Higher frequencies of functional HIV-envelope-specific memory B cells are associated with nonprogressive HIV infection in Indian population.

OBJECTIVE: The HIV-1-specific antibodies are being considered for prevention and therapy in HIV infection. For effective antibody response, presence of functionally competent memory B cells (MEBs) is important; however, HIV-infection is known to alter the B-cell functionality. Very limited data are available on the HIV-specific memory B-cell population in HIV-infected Indian population. METHODS: In this study, the frequencies of HIV-gp140-specific MEBs were measured in individuals with nonprogressive [long-term-nonprogressors (LTNPs), N = 20] and progressive (N = 19) HIV infection using multicolor flow cytometry. The activation and functional status of these MEBs were assessed as frequencies and mean fluorescence intensity (MFI) of the CD38 and CD40 expression, respectively. RESULTS: The percentages of gp140 + MEBs were higher in LTNPs than seen in progressors (P = 0.0475) and associated with higher CD4 cell count (P = 0.0312, r = 0.2833). As compared with the progressors, LTNPs also showed higher functional (CD40+) gp140 + MEBs both frequencies (P < 0.0001) and CD40 MFI (P = 0.0222), whereas the frequencies (<0.0001) and the MFI (P = 0.0047) of CD38 expression was significantly lower. Higher CD4 cell counts and lower plasma viral load values were associated with higher frequencies of CD40+ gp140 + MEBs (P < 0.0001, r = 0.4962) (P = 0.0036, r = -0.4202) and lower frequencies (P = 0.0008, r = -0.4231) and CD38 expression (MFI) (P = 0.004, r = -0.3719) (P = 0.0066, r = 0.4033). CONCLUSION: Our study suggests that LTNPs have functional HIV-specific memory B-cell compartment with reduced activation that may lead to effective HIV-specific humoral immune responses contributing to their nondisease progression status. These findings would help in better understanding of the characteristics of the HIV-specific memory B-cell population in nonprogressive HIV infection.

IL-1RN and IL-1ß Polymorphism and ARV-Associated Hepatotoxicity.

The severity of hepatic injury depends upon cytokines. Previous studies associated IL-1RN allele 2 with IL-1ß production. Hence, we examined the association of IL-1 RN and IL-1ß polymorphisms with ARV-associated hepatotoxicity. Genotyping of IL-1RN (VNTR), IL-1ß (-511C/T) polymorphisms was done in 162 HIV-infected patients, 34 with ARV hepatotoxicity, 128 without hepatotoxicity, and 152 healthy controls using PCR and PCR-RFLP method. The haplotypes 1T and 2C enhanced the risk for severe hepatotoxicity (OR = 1.41, P = 0.25; OR = 1.67, P = 0.31). IL-1ß-511TT genotype significantly represented among tobacco using HIV-infected individuals compared to nonusers (OR = 3.74, P = 0.05). IL-1ß-511TT genotype among alcohol users increased the risk for hepatotoxicity (OR = 1.80, P = 0.90). IL-1ß-511CT and -511TT genotypes overrepresented in alcohol using HIV-infected individuals (OR = 2.29, P = 0.27; OR = 2.64, P = 0.19). IL-RN 2/2 and 1/3 genotypes represented higher in nevirapine using hepatotoxicity patients (OR = 1.42, P = 0.64, OR = 8.79, P = 0.09). IL-1ß-511CT and -511 TT genotypes among nevirapine users enhanced the risk for severe hepatotoxicity (OR = 4.29, P = 0.20; OR = 1.95, P = 0.56). IL-1ß-511CT and -511TT genotypes were overrepresented in combined nevirapine and alcohol using HIV-infected individuals as compared to nevirapine users and alcohol nonusers (OR = 2.56, P = 0.26; OR = 2.84, P = 0.24). IL-1ß-511TT genotype with tobacco, alcohol, and nevirapine usage revealed a trend of risk for the development of ARV-associated hepatotoxicity and its severity.

