Anatoli Kamali

Syndromic management of sexually-transmitted infections and behaviour change interventions on transmission of HIV-1 in rural Uganda: a community randomised trial

BACKGROUND Treatment of sexually-transmitted infections (STIs) and behavioural interventions are the main methods to prevent HIV in developing countries. We aimed to assess the effect of these interventions on incidence of HIV-1 and other sexually-transmitted infections. METHODS We randomly allocated all adults living in 18 communities in rural Uganda to receive behavioural interventions alone (group A), behavioural and STI interventions (group B), or routine government health services and community development activities (group C). The primary outcome was HIV-1 incidence. Secondary outcomes were incidence of herpes simplex virus type 2 (HSV2) and active syphilis and prevalence of gonorrhoea, chlamydia, reported genital ulcers, reported genital discharge, and markers of behavioural change. Analysis was per protocol. FINDINGS Compared with group C, the incidence rate ratio of HIV-1 was 0.94 (0.60-1.45, p=0.72) in group A and 1.00 (0.63-1.58, p=0.98) in group B, and the prevalence ratio of use of condoms with last casual partner was 1.12 (95% CI 0.99-1.25) in group A and 1.27 (1.02-1.56) in group B. Incidence of HSV2 was lower in group A than in group C (incidence rate ratio 0.65, 0.53-0.80) and incidence of active syphilis for high rapid plasma reagent test titre and prevalence of gonorrhoea were both lower in group B than in group C (active syphilis incidence rate ratio, 0.52, 0.27-0.98; gonorrhoea prevalence ratio, 0.25, 0.10-0.64). INTERPRETATION The interventions we used were insufficient to reduce HIV-1 incidence in rural Uganda, where secular changes are occurring. More effective STI and behavioural interventions need to be developed for HIV control in mature epidemics.

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.

Rates of HIV-1 transmission within marriage in rural Uganda in relation to the HIV sero-status of the partners.

OBJECTIVE To assess the efficacy of transmission of HIV-1 within married couples in rural Uganda according to the sero-status of the partners. DESIGN Estimation of HIV incidence rates for 2200 adults in a population cohort followed for 7 years comparing male-to-female with female-to-male transmission and sero-discordant with concordant sero-negative couples. METHODS Each year, adults (over 12 years of age) resident in the study area were linked to their spouses if also censused as resident. The HIV sero-status was determined annually. RESULTS At baseline 7% of married adults were in sero-discordant marriages and in half of these the man was HIV-positive. Among those with HIV-positive spouses, the age-adjusted HIV incidence in women was twice that of men (rate ratio (RR) = 2.2 95% confidence interval (CI) 0.9-5.4) whereas, among those with HIV-negative spouses, the incidence in women was less than half that of men (RR = 0.4, 95% CI 0.2-0.8). The age-adjusted incidence among women with HIV-positive spouses was 105.8 times (95% CI 33.6-332.7) that of women with HIV-negative spouses, the equivalent ratio for men being 11.6 (95% CI 5.8-23.4). CONCLUSION Men are twice as likely as women to bring HIV infection into a marriage, presumably through extra-marital sexual behaviour. Within sero-discordant marriages women become infected twice as fast as men, probably because of increased biological susceptibility. Married adults, particularly women, with HIV-positive spouses are at very high risk of HIV infection. Married couples in this population should be encouraged to attend for HIV counselling together so that sero-discordant couples can be identified and advised accordingly.

HIV-1/AIDS and the control of other infectious diseases in Africa.

The effect of HIV-1 on other infectious diseases in Africa is an increasing public health concern. In this review, we describe the role that three major infectious diseases--malaria, sexually transmitted diseases (STDs), and tuberculosis--have had in the HIV-1 epidemic. The high prevalence of untreated STD infections has been a major factor facilitating the spread of HIV-1 in Africa; with the synergistic interaction between HIV-1 transmission and genital herpes being of special concern for control of both diseases. Increased susceptibility to tuberculosis after infection with HIV-1 has led to a rising incidence and threat of increased transmission of tuberculosis. Clinical malaria occurs with an increased frequency and severity in HIV-1-infected individuals, especially during pregnancy. As with tuberculosis, STDs, and other communicable HIV-1-associated diseases, the net effect of HIV-1 might include increased rates of malaria transmission across communities. In addition to enhancing access to HIV-1 prevention and care, public health surveillance and control programmes should be greatly intensified to cope with the new realities of infectious disease control in Africa.

