Sanjay Mehendale

Prevention of HIV-1 Infection with Early Antiretroviral Therapy

BACKGROUND Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. METHODS In nine countries, we enrolled 1763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative; 54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1-infected subjects with CD4 counts between 350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive antiretroviral therapy either immediately (early therapy) or after a decline in the CD4 count or the onset of HIV-1-related symptoms (delayed therapy). The primary prevention end point was linked HIV-1 transmission in HIV-1-negative partners. The primary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death. RESULTS As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the early-therapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P<0.001). Subjects receiving early therapy had fewer treatment end points (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P=0.01). CONCLUSIONS The early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and public health benefits from such therapy. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 052 ClinicalTrials.gov number, NCT00074581.).

Male circumcision and risk of HIV-1 and other sexually transmitted infections in India

Circumcised men have a lower risk of HIV-1 infection than uncircumcised men. Laboratory findings suggest that the foreskin is enriched with HIV-1 target cells. However, some data suggest that circumcision could simply be a marker for low-risk behaviours. In a prospective study of 2298 HIV-uninfected men attending sexually transmitted infection clinics in India, we noted that circumcision was strongly protective against HIV-1 infection (adjusted relative risk 0.15; 95% CI 0.04-0.62; p=0.0089); however, we noted no protective effect against herpes simplex virus type 2, syphilis, or gonorrhoea. The specificity of this relation suggests a biological rather than behavioural explanation for the protective effect of male circumcision against HIV-1.

The etiology of genital ulcer disease by multiplex polymerase chain reaction and relationship to HIV infection among patients attending sexually transmitted disease clinics in Pune, India

OBJECTIVES To determine the etiology of genital ulcer disease (GUD) among patients attending sexually transmitted disease (STD) clinics in Pune, India, and to examine the relationship to HIV infection and compare the clinical diagnosis of GUD with the results of a multiplex polymerase chain reaction (M-PCR) assay for Treponema pallidum, herpes simplex virus (HSV), and Hemophilus ducreyi infection. METHODS Between June 20, 1994, and September 26, 1994, 302 patients with a genital ulcer were evaluated. Clinical etiology of GUD was based on physical appearance and microbiologic evaluations which included darkfield microscopy and serology for syphilis. Swabs of each genital ulcer were tested for HSV antigen by enzyme immunoassay (Herpchek; Dupont, Wilmington, DE) and processed in a multiplex PCR assay (M-PCR; Roche, Branchburg, NJ) for simultaneous detection of HSV, Treponema pallidum, and Hemophilus ducreyi. RESULTS Two hundred seventy-seven men and 25 women with a median age of 25 were evaluated. The seroprevalence of HIV was 22.2%. The etiology of GUD as determined by M-PCR was HSV (26%), H. ducreyi (23%), T. pallidum (10%), and multiple infections (7%); no etiology was identified in 34%. HIV seroprevalence was higher among those patients positive for HSV compared with other etiologies (OR = 2.1, CI: 1.2-3.7; p = 0.01). When compared with M-PCR, the Herpchek test was 68.5% sensitive and 99.5% specific. Darkfield detection for T. pallidum was 39% sensitive and 82% specific, in contrast to rapid plasma reagin and fluorescent treponemal antibody absorption test, which was 66% sensitive and 90% specific. Clinical diagnosis alone or in combination with basic laboratory tests showed poor agreement with M-PCR.

Feasibility of pooling sera for HIV-1 viral RNA to diagnose acute primary HIV-1 infection and estimate HIV incidence.

ObjectiveTo develop a pooling method for detection of viral RNA for diagnosis of acute HIV infection and estimation of HIV-1 incidence. MethodsSera from 700 consecutive seronegative patients attending sexually transmitted disease clinics in Pune, India, were screened individually for p24 antigen, and pooled into seven pools of 100 for detection of HIV-1 RNA by reverse transcriptase-polymerase chain reaction. HIV-1 incidence was calculated by the traditional cohort method, the p24 antigen method, and a multistage pooling method in which RNA-positive pools were re-analyzed in smaller pools. ResultsSera from 700 individuals were grouped into seven pools of 100, of which four were positive. These four positive pools were subdivided into eight pools of 50, of which seven were positive. The seven positive pools were subdivided into 35 pools of 10, of which 10 were positive. Based on the 10 RNA-positive pools, the point estimate of HIV-1 incidence was 19.9% per year [95% confidence interval (CI), 7.3–31.8%]. Of the 700 samples analyzed for p24 antigen, eight were positive, resulting in a point estimate of incidence of 18.5%/year (8.0–36.5%). In contrast, the incidence rate based on the traditional cohort method of follow-up was lower at 9.4%/year (4.8–16.4%) due to a low follow-up rate. Testing of individual samples from the 10 RNA-positive pools identified 10 individuals with acute primary HIV-1. ConclusionThe multistage pooling method for detection of HIV-1 RNA was more sensitive than the p24 antigen method, and was five-fold less expensive than the p24 antigen assays. Pooling samples for RNA detection was effective in estimating current incidence rates with cost savings that would be practical for use in developing countries.