Effect of matrix metalloproteinase-21 (572C/T) polymorphism on HIV-associated neurocognitive disorder.

Remodeling of extracellular matrix (ECM) by matrix metalloproteinases (MMPs) is a presumed reason for the development of HIV-associated neurocognitive disorders (HAND). The coding region polymorphism in MMP-21 572C/T gene may have a potential functional effect on ECM remodeling. Hence, we aimed to examine the association of MMP-21 polymorphism with the modulation of HAND severity and its prevalence in HIV-infected and healthy individuals. Genotyping of MMP-21 572C/T polymorphism was performed by PCR-RFLP in total 150 HIV-infected individuals, 50 with HAND, 100 without HAND and 150 healthy controls. MMP-21 572TT genotype was predominantly higher in HAND patients compared with no HAND (OR = 1.63, p = 0.57). MMP-21 572T allele was associated with reduce risk for HAND severity (OR = 0.50, p = 0.04). Similarly, MMP-21 572TT genotype underrepresented in HIV-infected individuals compared to healthy controls (3.0% vs 6.7%, OR = 0.27, p = 0.08). MMP-21 572CT genotype and early HIV disease stage showed a higher risk for the advancement of HIV disease with marginal significance (OR = 1.89, p = 0.07). MMP-21 572CT genotype increased the risk for the modulation of HAND severity in tobacco users (OR = 1.98, p = 0.43). MMP-21 572CT genotype among tobacco and alcohol users showed elevated risk for the development of HAND in HIV-infected individuals (OR = 2.30, p = 0.15; OR = 1.86, p = 0.23). Similarly, MMP-21 572TT genotype enhanced the risk for the development of HAND in tobacco users (OR = 3.48, p = 0.40). In conclusion, the presence of coding region 572T allele may have protection for HAND severity. MMP-21 572C/T polymorphism and tobacco and alcohol usage may facilitate the development of HAND.

Prevalence of MMP-8 gene polymorphisms in HIV-infected individuals and its association with HIV-associated neurocognitive disorder.

Matrix metalloproteinases (MMPs) are well-known as mediators of neuroinflammation in HIV-associated neurocognitive disorder (HAND). Increased levels of MMP-8 have been observed in the HIV-infected patients. Thus, the aim of this study was to evaluate the association of MMP-8 gene polymorphisms with modulation of HAND severity and its prevalence in HIV-infected and healthy individuals. We enrolled a total of 150 HIV-infected individuals, 50 HAND patients, 100 HIV-infected and 150 healthy individuals. MMP-8 (-799C/T, +17C/G) polymorphisms were genotyped by PCR-RFLP. MMP-8 -799TT genotype and +17G allele showed the higher risk for modulation of HAND severity (OR=2.20, P=0.19; OR=1.97, P=0.23). MMP-8 -799TT genotype differed significantly in HIV-infected individuals compared to healthy controls (20.0% vs. 11.3%, OR=2.36, P=0.048). Haplotype TG increased the risk for modulation of HAND severity (OR=2.29, P=0.29). MMP-8 -799TT and +17CG genotypes were overrepresented in the intermediate HIV disease stage compared with healthy controls (25.9% vs. 11.3%, OR=4.34, P=0.021, 14.8% vs. 9.3%, OR=2.88, P=0.11). MMP-8 +17CG genotype enhanced the risk for modulation of HAND severity in tobacco using HAND patients (OR=5.01, P=0.17). MMP-8 -799TT genotype was more frequent in tobacco using HIV-infected individuals compared with nonusers (26.3% vs. 16.7%, OR=2.08, P=0.32). MMP-8 +17CG genotype increased the risk for modulation of HAND severity in alcohol using HAND patients (OR=4.99, P=0.18). In conclusion, MMP-8 polymorphisms independently and with alcohol and tobacco usage revealed a trend of higher risk for the modulation of HAND severity. MMP-8 -799TT genotype was associated with the advancement of HIV disease.

