Effect of cotrimoxazole prophylaxis on malaria occurrence in HIV-infected patients on antiretroviral therapy in sub-Saharan Africa.

OBJECTIVE: To systematically review the evidence on the effect of cotrimoxazole (CTX) on malaria in HIV-positive individuals on antiretroviral therapy (ART). METHODS: Web of Science, PubMed and MEDLINE, EMBASE, Global Health and Cochrane Library databases were searched using terms for malaria, HIV and CTX. Studies meeting the inclusion criteria were reviewed and assessed for bias and confounding. RESULTS: Six studies (in Uganda, Kenya, Malawi, Zambia and Zimbabwe) had relevant data on the effect of CTX on malaria in patients on ART: four were observational cohort studies (OCS) and two were randomised controlled trials (RCTs); two were in children and one in women only. Samples sizes ranged from 265 to 2200 patients. Four studies compared patients on ART and CTX with patients on ART alone; 2 (RCTs) found a significant increase in smear-positive malaria on ART alone: (IRR 32.5 CI = 8.6-275.0 and HR 2.2 CI = 1.5-3.3) and 2 (OCS) reported fewer parasitaemia episodes on CTX and ART (OR 0.85 CI = 0.65-1.11 and 3.6% vs. 2.4% of samples P = 0.14). One OCS found a 76% (95% CI = 63-84%) vs. 83% (95% CI = 74-89%) reduction in malaria incidence in children on CTX and ART vs. on CTX only, when both were compared with HIV-negative children. The other reported a 64% reduction in malaria incidence after adding ART to CTX (RR = 0.36, 95% CI = 0.18-0.74). The 2 RCTs were unblinded. Only one study reported adherence to CTX and ART, and only two controlled for baseline CD4 count. CONCLUSION: Few studies have investigated the effect of CTX on malaria in patients on ART. Their findings suggest that CTX is protective against malaria even among patients on ART.

Daily co-trimoxazole prophylaxis in severely immunosuppressed HIV-infected adults in Africa started on combination antiretroviral therapy: an observational analysis of the DART cohort.

BACKGROUND: Co-trimoxazole prophylaxis can reduce mortality from untreated HIV infection in Africa; whether benefits occur alongside combination antiretroviral therapy (ART) is unclear. We estimated the effect of prophylaxis after ART initiation in adults. METHODS: Participants in our observational analysis were from the DART randomised trial of management strategies in HIV-infected, symptomatic, previously untreated African adults starting triple-drug ART with CD4 counts lower than 200 cells per muL. Co-trimoxazole prophylaxis was not routinely used or randomly allocated, but was variably prescribed by clinicians. We estimated effects on clinical outcomes, CD4 cell count, and body-mass index (BMI) using marginal structural models to adjust for time-dependent confounding by indication. DART was registered, number ISRCTN13968779. FINDINGS: 3179 participants contributed 14 214 years of follow-up (8128 [57%] person-years on co-trimoxazole). Time-dependent predictors of co-trimoxazole use were current CD4 cell count, haemoglobin concentration, BMI, and previous WHO stage 3 or 4 events on ART. Present prophylaxis significantly reduced mortality (odds ratio 0.65, 95% CI 0.50-0.85; p=0.001). Mortality risk reduction on ART was substantial to 12 weeks (0.41, 0.27-0.65), sustained from 12-72 weeks (0.56, 0.37-0.86), but not evident subsequently (0.96, 0.63-1.45; heterogeneity p=0.02). Variation in mortality reduction was not accounted for by time on co-trimoxazole or current CD4 cell count. Prophylaxis reduced frequency of malaria (0.74, 0.63-0.88; p=0.0005), an effect that was maintained with time, but we observed no effect on new WHO stage 4 events (0.86, 0.69-1.07; p=0.17), CD4 cell count (difference vs non-users, -3 cells per muL [-12 to 6]; p=0.50), or BMI (difference vs non-users, -0.04 kg/m(2) [-0.20 to 0.13); p=0.68]. INTERPRETATION: Our results reinforce WHO guidelines and provide strong motivation for provision of co-trimoxazole prophylaxis for at least 72 weeks for all adults starting combination ART in Africa. FUNDING: UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial.

BACKGROUND: HIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa. METHODS: In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per microL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per microL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1.18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779. FINDINGS: Two participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85-88) in the CDM group and 90% (88-91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4.9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6.94 [95% CI 6.33-7.60] vs 5.24 [4.72-5.81] per 100 person-years; absolute difference 1.70 per 100 person-years [0.87-2.54]; HR 1.31 [1.14-1.51]; p=0.0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1.12 [0.94-1.32]; p=0.19), with anaemia the most common (76 vs 61 cases). INTERPRETATION: ART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment. FUNDING: UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

Morbidity in HIV-1-infected individuals before and after the introduction of antiretroviral therapy: a longitudinal study of a population-based cohort in Uganda.

