Tom Lutalo

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.

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.

Male circumcision and HIV acquisition and transmission: cohort studies in Rakai Uganda.

BACKGROUND Male circumcision is associated with reduced HIV acquisition. METHODS HIV acquisition was determined in a cohort of 5507 HIV-negative Ugandan men, and in 187 HIV-negative men in discordant relationships. Transmission was determined in 223 HIV-positive men with HIV-negative partners. HIV incidence per 100 person years (py) and adjusted rate ratios (RR) and 95% confidence intervals (CI) were estimated by Poisson regression. HIV-1 serum viral load was determined for the seropositive partners in HIV-discordant couples. RESULTS The prevalence of circumcision was 16.5% for all men; 99.1% in Muslims and 3.7% in non-Muslims. Circumcision was significantly associated with reduced HIV acquisition in the cohort as a whole (RR 0.53, CI 0.33-0.87), but not among non-Muslim men. Prepubertal circumcision significantly reduced HIV acquisition (RR 0.49, CI 0.26-0.82), but postpubertal circumcision did not. In discordant couples with HIV-negative men, no serconversions occurred in 50 circumcised men, whereas HIV acquisition was 16.7 per 100 py in uncircumcised men (P = 0.004). In couples with HIV-positive men, HIV transmission was significantly reduced in circumcised men with HIV viral loads less than 50000 copies/ml (P = 0.02). INTERPRETATION Prepubertal circumcision may reduce male HIV acquisition in a general population, but the protective effects are confounded by cultural and behavioral factors in Muslims. In discordant couples, circumcision reduces HIV acquisition and transmission. The assessment of circumcision for HIV prevention is complex and requires randomized trials.

HIV incidence and sexually transmitted disease prevalence associated with condom use: a population study in Rakai Uganda.

ObjectiveEvidence of condom effectiveness for HIV and sexually transmitted disease (STD) prevention is based primarily on high-risk populations. We examined condom effectiveness in a general population with high HIV prevalence in rural Africa. MethodsData were from a randomized community trial in Rakai, Uganda. Condom usage information was obtained prospectively from 17 264 sexually active individuals aged 15–59 years over a period of 30 months. HIV incidence and STD prevalence was determined for consistent and irregular condom users, compared to non-users. Adjusted rate ratios (RR) of HIV acquisition were estimated by Poisson multivariate regression, and odds ratios of STDs estimated by logistic regression. ResultsOnly 4.4% reported consistent condom use and 16.5% reported inconsistent use during the prior year. Condom use was higher among males, and younger, unmarried and better educated individuals, and those reporting multiple sex partners or extramarital relationships. Consistent condom use significantly reduced HIV incidence [RR, 0.37; 95% confidence interval (CI), 0.15–0.88], syphilis [odds ratio (OR), 0.71; 95% CI, 0.53–0.94] and gonorrhea/Chlamydia (OR, 0.50; 95% CI, 0.25–0.97) after adjustment for socio-demographic and behavioral characteristics. Irregular condom use was not protective against HIV or STD and was associated with increased gonorrhea/Chlamydia risk (OR, 1.44; 95% CI, 1.06–1.99). The population attributable fraction of consistent use for prevention of HIV was −4.5% (95% CI, −8.3 to 0.0), due to the low prevalence of consistent use in the population. ConclusionsConsistent condom use provides protection from HIV and STDs, whereas inconsistent use is not protective. Programs must emphasize consistent condom use for HIV and STD prevention.

Age differences in sexual partners and risk of HIV-1 infection in rural Uganda.

Objectives: To assess whether differences in age between sexual partners affect the risk of HIV infection in female adolescents and young adults. Methods: A total of 6177 ever sexually active women aged 15 to 29 years completed a sociodemographic and sexual behavior questionnaire and provided a blood sample for HIV‐1 serology. The age difference between partners was categorized as men 0 to 4 years older (referent group), 5 to 9 years older and 10 or more years older. HIV prevalence and incidence were assessed, and adjusted RR was estimated by multivariate regression. Results: Prevalent HIV‐1 infection in female participants increased with older male sexual partners. Among women aged 15 to 19 years, the adjusted risk of HIV infection doubled (RR = 2.04; 95% CI: 1.29‐3.22) among those reporting male partners 10 or more years older compared with those with male partners 0 to 4 years older; among women 20 to 24 years of age, the RR was 1.24 (95% CI: 0.96‐1.60). The attributable fraction (exposed) of prevalent HIV infection in women aged 15 to 24 years associated with partners 10 or more years older was 9.7% (95% CI: 5.2‐14.0). HIV incidence did not increase with differences in age of partners. Conclusion: The age difference between young women and their male partners is a significant HIV risk factor, suggesting that high HIV prevalence in younger women is caused, in part, by transmission from older male partners.