Impact of cellular restriction gene (TRIM5α, BST-2) polymorphisms on the acquisition of HIV-1 and disease progression.

BACKGROUND: TRIM5α and BST-2 are cellular restriction factors affecting the HIV-1 infection and its progression. Genetic variability in these genes alters the expression pattern. Hence, we aimed to examine the impact of the TRIM5α (rs10838525, rs7127617 and rs904375) and BST2 (rs3217318 and rs71694748) polymorphisms on the acquisition of HIV-1 and its progression. METHODS: Genotyping of TRIM5α and BST-2 polymorphisms was performed in a total of 153 HIV-infected patients and 158 unrelated healthy individuals using a polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: No significant differences were found in the genotype frequencies of TRIM5α polymorphisms between HIV patients and healthy controls. BST-2 Δ19/i19 and i19/i19+ Δ19/i19 genotypes appeared more frequently in HIV patients compared to healthy controls (10.4% versus 7.0%, p = 0.20; 11.10% versus 7.6%, p = 0.16). The BST-2 i19 allele was associated with the acquisition of HIV-1 [odds ratio (OR) = 2.76, p = 0.030)]. TRIM5α haplotypes ATG and ACA elevated the risk, whereas haplotype ATA reduced the risk for the acquisition of HIV-1 (OR = 1.92, p = 0.026; OR = 4.88, p = 0.016; OR = 0.31, p = 0.014). BST-2 Δ19/i19 and i19/i19+ Δ19/i19 genotypes were more prevalent in patients with early HIV disease stage compared to healthy controls (15.9% versus 7.0%, p = 0.096; 15.9% versus 7.6%, p = 0.12). The prevalence of TRIM5α rs7127617 CC and BST-2 Δ19/i19 genotypes was observed to be higher in alcohol-using HIV patients compared to non-users (27.8% versus 20.0%, p = 0.35, 22.2% versus 10.0%, p = 0.24). CONCLUSIONS: TRIM5α haplotypes and the BST-2 i19 allele may significantly affect the modulation of HIV-1 acquisition and its progression. TRIM5α rs7127617 CC and BST-2 Δ19/i19 genotypes in alcohol-using HIV patients elevated the risk of HIV disease progression.

Antiretroviral resistance following immunological monitoring in a resource-limited setting of western India: A cross-sectional study.

BACKGROUND: The free antiretroviral therapy (ART) program in India still relies on the clinico-immunological monitoring for diagnosis of treatment failure. As the nucleoside reverse transcriptase inhibitor (NRTI) backbone is shared in first- and second-line regimens, accumulation of drug resistant mutations (DRMs) can compromise the efficacy of NRTI. This study was undertaken to describe the pattern of HIV DRMs following immunological monitoring and investigate its impact on the cycling of NRTI between first- and second-line ART. METHODS AND FINDINGS: This cross-sectional study was performed at a state-sponsored ART clinic of Pune city in western India between January and June 2016. Consecutive adults receiving first-line ART with immunological failure (IF) were recruited for plasma viral load (PVL) estimation. Randomly selected 80 participants with PVL >1000 copies/mL underwent HIV drug resistance genotyping. Of these, 75 plasma sample were successfully genotyped. The median CD4 count and duration of ART at the time of failure were 98 (IQR: 61.60-153.50) cells/µL and 4.62 (IQR: 3.17-6.15) years, respectively. The prevalence of NRTI, non-NRTI, and major protease inhibitor resistance mutations were 89.30%, 96%, and 1.33%, respectively. Following first-line failure, sequences from 56.67% of individuals indicated low- to high-level resistance to all available NRTI. The proportion of sequences with ≥2 thymidine analogue mutations (TAMs) and ≥3 TAMs were 62.12% and 39.39%, respectively. An average of 1.98 TAMs per sequence were observed following IF as compared to 0.37 TAMs per sequence following targeted PVL monitoring at 12 months of ART from a prior study; this difference was significant (p<0.001). CONCLUSION: The option of cycling of NRTI analogues between first- and second-line regimens would no longer be effective if individuals are followed-up by immunological monitoring due to accumulation of mutations. Introduction of routine PVL monitoring is a priority for the long-term sustainability of free ART program in India.

