Robert C. Bollinger

Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials.

BACKGROUND UNICEF/WHO recommends that infants born to HIV-infected mothers who do not have access to acceptable, feasible, affordable, sustainable, and safe replacement feeding should be exclusively breastfed for at least 6 months. The aim of three trials in Ethiopia, India, and Uganda was to assess whether daily nevirapine given to breastfed infants through 6 weeks of age can decrease HIV transmission via breastfeeding. METHODS HIV-infected women breastfeeding their infants were eligible for participation. Participants were randomly assigned to receive either single-dose nevirapine (nevirapine 200 mg to women in labour and nevirapine 2 mg/kg to newborns after birth) or 6 week extended-dose nevirapine (nevirapine 200 mg to women in labour and nevirapine 2 mg/kg to newborn babies after birth plus nevirapine 5 mg daily from days 8-42 for the infant). The randomisation sequences were generated by computer at a central data coordinating centre. The primary endpoint was HIV infection at 6 months of age in infants who were HIV PCR negative at birth. Analyses were by modified intention to treat, excluding infants with missing specimens and those with indeterminate or confirmed HIV infection at birth. These studies are registered with ClinicalTrials.gov, numbers NCT00074399, NCT00061321, and NCT00639938. FINDINGS 2024 liveborn infants randomised in the study had at least one specimen tested before 6 months of age (1047 infants in the single-dose group and 977 infants in the extended-dose group). The modified intention-to-treat population included 986 infants in the single-dose group and 901 in the extended-dose group. At 6 months, 87 children in the single-dose group and 62 in the extended-dose group were infected with HIV (relative risk 0.80, 95% CI 0.58-1.10; p=0.16). At 6 weeks of age, 54 children in the single-dose group and 25 in the extended-dose group were HIV positive (0.54, 0.34-0.85; p=0.009). 393 infants in the single-dose group and 346 in the extended-dose group experienced grade 3 or 4 serious adverse events during the study (p=0.54). INTERPRETATION Although a 6-week regimen of daily nevirapine might be associated with a reduction in the risk of HIV transmission at 6 weeks of age, the lack of a significant reduction in the primary endpoint-risk of HIV transmission at 6 months-suggests that a longer course of daily infant nevirapine to prevent HIV transmission via breast milk might be more effective where access to affordable and safe replacement feeding is not yet available and where the risks of replacement feeding are high. FUNDING US National Institutes of Health; US National Institute of Allergy and Infectious Diseases; Fogarty International Center.

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.

Effect of Peer Health Workers on AIDS Care in Rakai, Uganda: A Cluster-Randomized Trial

Background Human resource limitations are a challenge to the delivery of antiretroviral therapy (ART) in low-resource settings. We conducted a cluster randomized trial to assess the effect of community-based peer health workers (PHW) on AIDS care of adults in Rakai, Uganda. Methodology/Principal Findings 15 AIDS clinics were randomized 2∶1 to receive the PHW intervention (n = 10) or control (n = 5). PHW tasks included clinic and home-based provision of counseling, clinical, adherence to ART, and social support. Primary outcomes were adherence and cumulative risk of virologic failure (>400 copies/mL). Secondary outcomes were virologic failure at each 24 week time point up to 192 weeks of ART. Analysis was by intention to treat. From May 2006 to July 2008, 1336 patients were followed. 444 (33%) of these patients were already on ART at the start of the study. No significant differences were found in lack of adherence (<95% pill count adherence risk ratio [RR] 0.55, 95% confidence interval [CI] 0.23–1.35; <100% adherence RR 1.10, 95% CI 0.94–1.30), cumulative risk of virologic failure (RR 0.81, 95% CI 0.61–1.08) or in shorter-term virologic outcomes (24 week virologic failure RR 0.93, 95% CI 0.65–1.32; 48 week, RR 0.83, 95% CI 0.47–1.48; 72 week, RR 0.81, 95% CI 0.44–1.49). However, virologic failure rates ≥96 weeks into ART were significantly decreased in the intervention arm compared to the control arm (96 week failure RR 0.50, 95% CI 0.31–0.81; 120 week, RR 0.59, 95% CI 0.22–1.60; 144 week, RR 0.39, 95% CI 0.16–0.95; 168 week, RR 0.30, 95% CI 0.097–0.92; 192 week, RR 0.067, 95% CI 0.0065–0.71). Conclusions/Significance A PHW intervention was associated with decreased virologic failure rates occurring 96 weeks and longer into ART, but did not affect cumulative risk of virologic failure, adherence measures, or shorter-term virologic outcomes. PHWs may be an effective intervention to sustain long-term ART in low-resource settings. Trial Registration ClinicalTrials.gov NCT00675389

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.

The human immunodeficiency virus epidemic in India. Current magnitude and future projections.

Since the first case of the human immunodeficiency virus (HIV) infection was documented in India in 1986, there has been an explosive increase in HIV transmission. In this review we describe the chronology of the HIV epidemic in India, preliminary information about the clinical presentation of the acquired immunodeficiency syndrome (AIDS), the biological and behavioral aspects of HIV transmission in the Indian setting, and projections regarding the future of the HIV epidemic in India. Using recent data obtained by searching the computerized literature and published abstracts, conference proceedings, and publications from the government of India, we show that India is experiencing a major epidemic of HIV transmission in high-risk populations of commercial sex workers, sexually transmitted disease clinic patients, intravenous drug users, and commercial blood donors. There is also evidence of recent spread of the epidemic from these high-risk groups to other risk groups in India, and from urban centers to rural populations. It is estimated that 1.6 million people are currently infected with HIV in India. At the present rate of transmission, India will have the largest number of HIV-infected individuals of any country in the world by the end of this decade, with more than 5 million infected individuals. Because limited data are available, comprehensive and well-designed epidemiologic surveys are urgently needed to adequately characterize the HIV epidemic in India and to help implement targeted and effective educational and prevention-oriented programs.

