, and transitions and their implications for HIV prevention. IDIs and FGDs were transcribed, translated, and underwent thematic analysis. Our findings document heterogeneous sexual identity formation, with MSM who have more gender nonconforming behaviors or appearance reporting greater family- and community-level disapproval, harassment, violence, and exclusion. Concealing feminine aspects of sexual identities was important in daily life, especially for married MSM. Some participants negotiated their identity practices in accordance with socioeconomic and cultural pressures, including taking on identity characteristics to suit consumer demand in sex work and on extended periods of joining communities of hijras (sometimes called TG or transgender women). Participants also reported that some MSM transition toward more feminine and hijra or transgender women identities, motivated by intersecting desires for feminine gender expression and by social exclusion and economic marginalization. Future studies should collect information on gender nonconformity stigma, and any changes in sexual identity practices or plans for transitions to other identities over time, in relation to HIV risk behaviors and outcomes.

HIV risks among women who are married to men who have sex with men in India: a qualitative investigation.

In countries such as India, men who have same-sex partnerships may marry women due to cultural pressures regardless of their sexual desires and preferences. The wives of such men may be at risk for HIV but limited existing research addresses this issue. This qualitative study used in-depth interviews to investigate HIV-related risk among married men who have sex with men (n = 34) and women who were aware of their husband's same-sex behaviour (n = 13) from six research sites in five states and a Union Territory in India: Delhi (Delhi), Visakhapatnam (Andhra Pradesh), Hyderabad (Telangana), Bengaluru (Karnataka), Chennai and Madurai (Tamil Nadu). Thematic analysis revealed that wives of men who have sex with men were at risk for HIV from their husbands' sexual practices, which are often hidden to avoid the potential consequences of stigmatisation, as well as from gender-based inequities that make husbands the primary decision-makers about sex and condom use, even when wives are aware of their husband's same-sex behaviour. Innovative interventions are needed to address HIV-related risk in couples where wives remain unaware of their husband's same-sex behaviour, and for wives who are aware but remain within these marriages.

Respondent-driven sampling for identification of HIV- and HCV-infected people who inject drugs and men who have sex with men in India: A cross-sectional, community-based analysis.

BACKGROUND: A major barrier to achieving ambitious targets for global control of HIV and hepatitis C virus (HCV) is low levels of awareness of infection among key populations such as men who have sex with men (MSM) and people who inject drugs (PWID). We explored the potential of a strategy routinely used for surveillance in these groups, respondent-driven sampling (RDS), to be used as an intervention to identify HIV- and HCV-infected PWID and MSM who are unaware of their status and those who are viremic across 26 Indian cities at various epidemic stages. METHODS AND FINDINGS: Data were collected as part of the baseline assessment of an ongoing cluster-randomized trial. RDS was used to accrue participants at 27 sites (15 PWID sites and 12 MSM sites) selected to reflect varying stages of the HIV epidemic among MSM and PWID in India. A total of 56 seeds recruited a sample of 26,447 persons (approximately 1,000 participants per site) between October 1, 2012, and December 19, 2013. Across MSM sites (n = 11,997), the median age was 25 years and the median number of lifetime male partners was 8. Across PWID sites (n = 14,450), 92.4% were male, the median age was 30 years, and 87.5% reported injection in the prior 6 months. RDS identified 4,051 HIV-infected persons, of whom 2,325 (57.4%) were unaware of their HIV infection and 2,816 (69.5%) were HIV viremic. It also identified 5,777 HCV-infected persons, of whom 5,337 (92.4%) were unaware that they were infected with HCV and 4,728 (81.8%) were viremic. In the overall sample (both MSM and PWID), the prevalence of HIV-infected persons who were unaware of their status increased with sampling depth, from 7.9% in participants recruited in waves 1 through 5 to 12.8% among those recruited in waves 26 and above (p-value for trend < 0.001). The overall detection rate of people unaware of their HIV infection was 0.5 persons per day, and the detection rate of HIV-infected persons with viremia (regardless of their awareness status) was 0.7 per day. The detection rate of HIV viremic individuals was positively associated with underlying HIV prevalence and the prevalence of HIV viremia (linear regression coefficient per 1-percentage-point increase in prevalence: 0.05 and 0.07, respectively). The median detection rate of PWID who were unaware of their HCV infection was 2.5 per day. The cost of identifying 1 unaware HIV-infected individual ranged from US$51 to US$2,072 across PWID sites and from US$189 to US$5,367 across MSM sites. The mean additional cost of identifying 1 unaware HCV-infected PWID was US$13 (site range: US$7-US$140). Limitations of the study include the exclusivity of study sites to India, lack of prior HIV/HCV diagnosis confirmation with clinic records, and lack of cost data from other case-finding approaches commonly used in India. CONCLUSIONS: In this study, RDS was able to rapidly identify at nominal cost a substantial number of unaware and viremic HIV-infected and HCV-infected individuals who were currently not being reached by existing programs and who were at high risk for transmission. Combining RDS (or other network-driven recruitment approaches) with strategies focused on linkage to care, particularly in high-burden settings, may be a viable option for achieving the 90-90-90 targets in key populations in resource-limited settings.