Promoter polymorphism MMP-1 (-1607 2G/1G) and MMP-3 (-1612 5A/6A) in development of HAND and modulation of pathogenesis of HAND.

The pathogenesis of HIV-associated neurocognitive disorder (HAND) is modulated by host genetic susceptibility factors such as Matrix metalloproteinases (MMPs). Promoter polymorphism of MMP-1 and MMP-3 may modify the expression of the gene. Hence, we evaluated the association of MMP-1-16072G/1G and MMP-3-1612 5A/6A polymorphisms with development of HAND and the modulation of pathogenesis of HAND. We enrolled a total of 180 individuals, 50 HIVinfected individuals with HAND, 130 without HAND, and 150 healthy controls. Polymorphism of MMP-1 and MMP-3 were genotyped by PCR-RFLP. MMP-1-1607 2G1G, -16071G/2G-1G/1G genotypes and -1607 1G allele were associated with the development of HAND (OR = 1.64, P = 0.05; OR = 1.45, P = 0.04; OR = 1.69, P = 0.05). MMP-1- 16071G1G, MMP-3-16125A5A genotypes increased the risk for the development of HAND (OR = 1.78, P = 0.25; OR = 2.39, P = 0.13). MMP-3-1612 5A5A, -1612 6A/5A-5A/5A genotypes and -1612 5A allele were associated with the reduced risk of HAND (OR = 0.40, P = 0.05; OR = 0.53, P = 0.04; OR = 0.40, P = 0.01). Haplotype 5A1G increased the risk of development of HAND (OR = 1.93, P = 0.05). As observed in advanced HIV disease stage, MMP-1-1607 1G1G genotype enhance the risk for advancement of HIV disease (OR = 1.69, P = 0.89). MMP-3-1612 6A5A genotype showed higher risk for development of HAND in alcohol users (0R = 1.65, P = 0.44). MMP-1 genotype may have an influence on development of HAND whereas MMP3-1612 5A5A genotype may reduce risk for pathogenesis of HAND.

Cross-sectional study of virological failure and multinucleoside reverse transcriptase inhibitor resistance at 12 months of antiretroviral therapy in Western India.

The free antiretroviral therapy (ART) program in India has scaled up to register second largest number of people living with HIV/AIDS across the globe. To assess the effectiveness of current first-line regimen we estimated virological suppression on completion of 1 year of ART. The study describes the correlates of virological failure (VF) and multinucleoside reverse transcriptase inhibitor (NRTI) drug resistance mutations (DRMs).In this cross-sectional study conducted between June and August 2014, consecutive adults from 4 State sponsored ART clinics of western India were recruited for plasma viral load screening at 12 ±â€Š2 months of ART initiation. Individuals with plasma viral load >1000 copies/mL were selected for HIV drug resistance (HIVDR) genotyping. Logistic regression analyses were performed to assess factors associated with VF and multi-NRTI resistance mutations. Criteria adopted for multi-NRTI resistance mutation were either presence of K65R or 3 or more thymidine analog mutations (TAMs) or presence of M184V along with 2 TAMs.Of the 844 study participants, virological suppression at 1 year was achieved in 87.7% of individuals. Factors significantly associated with VF (P < 0.005) were 12 months CD4 count of ≤100 cells/µL (adjusted OR -7.11), low reported adherence (adjusted OR -4.44), and those living without any partner (adjusted OR -1.98). In patients with VF, the prevalence of non-nucleoside reverse transcriptase inhibitor (NNRTI) DRM (78.75%) were higher as compared to NRTI (58.75%). Multi-NRTI DRMs were present in 32.5% of sequences and were significantly associated with CD4 count of ≤100 cells/µL at baseline (adjusted OR -13.00) and TDF-based failing regimen (adjusted OR -20.43). Additionally, low reported adherence was negatively associated with multi-NRTI resistance (adjusted OR -0.11, P = 0.015). K65R mutation was significantly associated with tenofovir (TDF)-based failing regimen (P < 0.001).The study supports early linkage of HIV-infected individuals to the program for ART initiation, adherence improvement, and introduction of viral load monitoring. With recent introduction of TDF-based regimen, the emergence of K65R needs to be monitored closely among HIV-1 subtype C-infected Indian population.

