Objective To evaluate the use of routine laboratory monitoring in terms of clinical outcomes among patients receiving antiretroviral therapy (ART) in Uganda. Design Randomised clinical trial Setting A home based ART programme in rural Uganda. Participants All participants were people with HIV who were members of the AIDS Support Organisation. Participants had CD4 cell counts <250 cells × 106/L or World Health Organization stage 3 or 4 disease. Interventions Participants were randomised to one of three different monitoring arms: a viral load arm (clinical monitoring, quarterly CD4 counts, and viral load measurements), CD4 arm (clinical monitoring and CD4 counts), or clinical arm (clinical monitoring alone). Main outcome measures Serious morbidity (newly diagnosed AIDS defining illness) and mortality. Results 1094 participants started ART; median CD4 count at baseline was 129 cells × 106/L. Median follow-up was three years. In total, 126 participants died (12%), 148 (14%) experienced new AIDS defining illnesses, and 61(6%) experienced virological failure, defined as two consecutive viral loads >500 copies/mL occurring more than three months after the start of ART. After adjustment for age, sex, baseline CD4 count, viral load, and body mass index, the rate of new AIDS defining events or death was higher in the clinical arm than the viral load arm (adjusted hazard ratio 1.83, P=0.002) or the CD4 arm (1.49, P=0.032). There was no significant difference between the CD4 arm and the viral load arm (1.23, P=0.31). Conclusion In patients receiving ART for HIV infection in Uganda, routine laboratory monitoring is associated with improved health and survival compared with clinical monitoring alone. Trial registration Clinical Trials NCT00119093.

CD4+ T lymphocyte (CD4) cell count testing is the standard method for determining eligibility for antiretroviral therapy (ART), but is not widely available in sub-Saharan Africa. Total lymphocyte counts (TLCs) have not proven sufficiently accurate in identifying subjects with low CD4 counts. We developed clinical algorithms using TLCs, hemoglobin (Hb), and body mass index (BMI) to identify patients who require ART.

Background:We evaluated clinical toxicity in HIV-infected persons receiving antiretroviral therapy (ART) in Uganda. Methods:From May 2003 through December 2004, adults with a CD4 cell count ≤250 cells/μL or World Health Organization stage 3/4 HIV disease were prescribed ART. We calculated probabilities for time to toxicity and single-drug substitution as well as multivariate-adjusted hazard ratios for development of toxicity. Results:ART (stavudine plus lamivudine with nevirapine [96%] or efavirenz [4%]) was prescribed for 1029 adults, contributing 11,268 person-months of observation. Toxicities developed in 543 instances in 411 (40%) patients (incidence rate = 4.47/100 person-months): 36% peripheral neuropathy (9% severe); 6% rash (2% severe); 2% hypersensitivity reaction; ≤0.5% acute hepatitis, anemia, acute pancreatitis, or lactic acidosis; and 13% other. Probabilities of remaining free from any toxicity at 6, 12, and 18 months were 0.76, 0.59, and 0.47 and from any severe toxicity at 6, 12, and 18 months were 0.92, 0.86, and 0.85, respectively. For 217 patients (21%), 222 single-drug substitutions were made, mostly because of peripheral neuropathy or rash. Conclusions:Clinical toxicities were common, but no patients discontinued ART because of toxicity. The most common toxicities, peripheral neuropathy and rash, were managed with single-drug substitutions. In resource-limited settings, toxicity from ART regimens containing stavudine or nevirapine is manageable but more tolerable regimens are needed.

BACKGROUND:Tuberculosis (TB) is the leading cause of death among people with HIV in sub-Saharan Africa. Expanding access to antiretroviral therapy (ART) may reduce the burden of TB, but to what extent is unknown. METHODS:In a study of 1044 adults who initiated home-based ART in Tororo, Uganda between 1 May 2003 and 30 June 2005, participants were screened for active TB at baseline and then monitored at weekly home visits. Participants with TB at baseline or follow-up were compared with those without TB to determine factors associated with mortality in those with TB. RESULTS:At baseline, 75 (7.2%) subjects had TB and a total of 53 (5.5%) were diagnosed with TB over a median of 1.4 years of follow-up (3.90 cases/100 person years). Cumulative mortality was 17.9/100 person-years for those with TB and 3.8/100 person-years for those without TB (P < 0.001). Mortality was associated with low baseline CD4 cell counts [relative hazard (RH), 0.99 per 1 cell/microl increase; P = 0.03] and marginally associated with a body mass index <or= 18 (RH, 2.04; P = 0.10) and increasing age (RH, 1.04 per year; P = 0.11). TB incidence and TB-associated mortality were highest within the first 6 months of ART and declined to 52% and 61% of expected values, respectively, from months 7 to 18 after ART initiation. CONCLUSION:TB remains an important cause of illness and death in patients receiving ART in Uganda. However, both appear to decline markedly, after 6 months of ART.