HIV testing and counseling among men attending sexually transmitted disease clinics in Pune, India: Changes in condom use and sexual behavior over time

Objectives:To describe changes in sexual behavior and condom use among male heterosexual clients at two public sexually transmitted disease (STD) clinics in Pune, after exposure to HIV testing, counseling, and condom promotion. Design:From 13 May 1993 to 11 April 1997, 6819 heterosexual men were screened for HIV infection as part of the HIV Network for Prevention Trials study. A total of 1628 HIV-seronegative men agreed to return at 3-month intervals for repeated HIV counseling and testing. Counseling at each visit focused on reinforcing messages of monogamy, condom use with sexual partners, and provision of government-provided condoms. Methods:Data were collected at baseline and at subsequent 3-month intervals, on demographics, previous STD diagnoses, medical history, sexual behavior, knowledge of HIV/AIDS, and practices related to the prevention of HIV. STD were assessed through physical examination and specimen collection, and blood was drawn for HIV-1 and HIV-2 antibody testing. Results:The level of consistent condom use with sex workers increased proportionately with follow-up time: at 6 months men were 2.8 times more likely to consistently use condoms (P < 0.001), at 18 months they were 3.6 times more likely (P < 0.001), and after 24 months they were 4.7 times more likely to be using condoms every time. The risk of HIV seroconversion in men was lowest for those who reported ‘always’ using condoms (adjusted relative risk, 0.68; P = 0.42; HIV incidence, 4.0) compared with those who reported ‘never’ using a condom (adjusted relative risk, 2.94; P < 0.001; HIV incidence, 14.0). Conclusion:Ongoing counseling and testing was positively associated with risk-reduction behaviors amongst a large proportion of men recruited for this study.

High rates of syphilis among STI patients are contributing to the spread of HIV-1 in India

Background: Recent syphilis outbreaks have raised concern regarding the potential enhancement of HIV transmission. The incidence of syphilis and its association with HIV-1 infection rates among a cohort of sexually transmitted infection (STI) clinic attendees was investigated. Methods: 2732 HIV-1 seronegative patients attending three STI and one gynaecology clinic, were enrolled from 1993–2000 in an ongoing prospective cohort study of acute HIV-1 infection in Pune, India. At screening and quarterly follow up visits, participants underwent HIV-1 risk reduction counselling, risk behaviour assessment and HIV/STI screening that included testing for serological evidence of syphilis by RPR with TPHA confirmation. Patients with genital ulcers were screened with dark field microscopy. Results: Among 2324 participants who were HIV-1 and RPR seronegative at baseline, 172 participants were found to have clinical or laboratory evidence of syphilis during follow up (5.4 per 100 person years, 95% CI 4.8 to 6.5 per 100 person years). Independent predictors of syphilis acquisition based on a Cox proportional hazards model included age less than 20 years, lack of formal education, earlier calendar year of follow up, and recent HIV-1 infection. Based on a median follow up time of 11 months, the incidence of HIV-1 was 5.8 per 100 person years (95% CI 5.0 to 6.6 per 100 person years). Using a Cox proportional hazards model to adjust for known HIV risk factors, the adjusted hazard ratio of HIV-1 infection associated with incident syphilis was 4.44 (95% CI 2.96 to 6.65; p<0.001). Conclusions: A high incidence rate of syphilis was observed among STI clinic attendees. The elevated risk of HIV-1 infection that was observed among participants with incident syphilis supports the hypothesis that syphilis enhances the sexual transmission of HIV-1 and highlights the importance of early diagnosis and treatment of syphilis.

phase 1 Trial of the Topical Microbicide Buffergel: Safety Results From Four International Sites

Aim: To evaluate the safety of BufferGel (ReProtect LLC, Baltimore, MD), a spermicidal microbicide that acidifies semen and maintains the protective acidity of the vagina, in a high‐dose tolerance trial. Methods: HIV/STD negative, sexually abstinent, and sexually active women in India, Thailand, Malawi, and Zimbabwe were asked to insert one applicator (˜5 ml) of BufferGel vaginally twice per day for 14 days. Sexually active women agreed to have sex (while using BufferGel and nonlubricated condoms) at least twice per week. Results: In total, 98 women (30 sexually abstinent and 68 sexually active) were enrolled. Overall compliance with product use was 93%. Epithelial abnormalities detected by pelvic examination or colposcopy were uncommon (8 cases in 271 examinations). Irritation was reported by approximately one quarter of the women (0.58 events per woman‐week) but was generally mild and of short duration. The prevalence of bacterial vaginosis (BV) fell significantly, from 30% at enrollment to 6% at one week, and 7% at two weeks of BufferGel use. Thirty‐two women acquired microscopically detectable yeast during BufferGel exposure, but only 3 developed symptomatic vaginitis. Conclusion: BufferGel appears to be safe and well tolerated by the cervicovaginal epithelium. Its effect on BV and yeasts merits further study.