Genetic variation of MMP-2(-735 C>T) and MMP-9(-1562 C>T) gene in risk of development of HAND and severity of HAND.

BACKGROUND: Astrocytes are susceptible to HIV-1 infection. Neurocognitive dysfunction has also been associated with the toxicity of certain antiretroviral drugs. HIV-1 induced neurological toxicity has been associated with deficiency of matrix metalloproteinases. Therefore, we evaluated the association of MMP-2(-735C > T) and MMP-9(-1562C > T) polymorphisms with respect to the susceptibility of developing HIV-associated neurocognitive disorders (HAND) and its severity. METHODS: We enrolled 50 HIV-infected individuals with HAND, 130 without HAND and 150 unrelated healthy controls. Polymorphism for MMP-2-735C > T and MMP-9-1562C > T genes was genotyped by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Individuals with the MMP-2 -735 CT genotype and -735 T allele were at higher risk of developing HAND [odds ratio (OR) = 5.27, 95% confidence interval (CI) = 1.30-21.35, p = 0.02 and OR = 2.27, 95% CI = 1.57-3.27, p = 0.0001 respectively]. The MMP-2 -735 CT genotype and -735 T allele of MMP-2 were associated with a reduced likelihood of severe HAND (OR =0.32, 95% CI = 0.15-0.66, p = 0.002 and OR = 0.32, 95% CI = 0.14-0.71, p = 0.005). When evaluating gene-gene interaction models, the combined genotype MMP-2-735TT + MMP-9-1562CC and MMP-2-735CT + MMP-9-1562CT was associated with the risk of developing HAND (OR = 4.84, p = 0.0001, OR = 1.81, p = 0.03). However, individuals with the combined genotype of MMP-2-735TT + MMP-9-1562CC were found to be protective for severe HAND (OR = 0.30, 95% CI = 0.13-0.67, p = 0.003). CONCLUSIONS: Individuals with the MMP-2 -735CT genotype, -735 T allele and combined genotype MMP-2 -735TT + MMP-9 -1562CC had an enhanced risk of developing HAND. Those with the MMP-2 -735 CT genotype, -735 T allele and combined genotype of MMP-2-735TT + MMP-9-1562CC were suggested to have protection from developing severe HAND.

APOBEC3B deletion impacts on susceptibility to acquire HIV-1 and its advancement among individuals in western India.

APOBEC3B deletion polymorphism has been associated with risk of HIV-1 acquisition and its progression. Therefore, we aimed to investigate the association of APOBEC3B ins/del polymorphism with risk of acquisition of HIV-1 and its progression. In the present case-control study, we enrolled a total of 150 HIV-infected individuals and 150 healthy controls. Polymorphism for APOBEC3B gene was genotyped by PCR. APOBEC3B ID, DD genotypes, and D allele were associated with higher risk of acquisition of HIV-1 (p = 0.004, OR = 4.96; p = 0.03, OR = 3.55; and p = 0.004; OR = 1.60). The individuals with ID genotypes and combined genotype ID+DD of APOBEC3B in the presence of tobacco and alcohol showed the higher risk of advancement of HIV disease; however, risk could not reach statistical significance (OR = 1.14, 95% CI: 0.59-2.18; OR = 1.33, 95% CI: 0.83-2.15 and OR = 1.44, 95% CI: 0.77-2.69; OR = 1.50, 95% CI: 0.94-2.40). Individuals in advanced HIV disease stage and ID genotype and combined genotype ID + DD of APOBEC3B were more likely to be associated with advanced HIV disease stage but risk could not reach significant (OR = 1.50, 95% CI: 0.94-2.40; OR = 1.27, 95% CI: 0.88-1.84). Individuals with ID and DD genotype of APOBEC3B had influence on susceptibility to acquisition of HIV-1. This suggests that APOBEC3B deletion may attenuate innate cellular immunity against HIV-1 and thus confer the host persistence for HIV infection.