Summary Objective To evaluate the association between a positive serum cryptococcal antigen (CRAG) test at baseline and mortality during the first 12 weeks on antiretroviral therapy (ART). Cryptococcal meningitis is a leading cause of HIV‐related mortality in Africa, but current guidelines do not advocate CRAG testing as a screening tool. Methods Between May 2003 and December 2004, we enrolled HIV‐1 infected individuals into a study of ART monitoring in rural Uganda. CRAG testing was conducted retrospectively on stored pre‐ART serum samples of participants whose baseline CD4 cell count was <100 cells/ μ l and who were without symptoms suggestive of disseminated cryptococcal disease at enrolment. Results Of 377 participants, 5.8% had serum CRAG titre ≥1:2. Of these, 23% died during follow‐up. Controlling for CD4 cell count, HIV‐1 viral load, anaemia, active tuberculosis and body mass index, relative risk of death during follow‐up among those with asymptomatic cryptococcal antigenemia at baseline was 6.6 [95% confidence interval (CI) 1.86–23.61, P = 0.0036]. The population attributable risk for mortality associated with a positive CRAG at baseline was 18% (CI 2–33%), similar to that associated with active tuberculosis (19%, CI 1–36%). Conclusion Asymptomatic cryptococcal antigenemia independently predicts death during the first 12 weeks of ART among individuals with advanced HIV disease in rural Uganda. Routine screening and provision of azole antifungal therapy prior to or simultaneous with the start of ART should be evaluated for the potential to prevent mortality in this population.

Background: Home-based antiretroviral therapy (ART) care in Africa has expanded; but social outcomes of home-based ART programs are unknown.Methods: Social experiences of participants in an antiretroviral therapy program involving weekly home visits in Uganda were assessed through interviews at enrollment and after 3 months and analyzed using generalized estimating equations.Results: Of 654 participants, 72% were women; median baseline CD4 cell-count was 123 cells/mu L. At follow-up, participants were more likely to report community support (adjusted odds ratio [OR] 2.10, 95% confidence interval [CI]: 1.46 to 3.03, P < 0.001), family support (OR 2.65, CI: 2.01 to 3.49, P < 0.001), and relationship strengthening (OR 2.10, Cl: 1.46 to 3.03, P = 0.001) than at baseline; 84% attributed these experiences to antiretroviral therapy program participation. There was no change in incidence of negative experiences (P = 0.3). Forty-six percent of women reported a history of partner abuse, but abuse rates 3 months before and after program initiation were low (1% vs. 2%, OR 3.20, Cl: 0.94 to 10.9, P = 0.063). Of five women who reported abuse associated with program participation, all had history of domestic violence. Of all participants reporting outcomes associated with antiretroviral therapy program participation at follow-up, 464 (79%) had only positive experiences, 35 (6%) had both positive and negative experiences, and < 1% had only negative experiences.Conclusions: Participation in a home-based antiretroviral therapy program was associated with multiple positive social outcomes.