The effects of male circumcision on female partners' genital tract symptoms and vaginal infections in a randomized trial in Rakai, Uganda.

OBJECTIVE The objective of the study was to assess effects of male circumcision on female genital symptoms and vaginal infections. STUDY DESIGN Human immunodeficiency virus (HIV)-negative men enrolled in a trial were randomized to immediate or delayed circumcision (control arm). Genital symptoms, bacterial vaginosis (BV), and trichomonas were assessed in HIV-negative wives of married participants. Adjusted prevalence risk ratios (adjPRR) and 95% confidence intervals (CIs) were assessed by multivariable log-binomial regression, intent-to-treat analyses. RESULTS A total of 783 wives of control and 825 wives of intervention arm men were comparable at enrollment. BV at enrollment was higher in control (38.3%) than intervention arm spouses (30.5%, P = .001). At 1 year follow-up, intervention arm wives reported lower rates of genital ulceration (adjPRR, 0.78; 95% CI, 0.63-0.97), but there were no differences in vaginal discharge or dysuria. The risk of trichomonas was reduced in intervention arm wives (adjPRR, 0.52; 95% CI, 0.05-0.98), as were the risks of any BV (adjPRR, 0.60; 95% CI, 0.38-0.94) and severe BV (prevalence risk ratios, 0.39; 95% CI, 0.24-0.64). CONCLUSION Male circumcision reduces the risk of ulceration, trichomonas, and BV in female partners.

Human Immunodeficiency Virus Acquisition Associated with Genital Ulcer Disease and Herpes Simplex Virus Type 2 Infection: A Nested Case-Control Study in Rakai, Uganda

To assess the timing of symptomatic genital ulcer disease (GUD) relative to human immunodeficiency virus (HIV) seroconversion, we studied 248 case subjects who underwent HIV seroconversion and 496 HIV-negative control subjects, at 3 interview visits conducted at 10-month intervals: visit 1, before HIV acquisition; visit 2, after seroconversion; and visit 3, 10 months after detection of seroconversion. Odds ratios (ORs) and 95% confidence intervals (CIs), for HIV acquisition, were estimated by logistic regression. HIV load was measured by RNA-polymerase chain reaction, and herpes simplex virus type 2 (HSV-2) serologic testing used HerpeSelect EIA with Western blot confirmation. The OR of HSV-2 seropositivity associated with HIV acquisition was 1.7 (95% CI, 1.2-2.4). Prevalence of GUD was increased among case subjects, at visits 2 (OR, 3.2; 95% CI, 1.9-5.3) and 3 (OR, 2.1; 95% CI, 1.1-3.9). HIV load was increased in HSV-2-seropositive case subjects, compared with that in HSV-2-seronegative subjects, at 5 (P=.04) and 15 (P=.02) months after seroconversion. HIV acquisition is associated with HSV-2 seropositivity, and GUD is increased after seroconversion. HIV load is increased in HSV-2-positive subjects who seroconverted, suggesting a role for treatment of HSV-2 infection in HSV-2-seropositive, dually infected individuals.

Mortality in HIV-infected and uninfected children of HIV-infected and uninfected mothers in rural Uganda