Correlates and Trend of HIV Prevalence Among Female Sex Workers Attending Sexually Transmitted Disease Clinics in Pune, India (1993–2002)

In India, substantial efforts have been made to increase awareness about HIV/AIDS among female sex workers (FSWs). We assessed the impact of awareness regarding safe sex in a cohort of FSWs by studying trends in HIV prevalence, sexually transmitted diseases (STDs), and risk behaviors measured from 1993 to 2002 in Pune, India. A total of 1359 FSWs attending 3 STD clinics were screened for HIV infection, and data on demographics, sexual behaviors, and past and current STDs were obtained. The overall HIV prevalence among FSWs was 54%. Not being married (adjusted odds ratio [AOR] = 1.74, 95% confidence interval [CI]: 1.17 to 2.59), being widowed (AOR = 2.10, 95% CI: 1.16 to 3.80), inconsistent condom use (AOR = 1.60, 95% CI: 1.02 to 2.50), clinical presence of genital ulcer disease (GUD; AOR = 1.66, 95% CI: 1.07 to 2.56), and genital warts (AOR = 4.70, 95% CI: 1.57 to 14.08) were independently associated with HIV infection among FSWs. The prevalence of HIV remained stable over 10 years (46% in 1993 and 50% in 2002; P = 0.80). The prevalence of GUD decreased over time (P < 0.001), whereas that of observed genital discharge remained stable. Reported consistent condom use as well as the proportion of FSWs who refused sexual contact without condoms increased over time (P < 0.001). These data collectively suggest that safe sex interventions have had a positive impact on FSWs in Pune, India.

HIV-1 DNA shedding in genital ulcers and its associated risk factors in Pune, India

HIV infection status was determined in 302 consecutive patients with genital ulcer disease (GUD) presenting to two sexually transmitted disease (STD) clinics in Pune, India. Of the 71 (24%) individuals with HIV infection, 67 (94%) were HIV antibody-positive, and 4 (6%) were HIV antibody-negative but p24 antigen-positive at the time of presentation. HIV-1 DNA was detected in 24 (34%) specimens. The genital ulcers of all four acutely infected p24-antigenemic subjects were HIV-1 DNA-positive by polymerase chain reaction (PCR) assay, compared with 20 of 67 (30%) seropositive patients (p = .01). Presence of chancroid, GUD symptoms for > 10 days, and concurrent diagnosis of cervicitis or urethritis were significantly associated risk factors for HIV-1 DNA shedding in ulcers. Early GUD diagnosis and aggressive treatment of HIV-infected patients may significantly reduce secondary transmission of HIV to other sex partners.

Incidence of common opportunistic infections in HIV-infected individuals in Pune, India: analysis by stages of immunosuppression represented by CD4 counts

BACKGROUND Opportunistic infections (OIs) influence the morbidity and mortality due to HIV infections. Data from India on the incidence of OIs among HIV-infected individuals by stages of immunodeficiency are scarce. METHODS Between September 2002 and November 2004, HIV-infected individuals were enrolled in a prospective study in Pune. They were clinically and immunologically evaluated quarterly. Incidence rates of specific OIs were calculated. RESULTS Median CD4 counts in HIV-infected male and female patients at baseline were 197/mm(3) and 413/mm(3), respectively. Tuberculosis was the most common OI with an incidence of 15.4 (95% CI 12.2-19.2) per 100 person-years, followed by oral candidiasis 11.3 (95% CI 8.6-14.5), herpes zoster 10.1 (95% CI 7.6-13.1), and cryptococcal meningitis 1.7 (95% CI 0.8-3.1) per 100 person-years. Patients with baseline CD4 counts of <200/mm(3) were six times more likely to develop OIs compared to those with CD4 counts of >350/mm(3) (p<0.001). CONCLUSIONS The high incidence of commonly reported OIs in Indian HIV-infected individuals highlights the need for early screening and also the need to increase awareness in healthcare providers, in order to improve decisions regarding prophylaxis for prevention and appropriate therapeutic intervention. Emphasis needs to be given to the early diagnosis and management of tuberculosis in HIV-infected individuals.