Impact of variants of MMP-7(-181A>G) gene in susceptibility to the development of HIV-associated neurocognitive disorder and its severity.

The HIV-1-induced neurological toxicity has been associated with the deficiency of matrix metalloproteinases. Tat protein of HIV up regulates MMP-7 release and activation, leading to neurotoxicity. The SNP -181A>G of MMP-7 is known to have functional effects on its promoter activity. Therefore, we aimed to evaluate the association of variants of MMP-7 -181A>G gene in HIV-associated neurocognitive disorder (HAND). In the present case-control study, we recruited 50 HIV-infected individuals with HAND, 130 HIV-infected individuals without HAND and 150 unrelated healthy individuals. Polymorphism for MMP-7 -181A>G gene was genotyped by PCR-RFLP method. Frequency of -181GG and G allele of MMP-7 did not differ significantly between patients with HAND and without HAND (8.0% vs 13.1%, p = 0.22 and 31% vs 38.1%, p = 0.21). Individuals with -181 AG, -181GG genotype, and G allele of MMP-7 were found to have reduced the risk of development of HAND but not significant (50.0% vs 51.9%, p = 0.09, OR = 0.54; 13.1% vs 19.0%, p = 0.33, OR = 0.71 and 38.1% vs 44.9%, p = 0.09, OR = 0.75). Individuals in early HIV disease stage having -181AG genotype and -181AG + GG combined genotype of MMP-7 were not associated with the development of HAND (OR = 1.27, p = 0.25 and OR = 1.25, p = 0.17). Tobacco and alcohol consumption among individuals with any genotype of MMP-7 was not associated with the risk of development of HAND. In conclusion, individuals with -181GG genotype and G allele had no impact on susceptibility to the development of HAND and its severity.

Retention of antiretroviral naïve patients registered in HIV care in a program clinic in Pune, India.

BACKGROUND: Retention in HIV care ensures delivery of services like secondary prevention, timely initiation of treatment, support, and care on a regular basis. The data on retention in pre antiretroviral therapy (ART) care in India is scanty. MATERIALS AND METHODS: Antiretroviral naïve HIV-infected adult patients registered between January 2011 and March 2012 in HIV care (pre-ART) were included in the study. The follow-up procedures were done as per the national guidelines. Patients who did not report to the clinic for 1 year were considered as pre-ART lost to follow-up (pre-ART LFU). They were contacted either telephonically or by home visits. Logistic regression analysis was done to find out factors associated with pre-ART loss to follow-up. RESULTS: A total of 689 antiretroviral naïve adult patients were registered in the HIV care. Fourteen (2%) patients died and 76 (11%) were LFU till March 2013. The multivariate analysis showed that baseline CD4 count >350 cells/mm(3) (P < 0.01) and illiteracy (P = 0.044) were significantly associated with LFU. Of the total pre-ART LFUs, 35 (46.1%) informed that they would visit the clinic at their convenient time. NGOs that referred 16 female sex workers (FSWs) who were LFU (21.1%) informed that they would make efforts to refer them to the clinic. CONCLUSION: Higher CD4 count and illiteracy were significantly associated with lower retention in pre-ART care. Developing effective "retention package" for patients and strengthening linkage strategies between key sub-population such as FSWs and ART programming will help to plug the leaky cascade in HIV care.

