Elizabeth A. Bukusi

Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women

BACKGROUND Antiretroviral preexposure prophylaxis is a promising approach for preventing human immunodeficiency virus type 1 (HIV-1) infection in heterosexual populations. METHODS We conducted a randomized trial of oral antiretroviral therapy for use as preexposure prophylaxis among HIV-1-serodiscordant heterosexual couples from Kenya and Uganda. The HIV-1-seronegative partner in each couple was randomly assigned to one of three study regimens--once-daily tenofovir (TDF), combination tenofovir-emtricitabine (TDF-FTC), or matching placebo--and followed monthly for up to 36 months. At enrollment, the HIV-1-seropositive partners were not eligible for antiretroviral therapy, according to national guidelines. All couples received standard HIV-1 treatment and prevention services. RESULTS We enrolled 4758 couples, of whom 4747 were followed: 1584 randomly assigned to TDF, 1579 to TDF-FTC, and 1584 to placebo. For 62% of the couples followed, the HIV-1-seronegative partner was male. Among HIV-1-seropositive participants, the median CD4 count was 495 cells per cubic millimeter (interquartile range, 375 to 662). A total of 82 HIV-1 infections occurred in seronegative participants during the study, 17 in the TDF group (incidence, 0.65 per 100 person-years), 13 in the TDF-FTC group (incidence, 0.50 per 100 person-years), and 52 in the placebo group (incidence, 1.99 per 100 person-years), indicating a relative reduction of 67% in the incidence of HIV-1 with TDF (95% confidence interval [CI], 44 to 81; P<0.001) and of 75% with TDF-FTC (95% CI, 55 to 87; P<0.001). Protective effects of TDF-FTC and TDF alone against HIV-1 were not significantly different (P=0.23), and both study medications significantly reduced the HIV-1 incidence among both men and women. The rate of serious adverse events was similar across the study groups. Eight participants receiving active treatment were found to have been infected with HIV-1 at baseline, and among these eight, antiretroviral resistance developed in two during the study. CONCLUSIONS Oral TDF and TDF-FTC both protect against HIV-1 infection in heterosexual men and women. (Funded by the Bill and Melinda Gates Foundation; Partners PrEP ClinicalTrials.gov number, NCT00557245.).

Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2.

BACKGROUND Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1. METHODS We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, > or = 250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses. RESULTS A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P=0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log(10) copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed. CONCLUSIONS Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)

Association between Mycoplasma genitalium and acute endometritis

Up to 70% of cases of pelvic inflammatory disease do not have a known cause. We recruited 115 women who had presented to a clinic for sexually transmitted diseases in Nairobi, Kenya with pelvic pain that had persisted for 14 days or less, to look for an association between Mycoplasma genitalium and endometritis. With PCR, we detected M genitalium in the cervix, endometrium, or both in nine (16%) of 58 women with histologically confirmed endometritis and in one (2%) of 57 women without endometritis (p=0.02). Our results suggest that infection with M genitalium is strongly associated with acute endometritis in this population.

Bacterial vaginosis associated with increased risk of female-to-male HIV-1 transmission: a prospective cohort analysis among African couples

In a prospective study, Craig Cohen and colleagues investigate the association between bacterial vaginosis and the risk of female-to-male HIV-1 transmission.

Regional Differences in Prevalence of HIV-1 Discordance in Africa and Enrollment of HIV-1 Discordant Couples into an HIV-1 Prevention Trial

Background Most HIV-1 transmission in Africa occurs among HIV-1-discordant couples (one partner HIV-1 infected and one uninfected) who are unaware of their discordant HIV-1 serostatus. Given the high HIV-1 incidence among HIV-1 discordant couples and to assess efficacy of interventions for reducing HIV-1 transmission, HIV-1 discordant couples represent a critical target population for HIV-1 prevention interventions and prevention trials. Substantial regional differences exist in HIV-1 prevalence in Africa, but regional differences in HIV-1 discordance among African couples, has not previously been reported. Methodology/Principal Findings The Partners in Prevention HSV-2/HIV-1 Transmission Trial (“Partners HSV-2 Study”), the first large HIV-1 prevention trial in Africa involving HIV-1 discordant couples, completed enrollment in May 2007. Partners HSV-2 Study recruitment data from 12 sites from East and Southern Africa were used to assess HIV-1 discordance among couples accessing couples HIV-1 counseling and testing, and to correlate with enrollment of HIV-1 discordant couples. HIV-1 discordance at Partners HSV-2 Study sites ranged from 8–31% of couples tested from the community. Across all study sites and, among all couples with one HIV-1 infected partner, almost half (49%) of couples were HIV-1 discordant. Site-specific monthly enrollment of HIV-1 discordant couples into the clinical trial was not directly associated with prevalence of HIV-1 discordance, but was modestly correlated with national HIV-1 counseling and testing rates and access to palliative care/basic health care (r = 0.74, p = 0.09). Conclusions/Significance HIV-1 discordant couples are a critical target for HIV-1 prevention in Africa. In addition to community prevalence of HIV-1 discordance, national infrastructure for HIV-1 testing and healthcare delivery and effective community outreach strategies impact recruitment of HIV-1 discordant couples into HIV-1 prevention trials.