BACKGROUND: We compared morbidities in HIV-1-infected patients before and after the introduction of antiretroviral therapy (ART) in a rural Ugandan cohort followed from 1990 to 2008. ART was introduced in 2004. METHODS: Random-effects Poisson regression models were used to estimate incidence rates of World Health Organization (WHO) stage-defining diseases in HIV-infected individuals aged 13 years or older with known seroconversion dates, and in an age-stratified sample of HIV-negative individuals. RESULTS: The most common morbid event was bacterial pneumonia, with an incidence of 7.4/100 person-years (pyr) among 309 HIV seroconverters and 1.3/100 pyr among 348 HIV-negative participants [hazard ratio (HR) 5.64; 95% confidence interval (CI) 3.6-8.8]. Among seroconverters, the incidence of the acquisition of any WHO stage-defining disease rose from 14.4/100 pyr (95% CI 11.1-18.6) in 1990-1998 to 46.0/100 pyr (95% CI 37.7-56.0) in 1999-2003. Following the introduction of ART, the incidence among seroconverters declined to 36.4/100 pyr (95% CI 27.1-48.9) in 2004-2005 and to 28.3/100 pyr (95% CI 21.2-37.8) in 2006-2008. At the individual level, a higher rate of acquiring any WHO stage-defining disease was independently associated with lower CD4 cell count, longer duration of HIV infection and older age. In addition, individuals who had been on ART for longer than 12 months had a substantially lower rate of any WHO stage disease than those not yet on ART (adjusted HR 0.35; 95% CI 0.2-0.6). CONCLUSION: Morbidity in HIV-positive participants decreased following the introduction of ART, and this decline was more marked with increasing duration on ART. The benefits of decreased HIV-related morbidity from ART lend support to urgent efforts to ensure universal access to early diagnosis of HIV infection and to ART, especially in rural Africa.

Nevirapine/zidovudine/lamivudine has superior immunological and virological responses not reflected in clinical outcomes in a 48-week randomized comparison with abacavir/zidovudine/lamivudine in HIV-infected Ugandan adults with low CD4 cell counts.

BACKGROUND: Triple nucleoside reverse transcriptase inhibitor regimens have advantages as first-line antiretroviral therapy (ART), avoiding hepatotoxicity and interactions with anti-tuberculosis therapy, and sparing two drug classes for second-line ART. Concerns exist about virological potency; efficacy has not been assessed in Africa. METHODS: A safety trial comparing nevirapine with abacavir was conducted in two Ugandan Development of Antiretroviral Therapy in Africa (DART) centres: 600 symptomatic antiretroviral-naïve HIV-infected adults with CD4 counts <200 cells/microL were randomized to zidovudine/lamivudine plus abacavir or nevirapine (placebo-controlled to 24-week primary toxicity endpoint, and then open-label). Documented World Health Organization (WHO) stage 4 events were independently reviewed and plasma HIV-1 RNA assayed retrospectively. Exploratory efficacy analyses are intention-to-treat. RESULTS: The median pre-ART CD4 count was 99 cells/microL, and the median pre-ART viral load was 284 600 HIV-1 RNA copies/mL. A total of 563 participants (94%) completed 48 weeks of follow-up, 25 (4%) died and 12 (2%) were lost to follow-up. The randomized drug was substituted in 21 participants (7%) receiving abacavir vs. 34 (11%) receiving nevirapine (P=0.09). At 48 weeks, 62% of participants receiving abacavir vs. 77% of those receiving nevirapine had viral loads <50 copies/mL (P<0.001), and mean CD4 count increases from baseline were +147 vs. +173 cells/microL, respectively (P=0.006). Nine participants (3%) receiving abacavir vs. 16 (5%) receiving nevirapine died [hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.24-1.25; P=0.15]; 20 receiving abacavir vs. 32 receiving nevirapine developed new or recurrent WHO 4 events or died (HR=0.60; 95% CI 0.34-1.05; P=0.07) and 48 receiving abacavir vs. 68 receiving nevirapine developed new or recurrent WHO 3 or 4 events or died (HR=0.67; 95% CI 0.46-0.96; P=0.03). Seventy-one participants (24%) receiving abacavir experienced 91 grade 4 adverse events compared with 130 events in 109 participants (36%) on nevirapine (P<0.001). CONCLUSIONS: The clear virological/immunological superiority of nevirapine over abacavir was not reflected in clinical outcomes over 48 weeks. The inability of CD4 cell count/viral load to predict initial clinical treatment efficacy is unexplained and requires further evaluation.

Research needs for an improved primary care response to chronic non-communicable diseases in Africa.

