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.

HIV care continuum among men who have sex with men and persons who inject drugs in India: barriers to successful engagement.

BACKGROUND: We characterize the human immunodeficiency virus (HIV) care continuum for men who have sex with men (MSM) and persons who inject drugs (PWID) across India. METHODS: We recruited 12 022 MSM and 14 481 PWID across 26 Indian cities, using respondent-driven sampling (September 2012 to December 2013). Participants were aged ≥18 years and either self-identified as male and reported sex with a man in the prior year (MSM) or reported injection drug use in the prior 2 years (PWID). Correlates of awareness of HIV-positive status were characterized using multilevel logistic regression. RESULTS: A total of 1146 MSM were HIV infected, of whom a median of 30% were aware of their HIV-positive status, 23% were linked to care, 22% were retained before antiretroviral therapy (ART), 16% had started ART, 16% were currently receiving ART, and 10% had suppressed viral loads. There was site variability (awareness range, 0%-90%; suppressed viral load range, 0%-58%). A total of 2906 PWID were HIV infected, of whom a median of 41% were aware, 36% were linked to care, 31% were retained before ART, 20% had started ART, 18% were currently receiving ART, and 15% had suppressed viral loads. Similar site variability was observed (awareness range: 2%-93%; suppressed viral load range: 0%-47%). Factors significantly associated with awareness were region, older age, being married (MSM) or female (PWID), use of other services (PWID), more lifetime sexual partners (MSM), and needle sharing (PWID). Ongoing injection drug use (PWID) and alcohol use (MSM) were associated with lower awareness. CONCLUSIONS: In this large sample, the major barrier to HIV care engagement was awareness of HIV-positive status. Efforts should focus on linking HIV testing to other essential services. CLINICAL TRIALS REGISTRATION: NCT01686750.

Performance characteristics of two new rapid HIV diagnostic assays and use of test band reader.

PURPOSE: Accurate HIV diagnosis is essential for appropriate patient care. This present study evaluated the performance of two different new rapid HIV diagnostic tests; 1) TRUSTline HIV-1/2 Ab rapid test (Athenese-DxPvt. Ltd, Chennai, India)and 2) OnSite HIV 1/2 Ab Plus Combo Rapid Test (CTK Biotech Inc., San Diego, USA) and also validated ALTA Rapid Test Reader (RTR-1) (CTK Biotech Inc., San Diego, USA), the device is a user-friendly and image-analysis based qualitative/semi-quantitative tabletop reader. METHODS: A total of n â€‹= â€‹500 characterized specimens were used for this evaluation and the results of the new test kits (TRUSTline and OnSite) were also compared with 4th generation ELISA kit (Genescreen™Ultra HIV Ag-Ab ELISA) and 3 other commercially available rapid tests that were in the market; 1)SD Bioline™ HIV 1/2 3.0, 2) Aspen® HIV 1/2 Rapid Ab Test and 3) Diagnostic enterprises HIVTRI-DOT. The test band intensities of the TRUSTline and OnSite tests were measured in an ALTA rapid test reader and compared with the naked eye reading. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value and efficacy of TRUSTline and OnSite were 100%, 99.6%, 99.5%, 100% and 99.8% and 100%, 100%, 100%, 100% and 100% respectively. CONCLUSIONS: The 'TRUSTline HIV-1/2' and 'OnSite HIV 1/2' kits are suitable to use in the HIV testing algorithm. Use of the ALTA rapid test reader could be user's friendly in the field level testing in resource-limited settings".

Deep learning and social network analysis elucidate drivers of HIV transmission in a high-incidence cohort of people who inject drugs.

Globally, people who inject drugs (PWID) experience some of the fastest-growing HIV epidemics. Network-based approaches represent a powerful tool for understanding and combating these epidemics; however, detailed social network studies are limited and pose analytical challenges. We collected longitudinal social (injection partners) and spatial (injection venues) network information from 2512 PWID in New Delhi, India. We leveraged network analysis and graph neural networks (GNNs) to uncover factors associated with HIV transmission and identify optimal intervention delivery points. Longitudinal HIV incidence was 21.3 per 100 person-years. Overlapping community detection using GNNs revealed seven communities, with HIV incidence concentrated within one community. The injection venue most strongly associated with incidence was found to overlap six of the seven communities, suggesting that an intervention deployed at this one location could reach the majority of the sample. These findings highlight the utility of network analysis and deep learning in HIV program design.

