Heiner Grosskurth

Control of sexually transmitted diseases for HIV-1 prevention: understanding the implications of the Mwanza and Rakai trials.

Two randomised controlled trials of sexually transmitted disease (STD) treatment for the prevention of HIV-1 Infection, in Mwanza, Tanzania, and Rakai, Uganda, unexpectedly produced contrasting results. A decrease in population HIV-1 incidence was associated with improved STD case management in Mwanza, but was not associated with STD mass treatment in Rakai. Some reductions in curable STDs were seen in both studies. These trials tested different interventions in different HIV-1 epidemic settings and used different evaluation methods; the divergent results may be complementary rather than contradictory. Possible explanations include: differences in stage of the HIV-1 epidemic, which can influence exposure to HIV-1 and the distribution of viral load in the infected population; potential differences in the prevalence of Incurable STDs (such as genital herpes); perhaps greater Importance of symptomatic than symptomless STDs for HIV-1 transmission; and possibly greater effectiveness of continuously available services than of intermittent mass treatment to control rapid STD reinfection. Implications of the trials for policy and future research agenda are discussed.

PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial

Summary Background Innovative prevention strategies for HIV-1 transmission are urgently needed. PRO2000 vaginal gel was efficacious against HIV-1 transmission in studies in macaques; we aimed to assess efficacy and safety of 2% and 0·5% PRO2000 gels against vaginal HIV-1 transmission in women in sub-Saharan Africa. Methods Microbicides Development Programme 301 was a phase 3, randomised, double-blind, parallel-group trial, undertaken at 13 clinics in South Africa, Tanzania, Uganda, and Zambia. We randomly assigned sexually active women, aged 18 years or older (≥16 years in Tanzania and Uganda) without HIV-1 infection in a 1:1:1 ratio to 2% PRO2000, 0·5% PRO2000, or placebo gel groups for 52 weeks (up to 104 weeks in Uganda). Randomisation was done by computerised random number generator. Investigators and participants were masked to group assignment. The primary efficacy outcome was incidence of HIV-1 infection before week 52, which was censored for pregnancy and excluded participants without HIV-1 follow-up data or with HIV-1 infection at enrolment. HIV-1 status was established by rapid tests or ELISA at screening at 12 weeks, 24 weeks, 40 weeks, and 52 weeks, and confirmed in a central reference laboratory. The primary safety endpoint was an adverse event of grade 3 or worse. Use of 2% PRO2000 gel was discontinued on Feb 14, 2008, on the recommendation of the Independent Data Monitoring Committee because of low probability of benefit. This trial is registered at http://isrctn.org, number ISRCTN 64716212. Findings We enrolled 9385 of 15 818 women screened. 2591 (95%) of 2734 participants enrolled to the 2% PRO2000 group, 3156 (95%) of 3326 in the 0·5% PRO2000 group, and 3112 (94%) of 3325 in the placebo group were included in the primary efficacy analysis. Mean reported gel use at last sex act was 89% (95% CI 86–91). HIV-1 incidence was much the same between groups at study end (incidence per 100 woman-years was 4·5 [95% CI 3·8–5·4] for 0·5% PRO2000 vs 4·3 [3·6–5·2] for placebo, hazard ratio 1·05 [0·82–1·34], p=0·71), and at discontinuation (4·7 [3·8–5·8] for 2% PRO2000 gel, 3·9 [3·0–4·9] for 0·5% PRO2000 gel, and 3·9 [3·1–5·0] for placebo gel). Incidence of the primary safety endpoint at study end was 4·6 per 100 woman-years (95% CI 3·9–5·4) in the 0·5% PRO2000 group and 3·9 (3·2–4·6) in the placebo group; and was 4·5 (3·7–5·5) in the 2% PRO2000 group at discontinuation. Interpretation Although safe, 0·5% PRO2000 and 2% PRO2000 are not efficacious against vaginal HIV-1 transmission and are not indicated for this use. Funding UK Department for International Development, UK Medical Research Council, European and Developing Countries Clinical Trials Partnership, International Partnership for Microbicides, and Endo Pharmaceuticals Solutions.

Biological and behavioural impact of an adolescent sexual health intervention in Tanzania : a community-randomized trial