With non-communicable diseases (NCDs) projected to become leading causes of morbidity and mortality in developing countries, research is needed to improve the primary care response, especially in sub-Saharan Africa. This region has a particularly high double burden of communicable diseases and NCDs and the least resources for an effective response. There is a lack of good quality epidemiological data from diverse settings on chronic NCD burden in sub-Saharan Africa, and the approach to primary care of people with chronic NCDs is currently often unstructured. The main primary care research needs are therefore firstly, epidemiological research to document the burden of chronic NCDs, and secondly, health system research to deliver the structured, programmatic, public health approach that has been proposed for the primary care of people with chronic NCDs. Documentation of the burden and trends of chronic NCDs and associated risk factors in different settings and different population groups is needed to enable health system planning for an improved primary care response. Key research issues in implementing the programmatic framework for an improved primary care response are how to (i) integrate screening and prevention within health delivery; (ii) validate the use of standard diagnostic protocols for NCD case-finding among patients presenting to the local health facilities; (iii) improve the procurement and provision of standardised treatment and (iv) develop and implement a data collection system for standardised monitoring and evaluation of patient outcomes. Important research considerations include the following: selection of research sites and the particular NCDs targeted; research methodology; local research capacity; research collaborations; ethical issues; translating research findings into policy and practice and funding. Meeting the research needs for an improved health system response is crucial to deliver effective, affordable and equitable care for the millions of people with chronic NCDs in developing countries in Africa.

Evaluation of affordable screening markers to detect CD4+ T-cell counts below 200 cells/mul among HIV-1-infected Ugandan adults.

OBJECTIVE: To evaluate validity of WHO staging, low body mass index (BMI) and anaemia in detecting HIV-infected adults with CD4+ T-cell counts < 200 cells/microl. METHODS: Between October 1995 and April 2006, we screened Ugandans aged 16 or older at enrollment into an open cohort. We analysed highly active anti-retroviral therapy (HAART)-naïve HIV-infected patients with WHO stages 1-3 and complete data in a secondary cross-sectional study. Low BMI was a BMI < 18.5 kg/m(2). Anaemia was a haemoglobin level < 11 or 12 g/dl among women and men respectively. RESULTS: Among 2892 HAART-naïve patients, the median age was 32 years. 71% were women, 54% had WHO stage 3 AIDS, 34% had anaemia, 16% had a low BMI and 43% had CD4+ T-cell counts < 200 cells/microl. WHO stage 3 compared to combined WHO stages 1 and 2 had a sensitivity (95% CI) of 70% (67, 72) and a specificity of 57% (55, 60) respectively to detect CD4+ T-cell counts < 200 cells/microl. Anaemia compared to normal haemoglobin had sensitivity (95% CI) of 47% (44, 50) and a specificity of 76% (74, 78). Low BMI compared to normal BMI had sensitivity (95% CI) of 23% (20, 25) and a specificity of 89% (87, 90) against CD4+ T-cell counts < 200 cells/microl. CONCLUSION: Only WHO stage 3 had reasonably high sensitivity in detecting CD4+ T-cell counts below 200 cells/microl in this setting. Targeted low-cost CD4 testing strategies are urgently needed to detect patients eligible for HAART in rural Africa and other resource-limited settings.

Septicaemia in a population-based HIV clinical cohort in rural Uganda, 1996-2007: incidence, aetiology, antimicrobial drug resistance and impact of antiretroviral therapy.

OBJECTIVES: To describe the incidence and aetiology of septicaemia, and antimicrobial drug resistance in HIV-infected and uninfected individuals, and the impact of antiretroviral therapy (ART) on septicaemia. METHODS: Between 1996 and 2007, we followed up a rural population-based cohort of HIV-infected and uninfected participants. The aetiology and incidence of septicaemia, and antimicrobial drug resistances were determined. ART became available in 2004, and its impact on the incidence of septicaemia was examined. RESULTS: The overall septicaemia incidence (per 1000 pyrs) was 32.4 (95% CI 26.2-40.6) but was only 2.6 (95% CI 1.3-6.2) in HIV-negative patients and 67.1 (95% CI 53.4-85.4) in HIV-positive patients not on ART. Among those on ART, the overall incidence was 71.5 (95% CI 47.1-114.3), although it was 121.4 (95%CI 77.9-200.4) in the first year on ART and 37.4 (95%CI 18.9-85.2) in the subsequent period. Septicaemia incidence was significantly associated with lower CD4 counts. The commonest isolates were Streptococcus pneumoniae (SPN, n = 68) and Non-typhi salmonellae (NTS, n = 42). Most SPN isolates were susceptible to ceftriaxone and erythromycin, while resistance to cotrimoxazole and penicillin was common. All NTS isolates were susceptible to ciprofloxacin, but resistance to cotrimoxazole and chloramphenicol was common. CONCLUSIONS: Septicaemia incidence was higher in HIV-infected than in HIV-uninfected participants, and it remained high for some time among those who started ART. Starting ART earlier at higher CD4 counts is likely to lead to lower septicaemia incidence. Both SPN and NTS, the commonest isolates, were resistant to most commonly available antimicrobials. Blood culture laboratory surveillance systems to monitor antibiotic susceptibility and inform treatment guidelines are needed in Africa.