Conformational Epitope-Specific Broadly Neutralizing Plasma Antibodies Obtained from an HIV-1 Clade C-Infected Elite Neutralizer Mediate Autologous Virus Escape through Mutations in the V1 Loop.

UNLABELLED: Broadly neutralizing antibodies isolated from infected patients who are elite neutralizers have identified targets on HIV-1 envelope (Env) glycoprotein that are vulnerable to antibody neutralization; however, it is not known whether infection established by the majority of the circulating clade C strains in Indian patients elicit neutralizing antibody responses against any of the known targets. In the present study, we examined the specificity of a broad and potent cross-neutralizing plasma obtained from an Indian elite neutralizer infected with HIV-1 clade C. This plasma neutralized 53/57 (93%) HIV pseudoviruses prepared with Env from distinct HIV clades of different geographical origins. Mapping studies using gp120 core protein, single-residue knockout mutants, and chimeric viruses revealed that G37080 broadly cross-neutralizing (BCN) plasma lacks specificities to the CD4 binding site, gp41 membrane-proximal external region, N160 and N332 glycans, and R166 and K169 in the V1-V3 region and are known predominant targets for BCN antibodies. Depletion of G37080 plasma with soluble trimeric BG505-SOSIP.664 Env (but with neither monomeric gp120 nor clade C membrane-proximal external region peptides) resulted in significant reduction of virus neutralization, suggesting that G37080 BCN antibodies mainly target epitopes on cleaved trimeric Env. Further examination of autologous circulating Envs revealed the association of mutation of residues in the V1 loop that contributed to neutralization resistance. In summary, we report the identification of plasma antibodies from a clade C-infected elite neutralizer that mediate neutralization breadth via epitopes on trimeric gp120 not yet reported and confer autologous neutralization escape via mutation of residues in the V1 loop. IMPORTANCE: A preventive vaccine to protect against HIV-1 is urgently needed. HIV-1 envelope glycoproteins are targets of neutralizing antibodies and represent a key component for immunogen design. The mapping of epitopes on viral envelopes vulnerable to immune evasion will aid in defining targets of vaccine immunogens. We identified novel conformational epitopes on the viral envelope targeted by broadly cross-neutralizing antibodies elicited in natural infection in an elite neutralizer infected with HIV-1 clade C. Our data extend our knowledge on neutralizing epitopes associated with virus escape and potentially contribute to immunogen design and antibody-based prophylactic therapy.

Association of mutations in V3/C3 domain with enhanced sensitivity of HIV-1 clade C primary envelopes to autologous broadly neutralizing plasma antibodies.

BACKGROUND: Broadly neutralizing antibodies to HIV-1 elicited in infected individuals evolves through shifts in their molecular specificities to viral envelope (Env) in the disease course. Recently, we showed that resistance of circulating HIV-1 clade C to the autologous plasma obtained from one Indian elite neutralizer is associated with mutations in V1 loop. In the present study, we examined the genetic attributes associated with exceptional sensitivity of pseudoviruses expressing an env gene obtained from the follow up visit contemporaneous plasma of the same donor. RESULTS: Examination of chimeric autologous Envs, we found that enhanced neutralization sensitivity is associated with mutations in the V3/C3 region. A positive association between V3/C3 mutation mediated enhanced autologous neutralization of autologous viruses with their sensitivity to both neutralizing and non-neutralizing monoclonal antibodies was found. Interestingly, we found that depletion of autologous plasma with trimeric and monomeric Envs conferred the sensitive Env with resistance indicating that mutations in V3/C3 region altered Env conformation towards optimal exposure of epitopes targeted by the neutralizing and non-neutralizing antibodies. CONCLUSION: In summary, we found distinct vulnerabilities associated with evasion of circulating viruses to broadly neutralizing antibodies mounted in an Indian elite neutralizer.