Role of direct and indirect social and spatial ties in the diffusion of HIV and HCV among people who inject drugs: a cross-sectional community-based network analysis in New Delhi, India.

Background: People who inject drugs (PWID) account for some of the most explosive human immunodeficiency virus (HIV) and hepatitis C virus (HCV) epidemics globally. While individual drivers of infection are well understood, less is known about network factors, with minimal data beyond direct ties. Methods: 2512 PWID in New Delhi, India were recruited in 2017-19 using a sociometric network design. Sampling was initiated with 10 indexes who recruited named injection partners (people who they injected with in the prior month). Each recruit then recruited their named injection partners following the same process with cross-network linkages established by biometric data. Participants responded to a survey, including information on injection venues, and provided a blood sample. Factors associated with HIV/HCV infection were identified using logistic regression. Results: The median age was 26; 99% were male. Baseline HIV prevalence was 37.0% and 46.8% were actively infected with HCV (HCV RNA positive). The odds of prevalent HIV and active HCV infection decreased with each additional degree of separation from an infected alter (HIV AOR: 0.87; HCV AOR: 0.90) and increased among those who injected at a specific venue (HIV AOR: 1.50; HCV AOR: 1.69) independent of individual-level factors (p<0.001). In addition, sociometric factors, for example, network distance to an infected alter, were statistically significant predictors even when considering immediate egocentric ties. Conclusions: These data demonstrate an extremely high burden of HIV and HCV infection and a highly interconnected injection and spatial network structure. Incorporating network and spatial data into the design/implementation of interventions may help interrupt transmission while improving efficiency. Funding: National Institute on Drug Abuse and the Johns Hopkins University Center for AIDS Research.

Understanding the social and spatial relationships that connect people is a key element to stop the spread of infectious diseases. These networks are particularly relevant to combat epidemics among populations that are hard to reach with public health interventions. Network-based approaches, for example, can help to stop HIV or hepatitis C from spreading amongst populations that use injectable drugs. Yet how social and geographic connections such as acquaintances, injection partners, or preferred drug use places impact the risk of infection is still poorly mapped out. To address this question, Clipman et al. focused on people who inject drugs in New Delhi, India, a population heavily impacted by HIV and hepatitis C. Over 2500 people were recruited, each participant inviting their injection partners to also take part. The volunteers answered survey questions, including where they used drugs, and provided a blood sample to be tested. The results showed that, even after adjusting for individual risk factors, where people used drugs and with whom affected their risk of becoming infected with HIV and hepatitis C. In terms of social ties, the likelihood of HIV and hepatitis C infection decreased by about 13% for each person separating a given individual from an infected person. However, geographical networks also had a major impact. Injecting at a popular location respectively increased the odds of HIV and hepatitis C infection by 50% and 69%. In fact, even if the participant was not using drugs at these specific places, having an injection partner who did was enough to increase the risk for disease: for each person separating an individual from the location, the likelihood of being infected with HIV and hepatitis C decreased by respectively 14% and 10%. The results by Clipman et al. highlight how the relationships between physical spaces and social networks contribute to the spread of dangerous diseases amongst people who inject drugs. Ultimately, this knowledge may help to shape better public health interventions that would take into account the importance of geographical locations.

Performance characteristics of an instrument-free point-of-care CD4 test (VISITECT®CD4) for use in resource-limited settings.