Do behavioural differences help to explain variations in HIV prevalence in adolescents in sub-Saharan Africa?

OBJECTIVE: To compare adolescent risk factors for HIV infection in two countries with high adolescent HIV prevalence and two lower prevalence countries with the aim of identifying risk factors that may help explain differences in adolescent HIV prevalence. METHODS: Data were available from two nationally representative surveys (South Africa, Zimbabwe), two behavioural intervention trials (Tanzania, Zimbabwe) and one population-based cohort (Uganda). Data on variables known or postulated to be risk factors for HIV infection were compared. RESULTS: Few risk behaviours were markedly more common in the high HIV prevalence populations. Risk factors more common in high HIV prevalence settings were genital ulcers and discharge, and women were more likely to report older male partners. DISCUSSION: Age mixing may be an important determinate of HIV prevalence in adolescents. Potential reasons for the general lack of association between other adolescent risk factors and adolescent HIV prevalence include adult HIV prevalence, misreported behaviour, different survey methods and other unmeasured adolescent behaviours. If adult factors dominate adolescent HIV risk, it would help explain the failure of behavioural interventions targeted at adolescents and suggests future interventions should include adults.

The experience of "medicine companions" to support adherence to antiretroviral therapy: quantitative and qualitative data from a trial population in Uganda.

Good adherence is critical for antiretroviral therapy (ART) in sub-Saharan Africa. We report on the characteristics of medicine companions (MCs) chosen by Ugandan patients enrolling on ART, and on how MCs were chosen, and what roles they played. Baseline data on MCs of 1453 participants in a randomized controlled trial comparing facility and home-based delivery of ART in Jinja, Uganda were analyzed. Textual data on experience with MCs were collected through in-depth interviews among a subsample of 40 trial participants equally divided by sex and trial arm. Significantly more women (71%) than men (29%) were recruited. The majority (75%) of women participants were either widowed (51%) or separated or divorced (24%), whereas most of the men (66%) were married. Women were most likely to choose a child as their MC while men were most likely to choose their spouse; 41% of women chose an MC under 21 compared with only 14% of men. Only 31% of married women chose their husband, compared with 66% of married men who chose their wife. Qualitative interviews suggested MCs proved useful for reminding and other supportive tasks in the first three months but were generally less essential by six months and beyond. Convenience, reliability, and trust were key considerations in choosing an MC. Children provided the only alternative for many unmarried women, but even some married women felt children made more reliable MCs than husbands. Participants who had disclosed their serostatus usually received drug-taking reminders from multiple household members. One participant in the qualitative sample with poor family relations delayed starting treatment due to unwillingness to identify an MC. MCs were generally welcome and useful in supporting early adherence. However, disclosure to an MC should not be a condition of obtaining treatment.

Is sexual risk taking behaviour changing in rural south-west Uganda? Behaviour trends in a rural population cohort 1993-2006.

OBJECTIVE: To describe sexual behaviour trends in a rural Ugandan cohort in the context of an evolving HIV epidemic, 1993-2006. METHODS: Sexual behaviour data were collected annually from a population cohort in which HIV serological surveys were also conducted. Behaviour trends were determined using survival analysis and logistic regression. Trends are reported based on the years in which the respective indicators were collected. RESULTS: Between 1993 and 2006, median age at first sex increased from 16.7 years to 18.2 years among 17-20-year-old girls and from 18.5 years to 19.9 years among boys. Both sexes reported a dip in age at sexual debut between 1998 and 2001. One or more casual partners in the past 12 months among men rose from 11.6% in 1997 to 12.7% in 2004 and then declined to 10.2% in 2006. Among women it increased from 1.4% in 1997 to 3.7% in 2004 and then reduced to 1.4% in 2006. The rise in casual partners between 1997 and 2004 was driven mainly by older age groups. Trends in condom use with casual partners varied by age, increasing among those aged 35+ years, declining in the middle age groups and presenting a dip and then a rise in the youngest aged group (13-19 years). CONCLUSION: Among youth, risky behaviour declined but increased in the late 1990s/early 2000s. Among those aged 35+ years, condom use rose but casual partners also rose. Several indicators portrayed a temporary increase in risk taking behaviour from 1998 to 2002.

Community engagement in health research: two decades of experience from a research project on HIV in rural Uganda.

OBJECTIVES: To describe how a research project on HIV epidemiology in rural Uganda has engaged the community over the past two decades, describing activities, opportunities and challenges that have arisen. METHOD: The review draws on the experience of the authors as investigators involved in the project at various times since its inception in 1989, and on project documents and peer-reviewed publications. RESULTS: The project attracts community interest, participation and support mostly through community groups. The three main areas of activity are: health care and promotion, HIV/AIDS prevention and care, and community development aimed at poverty reduction. Key opportunities arise from the long-term joint commitment of the project and the community over nearly 20 years, and the potential to accommodate research beyond HIV. Challenges arise from participation fatigue, countered by innovations for the community and investment in capacity development for staff, and from the need to balance community development expectations and the project focus on HIV research. CONCLUSIONS: Judged by criteria of longevity, acceptance, and scientific output, community engagement in this HIV research project in rural Uganda has been successful. The experience from this project contributes to the collective documentation and analysis of case studies from various research projects in developing countries which identify good practices from multiple stakeholder perspectives.