Correlates of lower comprehension of informed consent among participants enrolled in a cohort study in Pune, India.

BACKGROUND: Optimum comprehension of informed consent by research participants is essential yet challenging. This study explored correlates of lower comprehension of informed consent among 1334 participants of a cohort study aimed at estimating HIV incidence in Pune, India. METHODS: As part of the informed consent process, a structured comprehension tool was administered to study participants. Participants scoring ≥90% were categorised into the 'optimal comprehension group', whilst those scoring 80-89% were categorised into the 'lower comprehension group'. Data were analysed to identify sociodemographic and behavioural correlates of lower consent comprehension. RESULTS: The mean ± SD comprehension score was 94.4 ± 5.00%. Information pertaining to study-related risks was not comprehended by 61.7% of participants. HIV-negative men (adjusted OR [AOR] = 4.36, 95% CI 1.71-11.05) or HIV-negative women (AOR = 13.54, 95% CI 6.42-28.55), illiteracy (AOR= 1.65, 95% CI 1.19-2.30), those with a history of multiple partners (AOR = 1.73, 95% CI 1.12-2.66) and those never using condoms (AOR = 1.35, 95% CI 1.01-1.82) were more likely to have lower consent comprehension. CONCLUSIONS: We recommend exploration of domains of lower consent comprehension using a validated consent comprehension tool. Improved education in these specific domains would optimise consent comprehension among research participants.

Declining HIV incidence among patients attending sexually transmitted infection clinics in Pune, India.

OBJECTIVE: A recent report suggesting declining HIV transmission rates in southern India has been based on HIV seroprevalence data to estimate HIV incidence. We analyzed HIV incidence rates among 3 cohorts (male, female non-sex worker, female sex worker [FSW]) presenting to sexually transmitted infection (STI) clinics in Pune, India over 10 years. METHODS: Between 1993 and 2002, consenting HIV-uninfected individuals were enrolled in a prospective study of the risks for HIV seroconversion. Standardized HIV incidence estimates were calculated separately for the 3 cohorts. RESULTS: HIV acquisition risk declined by more than 70% for FSWs (P = 0.02) and men (P < 0.001) attending the STI clinics. There was no significant reduction in HIV incidence among women attending STI clinics (P = 0.74). The decline in HIVacquisition risk among male patients with STIs was associated with an increase in reported condom use with recent FSW contact and a decrease in genital ulcer disease. CONCLUSIONS: We report the first direct evidence for a decline in HIV incidence rates in FSWs and male patients with STIs over time. The lack of change in HIV infection risk among non-sex worker women highlights the need for additional targeted HIV prevention interventions.

Extensive cross-reactive neutralizing antibody response in Indian patients with limited genetic diversity of HIV-1.

Genome sequence analysis of HIV-1 subtype C viruses from India shows monophyletic lineage and relatively limited genetic diversity. To understand its immunological implication, cross-reactivity of neutralizing antibody response was investigated. In primary screening, neutralizing antibody response to single heterologous primary HIV-1 subtype C isolate was assessed in plasma samples from 235 HIV-1 infected, anti-retroviral treatment naive individuals from Pune, India. Plasma samples that showed > or =90% neutralization and two randomly selected plasma samples that showed 50-60% neutralization were tested against a panel of primary HIV-1 subtype C isolates obtained from epidemiologically unlinked individuals from India. The neutralizing antibody response showed extensive cross-neutralization, suggesting presence of shared neutralization determinants among circulating HIV-1 subtype C viruses in India.

Recent herpes simplex virus type 2 infection and the risk of human immunodeficiency virus type 1 acquisition in India.