The African Genome Variation Project shapes medical genetics in Africa

Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with which to design, implement and interpret genomic studies in sub-Saharan Africa and worldwide. The African Genome Variation Project represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa. We identify new loci under selection, including loci related to malaria susceptibility and hypertension. We show that modern imputation panels (sets of reference genotypes from which unobserved or missing genotypes in study sets can be inferred) can identify association signals at highly differentiated loci across populations in sub-Saharan Africa. Using whole-genome sequencing, we demonstrate further improvements in imputation accuracy, strengthening the case for large-scale sequencing efforts of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa.

Seven-year trends in HIV-1 infection rates, and changes in sexual behaviour, among adults in rural Uganda

ObjectiveTo assess trends in HIV-1 infection rates and changes in sexual behaviour over 7 years in rural Uganda. MethodsAn adult cohort followed through eight medical–serological annual surveys since 1989–1990. All consenting participants gave a blood sample and were interviewed on sexual behaviour. ResultsOn average, 65% of residents gave a blood sample at each round. Overall HIV-1 prevalence declined from 8.2% at round 1 to 6.9% at round 8 (P = 0.008). Decline was most evident among men aged 20–24 years (11.7 to 3.6%;P < 0.001) and women aged 13–19 (4.4% to 1.4%;P = 0.003) and 20–24 (20.9% to 13.8%;P = 0.003). However, prevalence increased significantly among women aged 25–34 (13.1% to 16.6%;P = 0.04). Although overall incidence declined from 7.7/1000 person-years (PY) in 1990 to 4.6/1000 PY in 1996, neither this nor the age-sex specific rates changed significantly (P > 0.2). Age-standardized death rates for HIV-negative individuals were 6.5/1000 PY in 1990 and 8.2/1000 PY in 1996; corresponding rates for HIV-positive individuals were 129.7 and 102.7/1000 PY, respectively. There were no significant trends in age-adjusted death rates during follow-up for either group. There was evidence of behaviour change towards increase in condom use in males and females, marriage at later age for girls, later sexual debut for boys and a fall in fertility especially among unmarried teenagers. ConclusionsThis is the first general population cohort study showing overall long-term significant reduction in HIV prevalence and parallel evidence of sexual behaviour change. There are however no significant reductions in either HIV incidence or mortality.

Declining HIV-1 incidence and associated prevalence over 10 years in a rural population in south-west Uganda: a cohort study

BACKGROUND In Uganda, there have been encouraging reports of reductions in HIV-1 prevalence but not in incidence, which is the most reliable measure of epidemic trends. We describe HIV-1 incidence and prevalence trends in a rural population-based cohort between 1989 and 1999. METHODS We surveyed the adult population of 15 neighbouring villages for HIV-1 infection using annual censuses, questionnaires, and serological surveys. We report crude annual incidence rates by calendar year and prevalence by survey round. FINDINGS 6566 HIV-1 seronegative adults were bled two or more times between January, 1990, and December, 1999, contributing 31984 person years at risk (PYAR) and 190 seroconversions. HIV-1 incidence fell from 8.0 to 5.2 per 1000 PYAR between 1990 and 1999 (p=0.002, chi(2) for trend). Significant sex-specific and age-group-specific reductions in incidence were evident. Incidence was 37% lower for 1995-99 than for 1990-94 (p=0.002, t-test). On average, 4642 adult residents had a definite HIV-1 serostatus at each yearly survey round. HIV-1 prevalence fell significantly between the first and tenth annual survey rounds (p=0.03, chi(2) for trend), especially among men aged 20-24 years (6.5% to 2.2%) and 25-29 years (15.2% to 10.9%) and women aged 13-19 years (2.8% to 0.9%) and 20-24 years (19.3% to 10.1%) (all p<0.001, chi(2) for trend). INTERPRETATION Our findings of a significant drop in adult HIV-1 incidence in rural Ugandans give hope to AIDS control programmes elsewhere in sub-Saharan Africa where rates of HIV-1 infection remain high.