Association between active GB virus-C (hepatitis G) infection and HIV-1 disease in Uganda.

Although not linked to a disease, GB virus-C viraemia has been associated with an improved prognosis in HIV-1-co-infected individuals. Most studies have been conducted on men (men who have sex with men or injection drug users) infected with HIV-1 subtype B, whereas here we report on both male and female subjects from rural Uganda, predominantly infected via the heterosexual route with HIV-1 subtypes A and D. In a longitudinal study of 272 participants, 47 were GBV-C positive and 181 negative, as determined by reverse transcription-polymerase chain reaction, in both of two plasma samples taken a median of 5.0 years apart. The remainder either acquired (25) or cleared (19) infection. Multilevel regression analyses and Cox survival analyses revealed that participants chronically infected with GBV-C had a slower decline in CD4(+) T cells (P<0.001) and increased survival time (P=0.041) compared with GBV-C RNA-negative, HIV-positive adults. We show that the association between active GBV-C co-infection and improved survival of HIV-1-infected adults is not restricted to HIV subtype B, but is also observed in both males and females infected with HIV subtypes A and D.

Model-based evaluation of single-round mass treatment of sexually transmitted diseases for HIV control in a rural African population.

OBJECTIVES: To compare the impact of single-round mass treatment of sexually transmitted diseases (STD), sustained syndromic treatment and their combination on the incidence of HIV in rural Africa. METHODS: We studied the effects of STD interventions by stochastic simulation using the model STDSIM. Parameters were fitted using data from a trial of improved STD treatment services in Mwanza, Tanzania. Effectiveness was assessed by comparing the prevalences of gonorrhoea, chlamydia, syphilis and chancroid, and the incidence of HIV, in the general adult population in simulations with and without intervention. RESULTS: Single-round mass treatment was projected to achieve an immediate, substantial reduction in STD prevalences, which would return to baseline levels over 5-10 years. The effect on syphilis was somewhat larger if participants cured of latent syphilis were not immediately susceptible to re-infection. At 80% coverage, the model projected a reduction in cumulative HIV incidence over 2 years of 36%. A similar impact was achieved if treatment of syphilis was excluded from the intervention or confined to those in the infectious stages. In comparison with sustained syndromic treatment, single-round mass treatment had a greater short-term impact on HIV (36 versus 30% over 2 years), but a smaller long-term impact (24 versus 62% over 10 years). Mass treatment combined with improved treatment services led to a rapid and sustained fall in HIV incidence (57% over 2 years; 70% over 10 years). CONCLUSIONS: In populations in which STD control can reduce HIV incidence, mass treatment may, in the short run, have an impact comparable to sustained syndromic treatment. Mass treatment combined with sustained syndromic treatment may be particularly effective.

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

OBJECTIVE: To 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. METHODS: The 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. RESULTS: Results of the baseline survey of the cohort of over 12,000 adults in 12 communities are presented in a companion paper. CONCLUSION: There 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.

PIP: Given the likelihood that other sexually transmitted diseases (STDs) act as co-factors in the sexual transmission of human immunodeficiency virus (HIV) in Africa, programs to improve the diagnosis and treatment of STDs may be an important component of acquired immunodeficiency syndrome (AIDS) control. To evaluate the impact of such a strategy, a randomized trial involving the integration of improved STD treatment into the existing primary health care system was initiated in Tanzania's Mwanza Region in late 1991. Program components include health personnel training, development of syndromic treatment algorithms, regular drug deliveries, supervisory visits to health facilities, and establishment of an STD reference clinic. The region's rural population was targeted due to its low yet increasing HIV prevalence, high prevalence of STDs, and amenability to a community-randomized study design. Twelve communities, defined as the population served by a health center and its satellite dispensaries, were selected for the trial and formed into six matched pairs on the basis of geographic area, HIV prevalence, and pre-existing levels of STD attendance. One set of communities was randomly selected to receive the intervention during the first year of the trial; the others will receive services at the end of the two-year follow-up period. Program outcome--defined as the incidence of HIV infection in intervention and control communities during the two-year follow-up--will be measured in a cohort of 12,000 randomly selected adults (1000 per community). This sample size offers a high power of detecting a halving of the annual HIV incidence rate from 1% to 0.5%.

A community trial of the impact of improved sexually transmitted disease treatment on the HIV epidemic in rural Tanzania: 2. Baseline survey results.