BACKGROUND:HIV-1 and malaria are common infections in Africa, and cause substantial morbidity and mortality. HIV infection has been associated with an increased incidence of malaria, and more severe disease. Our aim was to assess the effect of antiretroviral treatment (ART) on the frequency of clinical malaria in people with HIV, and to measure the additive effects of co-trimoxazole (trimethoprim and sulfamethoxazole) prophylaxis, ART, and insecticide-treated bednets. METHODS:In 2001, we enrolled 466 HIV-infected individuals aged 18 years or older in Uganda in a prospective cohort study that provided co-trimoxazole prophylaxis to 399 participants after 5 months of no intervention. In 2003, we enrolled 138 survivors from the initial study, and 897 new participants from the same community, to take antiretroviral therapy (ART) in addition to co-trimoxazole prophylaxis. The ART was in most cases a combination of stavudine, lamivudine, and nevirapine or efavirenz. In 2004, we also gave participants insecticide-treated bednets. Households were visited weekly by study staff to record fever, illness, or death in the preceding 7 days. In cases of reported fever in the previous 2 days, we took blood to test for malaria parasites. We compared the frequency of clinical malaria, adjusting for CD4-cell count, age, sex, and season. FINDINGS:1035 individuals were given co-trimoxazole and ART (median age 38 years, 74% female, and median CD4-cell count 124 cells/microL); 985 of these, plus four new participants, received co-trimoxazole, ART, and bednets. There were 166 cases of clinical malaria in the study. Compared with a baseline malaria incidence of 50.8 episodes per 100 person-years, co-trimoxazole prophylaxis was associated with 9.0 episodes per 100 person-years (adjusted incidence rate ratio [IRR] 0.24, 95% CI 0.15-0.38); ART and co-trimoxazole with 3.5 episodes per 100 person-years (0.08, 0.04-0.17); and co-trimoxazole, ART, and bednets with 2.1 episodes per 100 person-years (0.05, 0.03-0.08). Malaria incidence was significantly lower during ART and co-trimoxazole than during co-trimoxazole alone (IRR 0.36 [95% CI 0.18-0.74], p=0.0056). INTERPRETATION:A combination of co-trimoxazole, antiretroviral therapy, and insecticide-treated bednets substantially reduced the frequency of malaria in adults with HIV.

Despite the importance of mental illness and the high prevalence of HIV in Africa, few studies have documented depressive symptoms among HIV-infected persons in Africa. We assessed factors associated with depression among HIV-infected adults undergoing anti-retroviral eligibility screening in Eastern Uganda. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale (CES-D). Univariate and multiple regression analyses were conducted to identify socio-demographic characteristics and disease-related factors associated with depression. Among 1017 HIV-infected participants assessed for depression, 47% (476/1017) reported depressive symptoms (CES-D ≥ 23). Adjusting for age, gender, education, and source of income, patients with CD4 counts <50 cells/μl were more likely to be depressed (odds ratio 2.34, 95% confidence interval, 1.39–3.93, P = 0.001). Women, participants >50 years, and those without an income source were more likely to be depressed. Depression was common among HIV-infected persons in rural Uganda and was associated with low CD4 cell counts. Appropriate screening and treatment for depression should be considered for comprehensive HIV care.

Background:The impact of antiretroviral therapy (ART) on sexual risk behavior and HIV transmission among HIV-infected persons in Africa is unknown. Objective:To assess changes in risky sexual behavior and estimated HIV transmission from HIV-infected adults after 6 months of ART. Design and methods:A prospective cohort study was performed in rural Uganda. Between May 2003 and December 2004 a total of 926 HIV-infected adults were enrolled and followed in a home-based ART program that included prevention counselling, voluntary counseling and testing (VCT) for cohabitating partners and condom provision. At baseline and follow-up, participants’ HIV plasma viral load and partner-specific sexual behaviors were assessed. Risky sex was defined as inconsistent or no condom use with partners of HIV-negative or unknown serostatus in the previous 3 months. The rates of risky sex were compared using a Poisson regression model and transmission risk per partner was estimated, based on established viral load-specific transmission rates. Results:Six months after initiating ART, risky sexual behavior reduced by 70% [adjusted risk ratio, 0.3; 95% confidence interval (CI), 0.2–0.7; P = 0.0017]. Over 85% of risky sexual acts occurred within married couples. At baseline, median viral load among those reporting risky sex was 122 500 copies/ml, and at follow-up, < 50 copies/ml. Estimated risk of HIV transmission from cohort members declined by 98%, from 45.7 to 0.9 per 1000 person years. Conclusions:Providing ART, prevention counseling, and partner VCT was associated with reduced sexual risk behavior and estimated risk of HIV transmission among HIV-infected Ugandan adults during the first 6 months of therapy. Integrated ART and prevention programs may reduce HIV transmission in Africa.