To estimate the impact of prevalent and incident herpes simplex virus type 2 (HSV-2) infection on the acquisition of human immunodeficiency virus type 1 (HIV-1), stored serum samples from a cohort of 2732 HIV-1-seronegative patients attending 3 sexually transmitted infection clinics and 1 reproductive tract infection clinic in Pune, India, were screened for HSV-2-specific antibodies. Incident HSV-2 infection was defined serologically as "recent" if a negative result of testing for HSV-2 could be documented within the previous 6 months or "remote" if >6 months had elapsed since the last negative test result. The prevalence of HSV-2 at enrollment was 43%. The HSV-2 incidence was 11.4 cases/100 person-years, and the HIV-1 incidence was 5.8 cases/100 person-years. The adjusted hazard ratios of HIV-1 acquisition from exposure to HSV-2 infection were 1.67 for prevalent HSV-2, 1.92 for remote incident HSV-2, and 3.81 for recent incident HSV-2. Recent incident HSV-2 infection was associated with the highest risk of HIV-1 in this study, which suggests that prevention of HSV-2 infection may reduce the risk of HIV-1 acquisition.

Incident HIV infection among men attending STD clinics in Pune, India: pathways to disparity and interventions to enhance equity.

Systematic disparities in rates of HIV incidence by socioeconomic status were assessed among men attending three sexually transmitted disease (STD) clinics in Pune, India, to identify key policy-intervention points to increase health equity. Measures of socioeconomic status included level of education, family income, and occupation. From 1993 to 2000, 2,260 HIV-uninfected men who consented to participate in the study were followed on a quarterly basis. Proportional hazards regression analysis of incident HIV infection identified a statistically significant interaction between level of education and genital ulcer disease. Compared to the lowest-risk men without genital ulcer disease who completed high school, the relative risk (RR) for acquisition of HIV was 7.02 (p < 0.001) for illiterate men with genital ulcer disease, 3.62 (p < 0.001) for men with some education and genital ulcer disease, and 3.02 (p < 0.001) for men who completed high school and had genital ulcer disease. For men with no genital ulcer disease and those with no education RR was 1.09 (p = 0.84), and for men with primary/middle school it was 1.70 (p = 0.03). The study provides evidence that by enhancing access to treatment and interventions that include counselling, education, and provision of condoms for prevention of STDs, especially genital ulcer disease, among disadvantaged men, the disparity in rates of HIV incidence could be lessened considerably. Nevertheless, given the same level of knowledge on AIDS, the same level of risk behaviour, and the same level of biological co-factors, the most disadvantaged men still have higher rates of HIV incidence.

Rapid disease progression in human immunodeficiency virus type 1-infected seroconverters in India.

To determine if the early immunological and virological events of HIV infection are unique in a setting with limited access to health care and HIV-1 subtype C infection, we undertook a prospective cohort study to characterize the early natural history of HIV viral load and CD4(+) T lymphocyte counts in individuals with recent HIV seroconversion in India. CD4(+) T lymphocyte counts were prospectively measured for up to 720 days in 46 antiviral drug-naive persons with very early HIV infection, documented by HIV antibody seroconversion. HIV viral RNA levels were measured subsequently on reposited plasma samples from these same time points. The median viral load "set point" for Indian seroconverters was 28,729 RNA copies/ml. The median CD4(+) cell count following acute primary HIV infection was 644 cells/mm(3). Over the first 2 years since primary infection, the annual rate of increase in HIV viral load was +8274 RNA copies/ml/year and the annual decline in CD4 cell count was -120 cells/year. Although the viral "set point" was similar, the median trajectory of increasing viral load in Indian seroconverters was greater than what has been reported in untreated HIV seroconverters in the United States. These data suggest that the more rapid HIV disease progression described in resource-poor settings may be due to very early virological and host events following primary HIV infection. A rapid increase in viral load within the first 2 years after primary infection may have to be considered when applying treatment guidelines for antiretroviral therapy and opportunistic infection prophylaxis.