OBJECTIVES: To determine baseline HIV prevalence in a trial of improved sexually transmitted disease (STD) treatment, and to investigate risk factors for HIV. To assess comparability of intervention and comparison communities with respect to HIV/STD prevalence and risk factors. To assess adequacy of sample size. SETTING: Twelve communities in Mwanza Region, Tanzania: one matched pair of roadside communities, four pairs of rural communities, and one pair of island communities. One community from each pair was randomly allocated to receive the STD intervention following the baseline survey. METHODS: Approximately 1000 adults aged 15-54 years were randomly sampled from each community. Subjects were interviewed, and HIV and syphilis serology performed. Men with a positive leucocyte esterase dipstick test on urine, or reporting a current STD, were tested for urethral infections. RESULTS: A total of 12,534 adults were enrolled. Baseline HIV prevalences were 7.7% (roadside), 3.8% (rural) and 1.8% (islands). Associations were observed with marital status, injections, education, travel, history of STD and syphilis serology. Prevalence was higher in circumcised men, but not significantly after adjusting for confounders. Intervention and comparison communities were similar in the prevalence of HIV (3.8 versus 4.4%), active syphilis (8.7 versus 8.2%), and most recorded risk factors. Within-pair variability in HIV prevalence was close to the value assumed for sample size calculations. CONCLUSIONS: The trial cohort was successfully established. Comparability of intervention and comparison communities at baseline was confirmed for most factors. Matching appears to have achieved a trial of adequate sample size. The apparent lack of a protective effect of male circumcision contrasts with other studies in Africa.

PIP: To measure the impact of a sexually transmitted disease (STD) treatment program on the incidence of human immunodeficiency virus (HIV) in Zimbabwe's Mwanza Region, a pre-intervention baseline survey was conducted. Included in the survey were approximately 1000 randomly selected adults from each of the six intervention communities (defined as the population served by a health center and its satellite dispensaries) and six matched comparison communities. Overall HIV seroprevalence was 4.1% (3.7% in men and 4.4% in women), with a range of 1.6-8.6% and no significant differences between intervention and control communities. Peak prevalences for both sexes were found in the 25-34 year age groups and in roadside communities. The following factors were associated with an increased likelihood of HIV infection: separation, divorce, or widowhood; multiple injections in the preceding year; educational achievement of at least Standard 4; travel out of the district in the prior year; history of genital ulcers or discharge; and past or present infection with syphilis. HIV prevalence was significantly higher in circumcised men, but not when adjustment was made for other risk factors. Syphilis prevalence ranged from a low of 4.2% in island communities to a high of 11.1% in roadside communities. The baseline survey indicates that intervention and control populations are generally comparable, and that the goal of locating a study area with a relatively low incidence of HIV and high rates of other STDs has been achieved.

Syndromic treatment of sexually transmitted diseases reduces the proportion of incident HIV infections attributable to these diseases in rural Tanzania.

OBJECTIVES: To compare the proportion of HIV seroconversions attributable to other sexually transmitted diseases in the intervention and comparison arms of the Mwanza sexually transmitted diseases (STD) intervention trial. DESIGN: Case-control study of 96 cases of HIV seroconversion and 974 HIV-negative controls, nested within the Mwanza trial cohort. METHODS: Data on reported STD symptoms during 2 years of follow-up, and serological evidence of recent syphilis, were used to obtain odds ratios (ORs) for HIV seroconversion, adjusted for community, age, marital status, sex partners and travel. Population-attributable fractions (PAF) of HIV seroconversions associated with these STD exposures were calculated separately for the intervention and comparison arms, and for men and women. RESULTS: In men in the comparison arm, adjusted ORs for ulcers (14.8), discharge (3.3), any symptom (4.1) and any STD (4.0) were highly significant. There were no significant associations between HIV incidence and STD exposures in the intervention arm. The PAF were consistently higher in the comparison arm than the intervention arm. In men, the PAF for any STD was 39.6% [95% confidence interval (CI), 12.4-58.3)] in the comparison arm but only 12.0% (CI, 0.0-35.9) in the intervention arm. The PAF for women were lower than for men. CONCLUSIONS: These are minimal PAF estimates and they do not account for STD effects on HIV infectiousness. Nevertheless, a substantial proportion of new HIV infections in men in the comparison arm were attributable to STD. Lower PAF in the intervention arm than in the comparison arm for men provide further evidence of the role of STD cofactors in HIV transmission, supporting the hypothesis that the Mwanza intervention reduced the duration of symptomatic STD, thus reducing the HIV risk associated with such STD.

HIV-associated adult mortality in a rural Tanzanian population.