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.

Adherence to Antiretroviral Therapy and Virologic Suppression among HIV-Infected Persons Receiving Care in Private Clinics in Mumbai, India

BACKGROUND Adherence to antiretroviral therapy (ART) and correlates of adherence and virologic suppression among human immunodeficiency virus (HIV)-infected persons receiving ART in private, outpatient clinics in India is unknown. METHODS Between December 2004 and April 2005, persons receiving ART at 3 private clinics in Mumbai, India, were interviewed regarding HIV care and adherence to ART. Physicians also completed a survey for each participant. Quantitative HIV-1 RNA level was determined for 200 participants. RESULTS Of 279 participants, 73% reported > or = 95% adherence to ART. Adherence was positively associated with age > or = 50 years (adjusted odds ratio [aOR], 3.90), presence of comorbid conditions (aOR, 1.92), medication self-efficacy (aOR, 4.01), absence of pain in the past month (aOR, 2.14), and support from family and friends (aOR, 2.57). Lack of reminders from family members to take medication (aOR, 0.27) was negatively associated with adherence. Of 200 participants, 127 (63.5%) had virologic suppression (RNA level, < 400 copies/mL). Independent correlates of suppression were a regimen containing > or = 3 ART drugs (aOR, 5.52), first ART regimen (aOR, 3.28), adherence to therapy > or = 95% (aOR, 5.70), female sex (aOR, 3.19), and a physical component score > or = 50 (aOR, 1.07). CONCLUSION Self-reported adherence to ART in a sample of patients attending Mumbais private clinics was relatively high. However, the fact that a detectable viral level was found in nearly 40% of patients suggests that second-line ART regimens, as well as an emphasis on adherence and appropriate ART regimens in India, is needed.

Postpartum Tuberculosis Incidence and Mortality among HIV-Infected Women and Their Infants in Pune, India, 2002–2005

BACKGROUND In contrast with many other countries, isoniazid preventative therapy is not recommended in clinical care guidelines for human immunodeficiency virus (HIV)-infected persons with latent tuberculosis (TB) in India. METHODS Seven hundred fifteen HIV-infected mothers and their infants were prospectively followed up for 1 year after delivery at a public hospital in Pune, India. Women were evaluated for active TB during regular clinic visits, and tuberculin skin tests were performed. World Health Organization definitions for confirmed, probable, and presumed TB were used. Poisson regression was performed to determine correlates of incident TB, and adjusted probabilities of mortality were calculated. RESULTS Twenty-four of 715 HIV-infected women who were followed up for 480 postpartum person-years developed TB, yielding a TB incidence of 5.0 cases per 100 person-years (95% confidence interval [CI], 3.2-7.4 cases per 100 person-years). Predictors of incident TB included a baseline CD4 cell count <200 cells/mm(3) (adjusted incident rate ratio [IRR], 7.58; 95% CI, 3.07-18.71), an HIV load >50,000 copies/mL (adjusted IRR, 3.92; 95% CI, 1.69-9.11), and a positive tuberculin skin test result (adjusted IRR, 3.08; 95% CI, 1.27-7.47). Three (12.5%) of 24 women with TB died, compared with 7 (1.0%) of 691 women without TB (IRR, 12.2; 95% CI, 2.03-53.33). Among 23 viable infants with mothers with TB, 2 received a diagnosis of TB. Four infants with mothers with TB died, compared with 28 infants with mothers without TB (IRR, 4.71; 95% CI, 1.19-13.57). Women with incident TB and their infants had a 2.2- and 3.4-fold increased probability of death, respectively, compared with women without active TB and their infants, controlling for factors independently associated with mortality (adjusted IRR, 2.2 [95% CI, 0.6-3.8] and 3.4 [95% CI, 1.22-10.59], respectively). CONCLUSIONS Among Indian HIV-infected women, we found a high incidence of postpartum TB and associated postpartum maternal and infant death. Active screening and targeted use of isoniazid preventative therapy among HIV-infected women in India should be considered to prevent postpartum maternal TB and associated mother-to-child morbidity and mortality.

Highly complex neutralization determinants on a monophyletic lineage of newly transmitted subtype C HIV-1 Env clones from India

Little is known about the neutralization properties of HIV-1 in India to optimally design and test vaccines. For this reason, a functional Env clone was obtained from each of ten newly acquired, heterosexually transmitted HIV-1 infections in Pune, Maharashtra. These clones formed a phylogenetically distinct genetic lineage within subtype C. As Env-pseudotyped viruses the clones were mostly resistant to IgG1b12, 2G12 and 2F5 but all were sensitive to 4E10. When compared to a large multi-subtype panel of Env-pseudotyped viruses (subtypes B, C and CRF02_AG) in neutralization assays with a multi-subtype panel of HIV-1-positive plasma samples, the Indian Envs were remarkably complex. With the exception of the Indian Envs, results of a hierarchical clustering analysis showed a strong subtype association with the patterns of neutralization susceptibility. From these patterns we were able to identify 19 neutralization cluster-associated amino acid signatures in gp120 and 14 signatures in the ectodomain and cytoplasmic tail of gp41. We conclude that newly transmitted Indian Envs are antigenically complex in spite of close genetic similarity. Delineation of neutralization-associated amino acid signatures provides a deeper understanding of the antigenic structure of HIV-1 Env.