Increased Interleukin-10 in the Endocervical Secretions of Women With Non-Ulcerative Sexually Transmitted Diseases: A Mechanism for Enhanced HIV-1 Transmission?

OBJECTIVE Although non-ulcerative sexually transmitted diseases (STD) and bacterial vaginosis are implicated as cofactors in heterosexual HIV-1 transmission, the mechanisms have not been defined. Recent in vitro data suggest that interleukin (IL)-10 may increase susceptibility of macrophages to HIV-1 infection. Therefore, we performed this study to assess whether non-ulcerative STD are associated with detection of IL-10 in the female genital tract. METHODS Women with clinical pelvic inflammatory disease with or without cervicovaginal discharge were recruited from an STD clinic in Nairobi, Kenya. Endocervical and endometrial specimens were obtained for Neisseria gonorrhoeae and Chlamydia trachomatis DNA detection, Trichonomas vaginalis culture, and CD4 and CD8 T-cell enumeration. Bacterial vaginosis was diagnosed by Gram stain. IL-10 was detected in endocervical specimens using enzyme-linked immunosorbent assay. Blood was obtained for HIV-1 serology. RESULTS One hundred and seventy-two women were studied. N. gonorrhoeae, C. trachomatis, bacterial vaginosis, and T. vaginalis were detected in 38 (21%), 17 (9%), 71 (43%), and 22 (12%) women, respectively. Cervical IL-10 was detected more often in women with N. gonorrhoeae [adjusted odds ratio (AOR), 3.4; 95% confidence interval (CI), 1.4-8.4], C. trachomatis (AOR, 4.4; 95% CI, 1.2-15.6), and bacterial vaginosis (AOR, 3.1; 95% CI, 1.4-6.9) than in women without these infections. CONCLUSIONS The association of non-ulcerative STD and bacterial vaginosis with increased frequency of IL-10 detection in endocervical secretions suggests a potential mechanism through which these infections may alter susceptibility to HIV-1 infection in women.

HIV/AIDS AND MATERNITY CARE IN KENYA: HOW FEARS OF STIGMA AND DISCRIMINATION AFFECT UPTAKE AND PROVISION OF LABOR AND DELIVERY SERVICES

Abstract Although policies and programs exist to promote safe motherhood in sub-Saharan Africa, maternal health has not improved and may be deteriorating in some countries. Part of the explanation may be the adverse effects of HIV/AIDS on maternity care. We conducted a study in Kisumu, Kenya to explore how fears related to HIV/AIDS affect womens uptake and health workers’ provision of labor and delivery services. In-depth qualitative interviews with 17 maternity workers, 14 pregnant or postpartum women, four male partners and two traditional birth attendants; as well as structured observations of 22 births; were conducted at four health facilities. Participants reported that fears of HIV testing; fears of involuntary disclosure of HIV status to others, including spouses; and HIV/AIDS stigma are among the reasons that women avoid delivering in health facilities. Maternity workers now have to take into account the HIV status of the women they serve (as well as their own fears of becoming infected and stigmatized) but do not seem to be adequately prepared to handle issues related to consent, confidentiality and disclosure. Importantly, it appeared that women of unknown HIV status during labor and delivery were likely to be targets of stigma and discriminatory practices and that these women were not receiving needed counseling services. The findings suggest that increasing infection control precautions will not be enough to address the challenges faced by maternity care providers in caring for women in high-HIV-prevalence settings. Maternity workers need enhanced culturally sensitive training regarding consent, confidentiality and disclosure. Furthermore, this study points to the necessity of paying more attention to the care of women of unknown HIV-serostatus during labor and delivery. Such interventions may improve the quality of maternity care, increase utilization and contribute to overall improvements in maternal health, while also enhancing prevention of mother-to-child-transmission and HIV care.

Infectious correlates of HIV-1 shedding in the female upper and lower genital tracts.

Objectives: To determine the effects of vaginal, cervical, and endometrial infections on shedding of HIV-1 RNA in the female genital tract. Design: Cross-sectional. Methods: Antiretroviral-naive women from Nairobi, Kenya with CD4 cell counts ≥ 350 cells/μl had plasma and endocervical wick samples collected for HIV quantification by real-time RNA reverse transcriptase-polymerase chain reaction. Vaginal and cervical Gram stains and endometrial biopsies were obtained. Vaginal Gram stain was used to diagnose bacterial vaginosis and to quantify Lactobacillus levels. Results: Twenty-six of 50 (52%) women had detectable endocervical HIV-1 RNA with a median endocervical viral load of 1760 copies/ml (range: undetectable to 1 030 000 copies/ml). Women with decreased Lactobacillus had 15.8-fold [95% confidenceinterval (CI), 2.0–123] greater endocervical HIV-1 RNA than women with normal Lactobacillus levels. Women with plasma cell (PC) endometritis [≥ 1 PC/high-power field (hpf)] had a 15.8-fold (95% CI, 2.0–120) higher endocervical HIV RNA level than women without PC endometritis. Both these associations remained after controlling for plasma viral load. Cervicitis (≥ 30 polymorphonuclear leukocytes/hpf), however, was not associated with endocervical HIV-1 RNA shedding (P = 0.81). Conclusions: In HIV-1-infected, antiretroviral-naive women without symptoms of pelvic inflammatory disease infection, abnormal vaginal flora and inflammatory cells in the endometrium affected HIV-1 shedding from the lower genital tract. These data suggest that both the upper and lower genital tracts contribute to female HIV-1 genital shedding.