OBJECTIVE: To measure HIV-associated adult mortality in a rural population in Tanzania. To record the signs and symptoms associated with deaths of HIV-positive adults. DESIGN: Prospective cohort study conducted in the context of a randomized controlled trial to evaluate the impact of a sexually transmitted disease treatment programme. METHODS: A cohort consisting of a random sample of 12501 adults aged 15-54 years was recruited from 12 rural communities in Mwanza region, Tanzania in 1991/1992. Baseline HIV prevalence was 4.0%. The cohort was followed up after 2 years to record mortality according to baseline HIV status. A verbal autopsy questionnaire was administered for each of the deaths reported. RESULTS: A total of 196 deaths were recorded, of which 73 (37%) occurred in HIV-positive individuals. Mortality rates per 1000 person-years were 6.0 in HIV-negatives and 93.5 in HIV-positives. The age-adjusted mortality rate ratio was 15.68 (95% confidence interval, 11.18-21.03). The proportion of adult deaths attributed to HIV infection was 35% overall and 53% in those aged 20-29 years. Verbal autopsies showed that HIV-positive deaths were significantly associated with fever, rash, weight loss, anaemia, cough, chest pain, abdominal pain and headache, but the specificity of individual symptoms was low. The World Health Organization clinical case definition of AIDS was satisfied for only 13 deaths, of which seven were HIV-positive at baseline. Only seven respondents reported that the death was associated with HIV or AIDS. CONCLUSIONS: This study confirms the strong association of HIV infection and mortality in rural Africa, with an annual death rate in adult seropositives of over 9%. In this rural population with a relatively low HIV prevalence of 4%, HIV has increased overall adult mortality by more than 50%. Signs and symptoms associated with HIV deaths were non-specific, and the population seemed largely unaware of the contribution of HIV to mortality, an important obstacle to prevention efforts.

PIP: A cohort of 12,501 adults aged 15-54 years was randomly selected from 12 rural communities in Mwanza region, Tanzania, in 1991-92 and followed for 2 years to assess the contribution of HIV/AIDS to mortality in the region. HIV seroprevalence in the sample was 4% at baseline. 73 of the 196 deaths recorded over the period occurred among HIV-positive individuals. Mortality rates per 1000 person-years were 6.0 among the HIV-seronegative and 93.5 among the HIV-seropositive. The age-adjusted mortality rate ratio was 15.68 overall. 35% of overall mortality was attributed to HIV infection, 53% among those age 20-29 years. Verbal autopsies administered for each death reported showed that HIV-positive deaths were significantly associated with fever, rash, weight loss, anemia, cough, chest pain, abdominal pain, and headache. The specificity of individual symptoms, however, was low. The World Health Organization clinical case definition of AIDS was satisfied for only 13 deaths, of which seven were HIV-positive at baseline. HIV/AIDS was mentioned during the verbal autopsy interview by only seven respondents as being associated with a given death.

Sentinel surveillance for HIV-1 infection: how representative are blood donors, outpatients with fever, anaemia, or sexually transmitted diseases, and antenatal clinic attenders in Mwanza Region, Tanzania?

OBJECTIVE: To assess the validity of extrapolation from sentinel data by comparing the HIV-1 prevalence of various sentinel groups with that of the general population in Mwanza Region, Tanzania. METHODS: In a population survey, 4161 individuals were selected in a stratified random cluster sample. Sentinel groups (all in the age group 15-54 years) included blood donors (n = 1090); patients examined at district hospitals for the presence of malaria parasites (n = 1488), anaemia (n = 1339), or syphilis (n = 33); and antenatal clinic attenders (n = 1193). The HIV-1 serostatus of individuals selected from the population survey was tested using enzyme-linked immunosorbent assay (ELISA) and Western blot; 51% of the blood donors were tested using HIVCHEK, and all others using ELISA. HIV-1 prevalence was standardized for age, sex, and urban/non-urban location. RESULTS: HIV-1 prevalence (standardized by age, sex, and residence) in Mwanza Region was 4.0% (3.0% in non-urban areas and 11.3% in town). The standardized HIV-1 prevalences in the sentinel groups were: blood donors, 4.5%; patients with fever, 11.6%; patients with anaemia, 8.9%; urban sexually transmitted disease patients, 27.1%; urban antenatal clinic attenders, 11.8%. The crude prevalence in blood donors was 6.0%. CONCLUSION: Blood donors who are related to blood recipients appear to be a representative sentinel group in this region, provided that data are standardized for age, sex, and urban/non-urban location. Patients with fever and antenatal clinic attenders may reflect trends, but data from patients with fever markedly overestimate, and data from antenatal clinic attenders underestimate, population HIV-1 prevalence. Because self-selection of blood donors may become more pronounced, this comparison should be repeated later or elsewhere, should the opportunity arise.