Migration and HIV-1 seroprevalence in a rural Ugandan population

Objective: To study the association between change of residence and HIV‐1 serostatus in a rural Ugandan population. Design: A longitudinal cohort study. Methods: As part of the annual surveillance of a population cohort of approximately 10000 individuals in a rural subcounty of southwest Uganda, information has been collected for all adults on change of residence over a 3‐year period and its association with HIV 1 serostatus. Sera were collected by a medical team during home visits. Antibody testing was performed at the Uganda Virus Research Institute using two independent enzyme immunoassay systems and Western blot when appropriate. Results: At the fourth survey‐round, age and sex‐standardized seroprevalence rates were 7.9% overall; the rate was 5.5% for 2129 adults who had not changed address since the first survey, 8.2% for 336 who moved within the village, 12.4% for 1 28 who moved to a neighbouring village, 11.5% for 1130 who had left the area and 16.3% for 541 who had joined the study area during the previous 3 years (P<< 0.001, 4 degrees of freedom). We also observed an inverse relationship between years lived at the present house at the time of the first survey and both seroprevalence and subsequent seroincidence rates. The reported numbers of lifetime sexual partners were higher in those who changed residence. Conclusion: Change of residence is strongly associated with an increased risk of HIV‐1 infection in this rural population and is likely to be the result of more risky sexual behaviour among those who move. These findings have important implications for the design of AIDS control programmes and intervention studies. AIDS 1995, 9:503‐506

Determinants of the impact of sexually transmitted infection treatment on prevention of HIV infection: A synthesis of evidence from the Mwanza, Rakai, and Masaka Intervention Trials

Community-randomized trials in Mwanza, Tanzania, and Rakai and Masaka, Uganda, suggested that population characteristics were an important determinant of the impact of sexually transmitted infection (STI) treatment interventions on incidence of human immunodeficiency virus (HIV) infection. We performed simulation modeling of HIV and STI transmission, which confirmed that the low trial impact in Rakai and Masaka could be explained by low prevalences of curable STI resulting from lower-risk sexual behavior in Uganda. The mature HIV epidemics in Uganda, with most HIV transmission occurring outside core groups with high STI rates, also contributed to the low impact on HIV incidence. Simulated impact on HIV was much greater in Mwanza, although the observed impact was larger than predicted from STI reductions, suggesting that random error also may have played some role. Of proposed alternative explanations, increasing herpetic ulceration due to HIV-related immunosuppression contributed little to the diminishing impact of antibiotic treatment during the Ugandan epidemics. The strategy of STI treatment also was unimportant, since syndromic treatment and annual mass treatment showed similar effectiveness in simulations of each trial population. In conclusion, lower-risk behavior and the mature HIV epidemic explain the limited impact of STI treatment on HIV incidence in Uganda in the 1990s. In populations with high-risk sexual behavior and high STI rates, STIs treatment interventions may contribute substantially to prevention of HIV infection.

HIV-1 incidence and HIV-1-associated mortality in a rural Ugandan population cohort.

ObjectiveTo determine the incidence of HIV-1 infection and HIV-1-associated mortality in a rural Ugandan population. DesignA prospective cohort study. MethodsA cohort consisting of the population (de jure census 9820) of a cluster of 15 villages in Masaka District, south-west Uganda was enrolled between 1989 and 1990 through a demographic and medical survey. The HIV-1 seroprevalence rate was 4.8% for all ages combined and 8.2% for those aged 13 years of more. The survey was repeated after 1 year. ResultsThe 1-year HIV-1 incidence rate among adults was 1% |9.2 per 1000 person-years of observation; 95% confidence interval (Cl), 5.5–12.9). A total of 84 deaths were observed. In adults, half of all deaths (31 out of 60) were in HIV-1-seropositive individuals. The age-adjusted overall mortality rate ratio for HIV-positive adults compared with HIV-negatives was 20.8 (95% Cl, 12.0–35.7). In the 13–44 age group the corresponding rate ratios for men, women and both sexes combined were 16.3, 108.9 and 58.7, respectively. The HIV-attributable mortality fractions, i.e., the proportion of deaths that would have been avoided in the absence of HIV, were 44, 50 and 89% for adult men, adult women and adults aged 25–34 years (both sexes combined), respectively. The 1-year progression to death among HIV-1-seropositive adults was 10.3%. ConclusionThese results demonstrate the profound impact that the HIV-1 epidemic has on adult mortality in a rural area of Uganda where the HIV-1 prevalence and incidence rates in adults are 8 and 1%, respectively.