Objective: To estimate 2-year mortality rates in HIV-1-infected and uninfected infants born to HIV+ and HIV− mothers. Methods: Data are from a prospective study in rural Rakai District, Uganda. Infant HIV status (determined by polymerase chain reaction) was evaluated at 1 to 6 weeks postpartum and during breast-feeding, and maternal HIV viral load and CD4 levels were measured at the postpartum visit. Multivariate Cox proportional hazards models and Kaplan-Meier survival analysis were used to assess survival of infants by maternal and infant HIV status and by quartiles of viral load. Log-rank tests were used to test the equality of survival functions. Results: Of the 4604 pregnant women, 16.9% were HIV+, and the proportion of children infected was 20.9%. Median survival of HIV-infected infants was 23 months. Two-year child mortality rates were 128 of 1000 children born to HIV− mothers, 165.5 of 1000 uninfected children born to HIV+ mothers, and 540.1 of 1000 HIV-infected children (P < 0.0001). Compared with children of HIV− mothers, the hazard of child mortality was 2.04 (P < 0.001) if the mother was HIV+and 3.78 (P < 0.001) if the infant was also infected. In the adjusted model, the highest quartiles of log10 HIV viral load in infants and mothers were associated with significantly increased hazard of child mortality (hazard ratio [HR] = 8.54 and HR = 2.50, respectively). Maternal CD4 counts <200 cells/mL were also significant predictors of child mortality (HR = 2.61). A total of 67.6% of HIV-infected children with viral loads above the median died by the age of 2 years and are in need of early antiretroviral therapy (ART). Conclusions: More than half of HIV-infected infants died at less than 2 years of age. Therefore, ART may need to be initiated earlier in HIV-infected African children.

Time from HIV seroconversion to death: a collaborative analysis of eight studies in six low and middle-income countries before highly active antiretroviral therapy.

Objectives:To estimate survival patterns after HIV infection in adults in low and middle-income countries. Design:An analysis of pooled data from eight different studies in six countries. Methods:HIV seroconverters were included from eight studies (three population-based, two occupational, and three clinic cohorts) if they were at least 15 years of age, and had no more than 4 years between the last HIV-negative and subsequent HIV-positive test. Four strata were defined: East African cohorts; South African miners cohort; Thai cohorts; Haitian clinic cohort. Kaplan–Meier functions were used to estimate survival patterns, and Weibull distributions were used to model and extend survival estimates. Analyses examined the effect of site, age, and sex on survival. Results:From 3823 eligible seroconverters, 1079 deaths were observed in 19 671 person-years of follow-up. Survival times varied by age and by study site. Adjusting to age 25–29 years at seroconversion, the median survival was longer in South African miners: 11.6 years [95% confidence interval (CI) 9.8–13.7] and East African cohorts: 11.1 years (95% CI 8.7–14.2) than in Haiti: 8.3 years (95% CI 3.2–21.4) and Thailand: 7.5 years (95% CI 5.4–10.4). Survival was similar for men and women, after adjustment for age at seroconversion and site. Conclusion:Without antiretroviral therapy, overall survival after HIV infection in African cohorts was similar to survival in high-income countries, with a similar pattern of faster progression at older ages at seroconversion. Survival appears to be significantly worse in Thailand where other, unmeasured factors may affect progression.

Stochastic simulation of the impact of antiretroviral therapy and HIV vaccines on HIV transmission; Rakai, Uganda

Objective: To model the effects of antiretroviral therapy (ART) and HIV vaccines on HIV transmission using empirical data from studies in Rakai, Uganda. Design: A stochastic simulation model estimated HIV incidence, probabilities of transmission per coital act and the reproductive number (R0) with ART and HIV vaccines. Model inputs included Rakai data on HIV transmission probabilities per coital act by HIV viral load, age and gender, and sexual behaviors. The impacts of therapy were derived from US programs, and vaccine assumptions included preventive efficacies ranging from 25 to 75%. Component projection models estimated the numbers of HIV-infected persons over 20 years. Results: The model incidence [1.57/100 person years (PY)] closely fitted empirical data (1.5/100 PY). Simulations of ART using DHHS treatment guidelines, predicted declines in HIV incidence, but R0 remained > 1.0, and the numbers of HIV-positive persons did not change substantially over 20 years. Preventive vaccines with > 50% efficacy and > 50% population coverage could reduce R0 to < 1.0, and substantially reduce the number of HIV-infected persons over 20 years. Concurrent ART and a preventive vaccine can have substantial impact at lower levels of population coverage and would markedly reduce the HIV infected population over 20 years. However, behavioral disinhibition with increased numbers of sexual partners in either ART or vaccine recipients, increased HIV incidence and diminished intervention impact. Conclusion: ART alone cannot control the HIV epidemic in mature epidemics such as Rakai, and persons in need of therapy will increase over time. ART in combination with a low efficacy vaccine could control the epidemic, if behavioral disinhibition is prevented.