Maria J. Wawer

VIRAL LOAD AND HETEROSEXUAL TRANSMISSION OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 1

BACKGROUND AND METHODS We examined the influence of viral load in relation to other risk factors for the heterosexual transmission of human immunodeficiency virus type 1 (HIV-1). In a community-based study of 15,127 persons in a rural district of Uganda, we identified 415 couples in which one partner was HIV-1-positive and one was initially HIV-1-negative and followed them prospectively for up to 30 months. The incidence of HIV-1 infection per 100 person-years among the initially seronegative partners was examined in relation to behavioral and biologic variables. RESULTS The male partner was HIV-1-positive in 228 couples, and the female partner was HIV-1-positive in 187 couples. Ninety of the 415 initially HIV-1-negative partners seroconverted (incidence, 11.8 per 100 person-years). The rate of male-to-female transmission was not significantly different from the rate of female-to-male transmission (12.0 per 100 person-years vs. 11.6 per 100 person-years). The incidence of seroconversion was highest among the partners who were 15 to 19 years of age (15.3 per 100 person-years). The incidence was 16.7 per 100 person-years among 137 uncircumcised male partners, whereas there were no seroconversions among the 50 circumcised male partners (P<0.001). The mean serum HIV-1 RNA level was significantly higher among HIV-1-positive subjects whose partners seroconverted than among those whose partners did not seroconvert (90,254 copies per milliliter vs. 38,029 copies per milliliter, P=0.01). There were no instances of transmission among the 51 subjects with serum HIV-1 RNA levels of less than 1500 copies per milliliter; there was a significant dose-response relation of increased transmission with increasing viral load. In multivariate analyses of log-transformed HIV-1 RNA levels, each log increment in the viral load was associated with a rate ratio of 2.45 for seroconversion (95 percent confidence interval, 1.85 to 3.26). CONCLUSIONS The viral load is the chief predictor of the risk of heterosexual transmission of HIV-1, and transmission is rare among persons with levels of less than 1500 copies of HIV-1 RNA per milliliter.

Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial

BACKGROUND Ecological and observational studies suggest that male circumcision reduces the risk of HIV acquisition in men. Our aim was to investigate the effect of male circumcision on HIV incidence in men. METHODS 4996 uncircumcised, HIV-negative men aged 15-49 years who agreed to HIV testing and counselling were enrolled in this randomised trial in rural Rakai district, Uganda. Men were randomly assigned to receive immediate circumcision (n=2474) or circumcision delayed for 24 months (2522). HIV testing, physical examination, and interviews were repeated at 6, 12, and 24 month follow-up visits. The primary outcome was HIV incidence. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, with the number NCT00425984. FINDINGS Baseline characteristics of the men in the intervention and control groups were much the same at enrollment. Retention rates were much the same in the two groups, with 90-92% of participants retained at all time points. In the modified intention-to-treat analysis, HIV incidence over 24 months was 0.66 cases per 100 person-years in the intervention group and 1.33 cases per 100 person-years in the control group (estimated efficacy of intervention 51%, 95% CI 16-72; p=0.006). The as-treated efficacy was 55% (95% CI 22-75; p=0.002); efficacy from the Kaplan-Meier time-to-HIV-detection as-treated analysis was 60% (30-77; p=0.003). HIV incidence was lower in the intervention group than it was in the control group in all sociodemographic, behavioural, and sexually transmitted disease symptom subgroups. Moderate or severe adverse events occurred in 84 (3.6%) circumcisions; all resolved with treatment. Behaviours were much the same in both groups during follow-up. INTERPRETATION Male circumcision reduced HIV incidence in men without behavioural disinhibition. Circumcision can be recommended for HIV prevention in men.

Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda

BACKGROUND The probability of HIV-1 transmission per coital act in representative African populations is unknown. We aimed to calculate this probability overall, and to estimate how it is affected by various factors thought to influence infectivity. METHODS 174 monogamous couples, in which one partner was HIV-1 positive, were retrospectively identified from a population cohort in Rakai, Uganda. Frequency of intercourse and reliability of reporting within couples was assessed prospectively. HIV-1 seroconversion was determined in the uninfected partners, and HIV-1 viral load was measured in the infected partners. Adjusted rate ratios of transmission per coital act were estimated by Poisson regression. Probabilities of transmission per act were estimated by log-log binomial regression for quartiles of age and HIV-1 viral load, and for symptoms or diagnoses of sexually transmitted diseases (STDs) in the HIV-1-infected partners. RESULTS The mean frequency of intercourse was 8.9 per month, which declined with age and HIV-1 viral load. Members of couples reported similar frequencies of intercourse. The overall unadjusted probability of HIV-1 transmission per coital act was 0.0011 (95% CI 0.0008-0.0015). Transmission probabilities increased from 0.0001 per act at viral loads of less than 1700 copies/mL to 0.0023 per act at 38 500 copies/mL or more (p=0.002), and were 0.0041 with genital ulceration versus 0.0011 without (p=0.02). Transmission probabilities per act did not differ significantly by HIV-1 subtypes A and D, sex, STDs, or symptoms of discharge or dysuria in the HIV-1-positive partner. INTERPRETATION Higher viral load and genital ulceration are the main determinants of HIV-1 transmission per coital act in this Ugandan population.

Rates of HIV-1 Transmission per Coital Act, by Stage of HIV-1 Infection, in Rakai, Uganda

BACKGROUND We estimated rates of human immunodeficiency virus (HIV)-1 transmission per coital act in HIV-discordant couples by stage of infection in the index partner. METHODS We retrospectively identified 235 monogamous, HIV-discordant couples in a Ugandan population-based cohort. HIV transmission within pairs was confirmed by sequence analysis. Rates of transmission per coital act were estimated by the index partners stage of infection (recent seroconversion or prevalent or late-stage infection). The adjusted rate ratio of transmission per coital act was estimated by multivariate Poisson regression. RESULTS The average rate of HIV transmission was 0.0082/coital act (95% confidence interval [CI], 0.0039-0.0150) within approximately 2.5 months after seroconversion of the index partner; 0.0015/coital act within 6-15 months after seroconversion of the index partner (95% CI, 0.0002-0.0055); 0.0007/coital act (95% CI, 0.0005-0.0010) among HIV-prevalent index partners; and 0.0028/coital act (95% CI, 0.0015-0.0041) 6-25 months before the death of the index partner. In adjusted models, early- and late-stage infection, higher HIV load, genital ulcer disease, and younger age of the index partner were significantly associated with higher rates of transmission. CONCLUSIONS The rate of HIV transmission per coital act was highest during early-stage infection. This has implications for HIV prevention and for projecting the effects of antiretroviral treatment on HIV transmission.

Control of sexually transmitted diseases for AIDS prevention in Uganda: a randomised community trial

BACKGROUND The study tested the hypothesis that community-level control of sexually transmitted disease (STD) would result in lower incidence of HIV-1 infection in comparison with control communities. METHODS This randomised, controlled, single-masked, community-based trial of intensive STD control, via home-based mass antibiotic treatment, took place in Rakai District, Uganda. Ten community clusters were randomly assigned to intervention or control groups. All consenting residents aged 15-59 years were enrolled; visited in the home every 10 months; interviewed; asked to provide biological samples for assessment of HIV-1 infection and STDs; and were provided with mass treatment (azithromycin, ciprofloxacin, metronidazole in the intervention group, vitamins/anthelmintic drug in the control). Intention-to-treat analyses used multivariate, paired, cluster-adjusted rate ratios. FINDINGS The baseline prevalence of HIV-1 infection was 15.9%. 6602 HIV-1-negative individuals were enrolled in the intervention group and 6124 in the control group. 75.0% of intervention-group and 72.6% of control-group participants provided at least one follow-up sample for HIV-1 testing. At enrolment, the two treatment groups were similar in STD prevalence rates. At 20-month follow-up, the prevalences of syphilis (352/6238 [5.6%]) vs 359/5284 [6.8%]; rate ratio 0.80 [95% CI 0.71-0.89]) and trichomoniasis (182/1968 [9.3%] vs 261/1815 [14.4%]; rate ratio 0.59 [0.38-0.91]) were significantly lower in the intervention group than in the control group. The incidence of HIV-1 infection was 1.5 per 100 person-years in both groups (rate ratio 0.97 [0.81-1.16]). In pregnant women, the follow-up prevalences of trichomoniasis, bacterial vaginosis, gonorrhoea, and chlamydia infection were significantly lower in the intervention group than in the control group. No effect of the intervention on incidence of HIV-1 infection was observed in pregnant women or in stratified analyses. INTERPRETATION We observed no effect of the STD intervention on the incidence of HIV-1 infection. In the Rakai population, a substantial proportion of HIV-1 acquisition appears to occur independently of treatable STD cofactors.