PIP: When full-scale surveys of HIV-1 prevalence are not possible, sentinel surveillance is conducted at specific sites with specific population groups. In this study, 2 sentinel groups have been monitored since 1989 in the Mwanza region on the shores of Lake Victoria in Tanzania. The groups included blood donors in all hospitals of the region an prenatal clinic attenders in Mwanza Municipality. Also considered specifically for this study were outpatients from all 6 district hospitals (including 2 roadside hospitals) who had given blood samples. Population survey data on HIV prevalence between August 1990 and February 1991 were available for reference use. The sample included 1090 blood donors aged 15-54 years, 800 outpatients from district hospitals, and 1193 pregnant women attending a prenatal clinic. Blood donors (49%) were tested with enzyme immunosorbent assay (ELISA). Outpatients provided capillary blood samples collected on filter paper, of which 4605 samples were further tested with ELISA. 1866 were excluded because of age, inadequate samples, or missing data. The results of the comparison of HIV prevalence in the sentinel group and in the population survey showed that in both groups HIV-1 infection was more common in women, particularly those 15-34 years old, than in men, who were particularly affected in the 25-44 year old group. Blood donors, who were mostly male and related to the recipient, showed a crude HIV-1 prevalence of 6% (65 out of 1090). Rates were standardized, and standardized prevalence ratios were calculated. In the general population in both surveys, prevalence was 4.5%. Men had a higher prevalence in non-urban areas. Among outpatients with fever who gave blood for anemia, the crude prevalence was 9% (115 out of 1339). Prevalence was higher in the sentinel group. Of the 33 sexually transmitted diseases outpatients screened for syphilis, 33% (11) were seropositive. Prenatal clinic attenders had a HIV-prevalence of 12% (138 out of 1193).

Sentinel surveillance for HIV-1 among pregnant women in a developing country: 3 years' experience and comparison with a population serosurvey.

OBJECTIVES: To establish unlinked, anonymous sentinel surveillance for HIV-1 among pregnant women attending an antenatal clinic, to determine age-specific seroprevalences, to monitor trends and to compare seroprevalence with that detected by a population serosurvey. To establish the sustainability and costs of surveillance. DESIGN: Sentinel surveillance for HIV through serial collection of unlinked, anonymous seroprevalence data from antenatal care; comparison of sentinel data with those from a population serosurvey; financial and general audit of the sentinel surveillance. SETTING: A community antenatal clinic in a large urban centre, Mwanza Municipality, Tanzania, eastern Africa, between October 1988 and September 1991. PATIENTS: Pregnant women attending for antenatal care. MAIN OUTCOME MEASURE: Age-specific HIV-1 seroprevalences, trends over time, difference from age-specific population seroprevalences, sustainability and costs. RESULTS: Overall HIV-1 seroprevalence was 11.5% (95% confidence interval, 10.5-12.4); differences in age-specific prevalences were not significant. There was no clear evidence of change in seroprevalence over the study period in any age group, although there was some indication of a rise in some age groups in 1988-1989. Sentinel surveillance among pregnant women may have significantly underestimated population HIV-1 seroprevalence for women under the age of 35 years. HIV-1 surveillance proved feasible and sustainable. Additional recurrent costs were US$1.7 per specimen for unlinked anonymous testing and US$0.57 per woman for syphilis screening. CONCLUSIONS: HIV-1 seroprevalence did not change significantly over 3 years, probably implying a substantial incidence of HIV-1 infection. In this setting seroprevalence in pregnant women may have underestimated population seroprevalence in women aged under 35 years. With modest inputs and good organization unlinked anonymous HIV-1 sentinel surveillance of pregnant women can be introduced and sustained in an African setting. This may usefully be carried out in conjunction with syphilis screening.

PIP: Between October 1989 and September 1991, health workers took blood samples from pregnant women attending Makongoro Clinic in Mwanza, Tanzania, to determine age-specific HIV-1 seroprevalence in pregnant women, trends over 3 years, and the feasibility, sustainability, and costs of HIV monitoring and to compare age-specific seroprevalences in pregnant women with those of all women. Overall, HIV prevalence among pregnant women stood at 11.5%. Even though the younger and older age groups had lower seroprevalence than the other age groups (10% for those under 20 years old, 11% for 30-34 year olds, and 8.3% for = or 35 year olds vs. 12.8% for 25-29 year olds and 12.3% for 20-24 year olds), the differences were not significant. HIV seroprevalence appeared to increase in 1988-89 in most age groups, but no significant evidence of a linear trend occurred during the study period for any age group. This absence of significant change in HIV seroprevalence over 3 years likely indicated a considerable HIV incidence. The population serosurvey revealed an HIV seroprevalence of 15.1% among the general adult female population, suggesting that the sentinel surveillance among pregnant women could have greatly underestimated population HIV seroprevalence for women under 35 years old (p = .02). Sentinel surveillance improved the clinic's ability to detect anemia and reintroduced syphilis screening. Unlinked anonymous testing resulted in additional recurrent costs of S$1.7/specimen. Syphilis screening added recurrent costs of US$0.57/woman. These findings indicated that health workers in Africa can successfully introduce and maintain anonymous HIV-1 sentinel surveillance of pregnant women and this can be accomplished with concurrent syphilis screening.