Characteristics of HIV-1 Discordant Couples Enrolled in a Trial of HSV-2 Suppression to Reduce HIV-1 Transmission: The Partners Study

Background The Partners HSV-2/HIV-1 Transmission Study (Partners Study) is a phase III, placebo-controlled trial of daily acyclovir for genital herpes (HSV-2) suppression among HIV-1/HSV-2 co-infected persons to reduce HIV-1 transmission to their HIV-1 susceptible partners, which requires recruitment of HIV-1 serodiscordant heterosexual couples. We describe the baseline characteristics of this cohort. Methods HIV-1 serodiscordant heterosexual couples, in which the HIV-1 infected partner was HSV-2 seropositive, had a CD4 count ≥250 cells/mcL and was not on antiretroviral therapy, were enrolled at 14 sites in East and Southern Africa. Demographic, behavioral, clinical and laboratory characteristics were assessed. Results Of the 3408 HIV-1 serodiscordant couples enrolled, 67% of the HIV-1 infected partners were women. Couples had cohabitated for a median of 5 years (range 2–9) with 28% reporting unprotected sex in the month prior to enrollment. Among HIV-1 susceptible participants, 86% of women and 59% of men were HSV-2 seropositive. Other laboratory-diagnosed sexually transmitted infections were uncommon (<5%), except for Trichomonas vaginalis in 14% of HIV-1 infected women. Median baseline CD4 count for HIV-1 infected participants was 462cells/mcL and median HIV-1 plasma RNA was 4.2 log10 copies/mL. After adjusting for age and African region, correlates of HIV-1 RNA level included male gender (+0.24 log10 copies/mL; p<0.001) and CD4 count (−0.25 and −0.55 log10 copies/mL for CD4 350–499 and >500 relative to <350, respectively, p<0.001). Conclusions The Partners Study successfully enrolled a cohort of 3408 heterosexual HIV-1 serodiscordant couples in Africa at high risk for HIV-1 transmission. Follow-up of this cohort will evaluate the efficacy of acyclovir for HSV-2 suppression in preventing HIV-1 transmission and provide insights into biological and behavioral factors determining heterosexual HIV-1 transmission. Trial Registration ClinicalTrials.gov NCT00194519

Characteristics of HIV-1 Serodiscordant Couples Enrolled in a Clinical Trial of Antiretroviral Pre-Exposure Prophylaxis for HIV-1 Prevention

Introduction Stable heterosexual HIV-1 serodiscordant couples in Africa have high HIV-1 transmission rates and are a critical population for evaluation of new HIV-1 prevention strategies. The Partners PrEP Study is a randomized, double-blind, placebo-controlled trial of tenofovir and emtricitabine-tenofovir pre-exposure prophylaxis to decrease HIV-1 acquisition within heterosexual HIV-1 serodiscordant couples. We describe the trial design and characteristics of the study cohort. Methods HIV-1 serodiscordant couples, in which the HIV-1 infected partner did not meet national guidelines for initiation of antiretroviral therapy, were enrolled at 9 research sites in Kenya and Uganda. The HIV-1 susceptible partner was randomized to daily oral tenofovir, emtricitabine-tenofovir, or matching placebo with monthly follow-up for 24–36 months. Results From July 2008 to November 2010, 7920 HIV-1 serodiscordant couples were screened and 4758 enrolled. For 62% (2966/4758) of enrolled couples, the HIV-1 susceptible partner was male. Median age was 33 years for HIV-1 susceptible and HIV-1 infected partners [IQR (28–40) and (26–39) respectively]. Most couples (98%) were married, with a median duration of partnership of 7.0 years (IQR 3.0–14.0) and recent knowledge of their serodiscordant status [median 0.4 years (IQR 0.1–2.0)]. During the month prior to enrollment, couples reported a median of 4 sex acts (IQR 2–8); 27% reported unprotected sex and 14% of male and 1% of female HIV-1 susceptible partners reported sex with outside partners. Among HIV-1 infected partners, the median plasma HIV-1 level was 3.94 log10 copies/mL (IQR 3.31–4.53) and median CD4 count was 496 cells/µL (IQR 375–662); the majority (64%) had WHO stage 1 HIV-1 disease. Conclusions Couples at high risk of HIV-1 transmission were rapidly recruited into the Partners PrEP Study, the largest efficacy trial of oral PrEP. (ClinicalTrials.gov NCT00557245)