HIV-1 infection associated with abnormal vaginal flora morphology and bacterial vaginosis

Summary Background In-vitro research has suggested that bacterial vaginosis may increase the survival of HIV-1 in the genital tract. Therefore, we investigated the association of HIV-1 infection with vaginal flora abnormalities, including bacterial vaginosis and depletion of lactobacilli, after adjustment for sexual activity and the presence of other sexually transmitted diseases (STDs). Methods During the initial survey round of our community-based trial of STD control for HIV-1 prevention in rural Rakai District, southwestern Uganda, we selected 4718 women aged 15–59 years. They provided interview information, blood for HIV-1 and syphilis serology, urine for detection of Chlamydia trachomatis and Neisseria gonorrhoeae , and two self-administered vaginal swabs for culture of Trichomonas vaginalis and gram-stain detection of vaginal flora, classified by standardised, quantitative, morphological scoring. Scores 0–3 were normal vaginal flora (predominant lactobacilli). Higher scores suggested replacement of lactobacilli by gram-negative, anaerobic microorganisms (4–6 intermediate; 7–8 and 9–10 moderate and severe bacterial vaginosis). Findings HIV-1 frequency was 14·2% among women with normal vaginal flora and 26·7% among those with severe bacterial vaginosis (p Interpretation This cross-sectional study cannot show whether disturbed vaginal flora increases susceptibility to HIV-1 infection. Nevertheless, the increased frequency of HIV-1 associated with abnormal flora among younger women, for whom HIV-1 acquisition is likely to be recent, but not among older women, in whom HIV-1 is likely to have been acquired earlier, suggests that loss of lactobacilli or presence of bacterial vaginosis may increase susceptibility to HIV-1 acquisition. If this inference is correct, control of bacterial vaginosis could reduce HIV-1 transmission.

Male circumcision for the prevention of HSV-2 and HPV infections and syphilis.

BACKGROUND Male circumcision significantly reduced the incidence of human immunodeficiency virus (HIV) infection among men in three clinical trials. We assessed the efficacy of male circumcision for the prevention of herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) infections and syphilis in HIV-negative adolescent boys and men. METHODS We enrolled 5534 HIV-negative, uncircumcised male subjects between the ages of 15 and 49 years in two trials of male circumcision for the prevention of HIV and other sexually transmitted infections. Of these subjects, 3393 (61.3%) were HSV-2-seronegative at enrollment. Of the seronegative subjects, 1684 had been randomly assigned to undergo immediate circumcision (intervention group) and 1709 to undergo circumcision after 24 months (control group). At baseline and at 6, 12, and 24 months, we tested subjects for HSV-2 and HIV infection and syphilis, along with performing physical examinations and conducting interviews. In addition, we evaluated a subgroup of subjects for HPV infection at baseline and at 24 months. RESULTS At 24 months, the cumulative probability of HSV-2 seroconversion was 7.8% in the intervention group and 10.3% in the control group (adjusted hazard ratio in the intervention group, 0.72; 95% confidence interval [CI], 0.56 to 0.92; P=0.008). The prevalence of high-risk HPV genotypes was 18.0% in the intervention group and 27.9% in the control group (adjusted risk ratio, 0.65; 95% CI, 0.46 to 0.90; P=0.009). However, no significant difference between the two study groups was observed in the incidence of syphilis (adjusted hazard ratio, 1.10; 95% CI, 0.75 to 1.65; P=0.44). CONCLUSIONS In addition to decreasing the incidence of HIV infection, male circumcision significantly reduced the incidence of HSV-2 infection and the prevalence of HPV infection, findings that underscore the potential public health benefits of the procedure. (ClinicalTrials.gov numbers, NCT00425984 and NCT00124878.)