Objective:The impact of a multicomponent intervention programme on the sexual health of adolescents was assessed in rural Tanzania. Design:A community-randomized trial. Methods:Twenty communities were randomly allocated to receive either a specially designed programme of interventions (intervention group) or standard activities (comparison group). The intervention had four components: community activities; teacher-led, peer-assisted sexual health education in years 5–7 of primary school; training and supervision of health workers to provide ‘youth-friendly’ sexual health services; and peer condom social marketing. Impacts on HIV incidence, herpes simplex virus 2 (HSV2) and other sexual health outcomes were evaluated over approximately 3 years in 9645 adolescents recruited in late 1998 before entering years 5, 6 or 7 of primary school. Results:The intervention had a significant impact on knowledge and reported attitudes, reported sexually transmitted infection symptoms, and several behavioural outcomes. Only five HIV seroconversions occurred in boys, whereas in girls the adjusted rate ratio (intervention versus comparison) was 0.75 [95% confidence interval (CI) 0.34, 1.66]. Overall HSV2 prevalences at follow-up were 11.9% in male and 21.1% in female participants, with adjusted prevalence ratios of 0.92 (CI 0.69, 1.22) and 1.05 (CI 0.83, 1.32), respectively. There was no consistent beneficial or adverse impact on other biological outcomes. The beneficial impact on knowledge and reported attitudes was confirmed by results of a school examination in a separate group of students in mid-2002. Conclusion:The intervention substantially improved knowledge, reported attitudes and some reported sexual behaviours, especially in boys, but had no consistent impact on biological outcomes within the 3-year trial period.

The epidemiology of HIV-1 infection in urban areas, roadside settlements and rural villages in Mwanza Region, Tanzania

ObjectiveTo determine the prevalence of HIV-1 infection and to identify the most important risk factors for infection. DesignA cross-sectional population survey carried out in 1990 and 1991 in Mwanza Region, Tanzania. MethodsAdults aged 15–54 years were selected from the region (population, 2 million) by stratified random cluster sampling: 2434 from 20 rural villages, 1157 from 20 roadside settlements and 1554 from 20 urban wards. Risk factor information was obtained from interviews. All sera were tested for HIV-1 antibodies using enzyme-linked immunosorbent assay (ELISA); sera non-negative on ELISA were also tested by Western blot. ResultsThe response rate was 81%. HIV-1 infection was 1.5 times more common in women than in men; 2.5% of the adult population in rural villages, 7.3% in roadside settlements and 11.8% in town were infected. HIV-1 infection occurred mostly in women aged 15–34 years and men aged 25–44 years. It was associated with being separated or widowed, multiple sex partners, presence of syphilis antibodies, history of genital discharge or genital ulcer, travel to Mwanza town, and receiving injections during the previous 12 months, but not with male circumcision. ConclusionThis study confirms that HIV-1 infection in this region in East Africa is more common in women than in men. The results are consistent with the spread of HIV-1 infection along the main roads. There is no evidence that lack of circumcision is a risk factor in this population.

Rates of virological failure in patients treated in a home-based versus a facility-based HIV-care model in Jinja, southeast Uganda: a cluster-randomised equivalence trial

BACKGROUND Identification of new ways to increase access to antiretroviral therapy in Africa is an urgent priority. We assessed whether home-based HIV care was as effective as was facility-based care. METHODS We undertook a cluster-randomised equivalence trial in Jinja, Uganda. 44 geographical areas in nine strata, defined according to ratio of urban and rural participants and distance from the clinic, were randomised to home-based or facility-based care by drawing sealed cards from a box. The trial was integrated into normal service delivery. All patients with WHO stage IV or late stage III disease or CD4-cell counts fewer than 200 cells per microL who started antiretroviral therapy between Feb 15, 2005, and Dec 19, 2006, were eligible, apart from those living on islands. Follow-up continued until Jan 31, 2009. The primary endpoint was virological failure, defined as RNA more than 500 copies per mL after 6 months of treatment. The margin of equivalence was 9% (equivalence limits 0.69-1.45). Analyses were by intention to treat and adjusted for baseline CD4-cell count and study stratum. This trial is registered at http://isrctn.org, number ISRCTN 17184129. FINDINGS 859 patients (22 clusters) were randomly assigned to home and 594 (22 clusters) to facility care. During the first year, 93 (11%) receiving home care and 66 (11%) receiving facility care died, 29 (3%) receiving home and 36 (6%) receiving facility care withdrew, and 8 (1%) receiving home and 9 (2%) receiving facility care were lost to follow-up. 117 of 729 (16%) in home care had virological failure versus 80 of 483 (17%) in facility care: rates per 100 person-years were 8.19 (95% CI 6.84-9.82) for home and 8.67 (6.96-10.79) for facility care (rate ratio [RR] 1.04, 0.78-1.40; equivalence shown). Two patients from each group were immediately lost to follow-up. Mortality rates were similar between groups (0.95 [0.71-1.28]). 97 of 857 (11%) patients in home and 75 of 592 (13%) in facility care were admitted at least once (0.91, 0.64-1.28). INTERPRETATION This home-based HIV-care strategy is as effective as is a clinic-based strategy, and therefore could enable improved and equitable access to HIV treatment, especially in areas with poor infrastructure and access to clinic care.

Incidence of HIV infection in stable sexual partnerships: A retrospective cohort study of 1802 couples in Mwanza region Tanzania.