OBJECTIVE: CD4+ T lymphocyte count remains the most common biomarker of immune status and disease progression in human immunodeficiency virus (HIV)-positive individuals. VISITECT®CD4 is an instrument-free, low-cost point-of-care CD4 test with a cut-off of 350 CD4 cells/µL. This study aimed to evaluate VISITECT®CD4 test's diagnostic accuracy. METHODS: Two hundred HIV-positive patients attending a tertiary HIV centre in South India were recruited. Patients provided venous blood for reference and VISITECT®CD4 tests. An additional finger-prick blood sample was obtained for VISITECT®CD4. VISITECT®CD4's diagnostic performance in identifying individuals with CD4 counts ≤350 cells/µL was assessed by calculating sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) taking flow cytometry as the reference. RESULTS: The overall agreement between VISITECT®CD4 and flow cytometry was 89.5% using venous blood and 81.5% using finger-prick blood. VISITECT®CD4 showed better performance using venous blood [sensitivity: 96.6% (95% confidence interval: 92.1%-98.9%), specificity: 70.9% (57.1%-82.4%), PPV: 89.7% (83.9%-94.0%) and NPV: 88.6% (75.4%-96.2%)] than using finger-prick blood [sensitivity: 84.8% (77.9%-90.2%), specificity: 72.7% (59.0%-83.9%), PPV: 89.1% (82.7%-93.8%) and NPV: 64.5% (51.3%-76.3%)]. CONCLUSION: VISITECT®CD4 performed well using venous blood, demonstrating its potential utility in decentralization of CD4 testing services in resource-constrained settings.

Brief Report: The Anti-HIV-1 ADCC-Mediating Antibodies From Cervicovaginal Secretions of HIV-Infected Women Have an Ability to Mediate Lysing of Autologous CD4+ HIV-Infected Cells.

BACKGROUND: Fragment crystallizable region of antibody-mediated mechanism such as antibody-dependent cellular cytotoxicity (ADCC) has been identified as an important component of immune protection against HIV. We assessed whether the anti-HIV antibodies mediating ADCC from cervicovaginal lavages (CVLs) of HIV-infected women have an ability to mediate lysing of autologous CD4 HIV-infected cells. METHODOLOGY: The CVLs of 62 HIV-infected (37 long-term slow progressors and 25 with progressive HIV infection: progressors) and 20 HIV-uninfected Indian women with high risk of HIV acquisition were tested for the presence of ADCC-mediating anti-HIV antibodies against HIV-1 C Env in a fluorometric assay. Furthermore, we tested the ability of these antibodies to mediate ADCC-dependent killing of the autologous HIV-infected CD4 T cells using paired peripheral blood mononuclear cells containing target and effector cells. RESULTS: The numbers of ADCC responders were significantly higher in long-term slow progressors (34/37) as compared to the progressor group (9/25) with no significant difference in the magnitude. The magnitude of response was inversely associated with detectable CVL viral load (P < 0.003). The lysis of target cells was significantly higher in enriched IgG fraction as compared to the respective non-IgG fraction. The ADCC antibodies from CVLs significantly reduced the frequency of HIV-1 Env-activated autologous CD4 T cells in the presence of autologous effector cells. CONCLUSIONS: The presence of ADCC antibodies in CVLs with an ability to mediate lysing of HIV-infected autologous CD4 T cells provides evidence of their promising contribution to mucosal defense against HIV-1 and has implications in designing prophylactic and immunotherapeutic strategies.

Hepatitis C care continuum and associated barriers among people who inject drugs in Chennai, India.

BACKGROUND: Little is known regarding barriers to hepatitis C virus (HCV) treatment among people who inject drugs (PWID) in low-resource settings, particularly in the era of direct-acting antiviral therapies. METHODS: Between March, 2015-August, 2016, a cross-sectional survey was administered to community-based PWID in Chennai, India to examine the HCV care continuum and associated barriers. Adjusted prevalence ratios (APR) were estimated by multivariable Poisson regression with robust variance. RESULTS: All participants were male (n = 541); 152 participants had HCV mono-infection and 61 participants had HIV/HCV co-infection. Only one HCV mono-infected and one HIV/HCV co-infected participant was linked to HCV care. Overall, there was moderate knowledge of HCV disease but poor knowledge of HCV treatment. Higher total knowledge scores were negatively associated with HIV/HCV co-infection (vs. HCV mono-infection), though this was not statistically significant in adjusted analysis (APR = 0.71 [95%CI = 0.47-1.06]). Participants ≥45 years (APR = 0.73 [95%CI = 0.58-0.92]) and participants with HIV/HCV co-infection (APR = 0.64 [95%CI = 0.47-0.87]) were less willing to take weekly interferon injections for 12 weeks. Willingness to undergo HCV treatment improved with decreasing duration of therapy, higher perceived efficacy, and use of pills vs. interferon, though willingness to use interferon improved with decreasing duration of therapy. Most participants preferred daily visits to a clinic for HCV treatment versus receiving a month's supply. Participants ≥45 years (vs. <45 years; APR = 0.70 [95%CI = 0.56-0.88]) and participants with HIV/HCV co-infection (APR = 0.75 [95%CI = 0.57-0.98]) were less likely to intend on seeking HCV care. Common reasons for not having already seen a provider for HCV treatment differed by HIV status, and included low perceived need for treatment (HCV-mono-infected), competing money/health priorities and costs/fears about treatment (HIV/HCV-co-infected). CONCLUSION: Residual gaps in HCV knowledge and continuing negative perceptions related to interferon-based therapy highlight the need to scale-up educational initiatives. Readiness for HCV treatment was particularly low among HIV/HCV co-infected and older PWID, emphasizing the importance of tailored treatment strategies.