Increased risk of incident HIV during pregnancy in Rakai, Uganda: a prospective study

BACKGROUND HIV acquisition is significantly higher during pregnancy than in the postpartum period. We did a prospective study to estimate HIV incidence rates during pregnancy and lactation. METHODS We assessed 2188 HIV-negative sexually active women with 2625 exposure intervals during pregnancy and 2887 intervals during breastfeeding, and 8473 non-pregnant and non-lactating women with 24,258 exposure intervals. Outcomes were HIV incidence rates per 100 person years and incidence rate ratios estimated by Poisson multivariate regression, with the non-pregnant or non-lactating women as the reference group. We also assessed the husbands of the married women to study male risk behaviours. FINDINGS HIV incidence rates were 2.3 per 100 person years during pregnancy, 1.3 per 100 person years during breastfeeding, and 1.1 per 100 person years in the non-pregnant and non-lactating women. The adjusted incidence rate ratios were 2.16 (95% CI 1.39-3.37) during pregnancy and 1.16 (0.82-1.63) during breastfeeding. Pregnant women and their male partners reported significantly fewer external sexual partners than did the other groups. In married pregnant women who had a sexual relationship with their male spouses, the HIV incidence rate ratio was 1.36 (0.63-2.93). In married pregnant women in HIV-discordant relationships (ie, with HIV-positive men) the incidence rate ratio was 1.76 (0.62-4.03). INTERPRETATION The risk of HIV acquisition rises during pregnancy. This change is unlikely to be due to sexual risk behaviours, but might be attributable to hormonal changes affecting the genital tract mucosa or immune responses. HIV prevention efforts are needed during pregnancy to protect mothers and their infants.

Domestic violence in rural Uganda: evidence from a community-based study

Although domestic violence is an increasing public health concern in developing countries, evidence from representative, community-based studies is limited. In a survey of 5109 women of reproductive age in the Rakai District of Uganda, 30% of women had experienced physical threats or physical abuse from their current partner--20% during the year before the survey. Three of five women who reported recent physical threats or abuse reported three or more specific acts of violence during the preceding year, and just under a half reported injuries as a result. Analysis of risk factors highlights the pivotal roles of the male partners alcohol consumption and his perceived human immunodeficiency virus (HIV) risk in increasing the risk of male against female domestic violence. Most respondents--70% of men and 90% of women--viewed beating of the wife or female partner as justifiable in some circumstances, posing a central challenge to preventing violence in such settings.

Population-based study of fertility in women with HIV-1 infection in Uganda

BACKGROUND To assess the effects of HIV-1 and other sexually transmitted infections on pregnancy, we undertook cross-sectional and prospective studies of a rural population in Rakai district, Uganda. METHODS 4813 sexually active women aged 15-49 years were surveyed to find out the prevalence of pregnancy by interview and selective urinary human chorionic gonadotropin tests. The incidence of recognised conception and frequency of pregnancy loss were assessed by follow-up. Samples were taken to test for HIV-1 infection, syphilis, and other sexually transmitted diseases. FINDINGS At time of survey 757 (21.4%) of 3544 women without HIV-1 infection or syphilis were pregnant, compared with 46 (14.6%) of 316 HIV-1-negative women with active syphilis, 117 (14.2%) of 823 HIV-1-positive women with no concurrent syphilis, and 11 (8.5%) of 130 women with both syphilis and HIV-1 infection. The multivariate adjusted odds ratio of pregnancy in HIV-1-infected women was 0.45 (95% CI 0.35-0.57); the odds of pregnancy were low both in HIV-1-infected women without symptoms (0.49 [0.39-0.62]) and in women with symptoms of HIV-1-associated disease (0.23 [0.11-0.48]). In women with concurrent HIV-1 infection and syphilis the odds ratio was 0.28 (0.14-0.55). The incidence rate of recognised pregnancy during the prospective follow-up study was lower in HIV-1-positive than in HIV-1-negative women (23.5 vs 30.1 per 100 woman-years; adjusted risk ratio 0.73 [0.57-0.93]). Rates of pregnancy loss were higher among HIV-1-infected than uninfected women (18.5 vs 12.2%; odds ratio 1.50 [1.01-2.27]). The prevalence of HIV-1 infection was significantly lower in pregnant than in non-pregnant women (13.9 vs 21.3%). INTERPRETATION Pregnancy prevalence is greatly reduced in HIV-1-infected women, owing to lower rates of conception and increased rates of pregnancy loss. HIV-1 surveillance confined to pregnant women underestimates the magnitude of the HIV-1 epidemic in the general population.