Objective: To describe the dynamics of HIV transmission in stable sexual partnerships in rural Tanzania. Design: Retrospective cohort study nested within community‐randomized trial to investigate the impact of a sexually transmitted disease treatment program. Methods: A cohort of 1802 couples was followed up for 2 years, with the HIV status of each couple assessed at baseline and follow‐up. Results: At baseline, 96.7% of couples were concordant‐negative, 0.9% were concordant‐positive, 1.2% were discordant with the male partner being HIV‐positive, and 1.2% were discordant with the female partner being HIV‐positive. Individuals living with an HIV‐positive partner were more likely to be HIV‐positive at baseline (women: odds ratio [OR] = 75.7, 95% confidence interval [CI]: 33.4‐172; men: OR = 62.4, CI: 28.5‐137). Seroincidence rates in discordant couples were 10 per 100 person‐years (py) and 5 per 100 py for women and men, respectively (rate ratio [RR] = 2.0, CI: 0.28‐22.1). In concordant‐negative couples, seroincidence rates were 0.17 per 100 py in women and 0.45 per 100 py in men (RR = 0.38, CI: 0.12‐1.04). Individuals living in discordant couples were at a greatly increased risk of infection compared with individuals in concordant‐negative couples (RR = 57.9, CI: 12.0‐244 for women; RR = 11.0, CI: 1.2‐47.5 for men). Conclusion: Men were more likely than women to introduce HIV infection in concordant‐negative partnerships. In discordant couples, incidence in HIV‐negative women was twice as high as in men. HIV‐negative individuals in discordant partnerships are at high risk of infection, and preventive interventions targeted at such individuals are urgently needed.

A community trial of the impact of improved sexually transmitted disease treatment on the HIV epidemic in rural Tanzania: 1. Design.

ObjectiveTo describe the rationale, and design of a randomized trial of the impact of improved services for the treatment of sexually transmitted diseases (STD) on the incidence of HIV infection in Mwanza Region, Tanzania. MethodsThe likely impact of improved STD treatment services on HIV incidence, and the need for empirical information on the effectiveness of this intervention strategy, are discussed. The rationale, and design of such an intervention programme in Mwanza Region, and of a community-randomized trial to measure the impact of the programme on HIV, and other STD, are presented. Problems in the design, and interpretation of the trial are reviewed. ResultsResults of the baseline survey of the cohort of over 12000 adults in 12 communities are presented in a companion paper. ConclusionThere is an urgent need for effective preventive measures against the HIV epidemic in sub-Saharan Africa, and other developing regions. Improved STD treatment has been promoted as a potentially effective strategy, but there is little empirical information on its impact. The trial in Mwanza Region is the first randomized study of this intervention, and should provide valuable data for health policy makers.

Antibody to Herpes Simplex Virus Type 2 as a Marker of Sexual Risk Behavior in Rural Tanzania

A serosurvey was conducted in a random sample of 259 women and 231 men in 12 rural communities in Mwanza Region, Tanzania, using a type-specific ELISA for Herpes simplex virus type 2 (HSV-2) infection. Seroprevalence rose steeply with age to approximately 75% in women >=25 years old and 60% in men >=30. After adjusting for age and residence, HSV-2 prevalence was higher in women who were married, in a polygamous marriage, Treponema pallidum hemagglutination assay (TPHA)-positive, had more lifetime sex partners, or who had not traveled. Prevalence was higher in men who were married, had lived elsewhere, had more lifetime partners, had used condoms, or were TPHA-positive. HSV-2 infection was significantly associated with recent history of genital ulcer. The association between HSV-2 infection and lifetime sex partners was strongest in those <25 years old in both sexes. This association supports the use of HSV-2 serology as a marker of risk behavior in this population, particularly among young people.

Cost-effectiveness of improved treatment services for sexually transmitted diseases in preventing HIV-1 infection in Mwanza Region, Tanzania

BACKGROUND A community-randomised trial was undertaken to assess the impact, cost, and cost-effectiveness of averting HIV-1 infection through improved management of sexually transmitted diseases (STDs) by primary-health-care workers in Mwanza Region, Tanzania. METHODS The impact of improved treatment services for STDs on HIV-1 incidence was assessed by comparison of six intervention communities with six matched communities. We followed up a random cohort of 12,537 adults aged 15-54 years for 2 years to record incidence of HIV-1 infection. The total and incremental costs of the intervention were estimated (ingredients approach) and used to calculate the total cost per case treated, the incremental cost per HIV-1 infection averted, and the incremental cost per disability-adjusted life-year (DALY) saved. FINDINGS During 2 years of follow-up, 11,632 cases of STDs were treated in the intervention health units. The baseline prevalence of HIV-1 infection was 4%. The incidence of HIV-1 infection during the 2 years was 1.16% in the intervention communities and 1.86% in the comparison communities. An estimated 252 HIV-1 infections were averted each year. The total annual cost of the intervention was US

Mortality and loss-to-follow-up during the pre-treatment period in an antiretroviral therapy programme under normal health service conditions in Uganda

59,060 (1993 prices), equivalent to