Serum Fibrosis Markers for the Diagnosis of Liver Disease Among People With Chronic Hepatitis C in Chennai, India.

Background. Access to hepatitis C virus (HCV) treatment is limited in low- and middle-income countries (LMICs). Noninvasive biomarkers, such as fibrosis 4 (FIB-4) and aminotransferase to platelet ratio index (APRI), are low-cost alternatives to staging liver disease and identifying treatment need in people with chronic HCV infection, but their accuracy has not been evaluated in LMICs. Methods. We tested the accuracy of FIB-4 and APRI at validated cutoffs (FIB-4 <1.45, >3.25; APRI <0.5, >1.5) in predicting severe liver stiffness by elastography among 281 persons chronically infected with HCV. Multivariable logistic and Cox regression were used to identify markers of improved prediction and mortality, respectively. Results. Sensitivity and specificity of FIB-4 and APRI for predicting severe stiffness were 62% and 87% and 61% and 83%, respectively. Fibrosis 4 and APRI were less accurate in excluding significant stiffness; however, performance of models significantly improved with γ-glutamyl transpeptidase (GGT) and body mass index (BMI) (area under receiver operating characteristic curve, 0.81; 95% confidence interval, .76-.87). Severe liver stiffness predicted via FIB-4 >3.25, APRI >1.5, and a modified FIB-4 that included GGT and BMI were significantly associated with increased mortality. Conclusions. Fibrosis 4 and APRI may be useful in identifying individuals with severe stiffness who need treatment and continued monitoring in LMICs. Exclusion of significant stiffness may be improved by including GGT and BMI to FIB-4 models.

Morbidity and Mortality Among Community-Based People Who Inject Drugs With a High Hepatitis C and Human Immunodeficiency Virus Burden in Chennai, India.

Background. There are limited data on clinical outcomes of hepatitis C virus (HCV) infection from low- and middle-income countries. We characterize mortality and liver disease progression in a cohort of people who inject drugs (PWID) with high HCV burden. Methods. In a cohort of PWID in Chennai, India, 851 persons were observed semiannually. Information on death was obtained through verbal autopsy and liver disease progression, which was defined as an incident liver stiffness measurement of ≥12.3 kPa if it was <12.3 at baseline. Poisson and Cox regression were used to identify factors associated with mortality and disease progression, respectively. Results. At baseline, 36.9% of cases were infected with HCV, 16.7% were infected with human immunodeficiency virus (HIV), 71.6% had no or mild stiffness, 14.9% had moderate stiffness, and 13.5% had severe stiffness or cirrhosis. Mortality was significantly higher among those with moderate (mortality rate ratio [MRR] = 2.31) and severe stiffness (MRR = 4.86) at baseline, those with ongoing substance use, those who were HIV monoinfected and not on antiretroviral therapy (ART) (MRR = 6.59), and those who were HIV/HCV coinfected regardless of ART status (MRR for no ART = 5.34; MRR for ART = 4.51). Of those with no or mild stiffness, 25.9% and 6.4% had evidence of progression to moderate and severe stiffness or cirrhosis, respectively; 38.3% of those with moderate stiffness had evidence of progression to severe stiffness or cirrhosis. Factors associated with progression included age, alcohol use, body mass index, and chronic HCV infection. Conclusions. We observed significant morbidity and mortality primarily driven by untreated HIV, HIV/HCV coinfection, and alcohol use. Even with improved access to HIV treatment, in the absence of HCV treatment, outcomes are unlikely to improve for HIV/HCV-coinfected persons.