INTRODUCTION:Systematic efforts to identify HIV-infected members and HIV-discordant couples in households of individuals taking antiretroviral therapy (ART) could theoretically reduce HIV transmission and improve ART adherence. METHODS:We enrolled HIV-infected clients of an AIDS support organization in a randomized evaluation of different ART monitoring regimens that offered home-based ART care to them and their clinically eligible household members. At baseline, counselors visited participants' homes and offered voluntary counseling and testing (VCT) to all household members. We assessed uptake, HIV prevalence, HIV discordance, and rate of ART eligibility. RESULTS:Of the 2373 household members, 2348 (99%) accepted VCT. HIV prevalence among household members was 7.5% and varied by age with 9.5% among children aged 0 to 5 years, 2.9% among persons aged 6 to 24 years, and 37.1% among adults aged 25 to 44 years. Of the household members with HIV, 74% had never been previously tested, and 39% of these were clinically eligible for ART. Of the 120 spouses of ART patients that were tested for HIV, 52 (43%) were HIV negative, and of these, 99% had not been previously tested. CONCLUSIONS:Provision of home-based VCT to household members of people initiating ART was well accepted and resulted in the detection of a large number of previously undiagnosed HIV infections and HIV-discordant relationships.

Background Poverty and limited health services in rural Africa present barriers to adherence to antiretroviral therapy that necessitate innovative options other than facility-based methods for delivery and monitoring of such therapy. We assessed adherence to antiretroviral therapy in a cohort of HIV-infected people in a home-based AIDS care programme that provides the therapy and other AIDS care, prevention, and support services in rural Uganda.Methods HIV-infected individuals with advanced HIV disease or a CD4-cell count of less than 250 cells per mu L were eligible for antiretroviral therapy. Adherence interventions included group education, personal adherence plans developed with trained counsellors, a medicine companion, and weekly home delivery of antiretroviral therapy by trained lay field officers. We analysed factors associated with pill count adherence (PCA) of less than 95%, medication possession ratio (MPR) of less than 95%, and HIV viral load of 1000 copies per mL or more at 6 months (second quarter) and 12 months (fourth quarter) of follow-up.Findings 987 adults who had received no previous antiretroviral therapy (median CD4-cell count 124 cells per mu L, median viral load 217 000 copies per mL) were enrolled between July, 2003, and May, 2004. PICA of less than 95% was calculated for 0.7-2.6% of participants in any quarter and MPR of less than 95% for 3.3-11.1%. Viral load was below 1000 copies per mL for 894 (98%) of 913 participants in the second quarter and for 860 (96%) of 894 of participants in the fourth quarter. In separate multivariate models, viral load of at least 1000 copies per mL was associated with both PICA below 95% (second quarter odds ratio 10.6 [95% CI 2.45-45.7]; fourth quarter 14.5 [2.51-83.6]) and MPR less than 95% (second quarter 9.44 [3.40-26.2]; fourth quarter 10.5 [4.22-25.9]).Interpretation Good adherence and response to antiretroviral therapy can be achieved in a home-based AIDS care Programme in a resource-limited rural African setting. Health-care systems must continue to implement, evaluate, and modify interventions to overcome barriers to comprehensive AIDS care programmes, especially the barriers to adherence with antiretroviral therapy.

Nevirapine is a standard component of first-line antiretroviral therapy (ART) regimens for the majority of HIV-infected individuals living in Africa [1], and is likely to remain in common use with the widespread availability of low-cost, fixed-dose combination formulations. As global ART expansion proceeds [1,2], hundreds of thousands more patients will initiate therapy with nevirapine. Although nevirapine is generally well tolerated, hepatological and dermatological toxicities have been documented [3]. Hepatotoxicity is rare and more likely to occur among women with CD4 cell counts greater than 250 cells/μl or men with CD4 cell counts greater than 400 cells/μl [4]. Minor dermatological reactions that do not necessitate drug discontinuation occur commonly during the first 6 weeks of treatment. Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis are rare and appear to occur across a wide range of CD4 cell counts [5]. We report two cases of SJS among first-degree relatives receiving stavudine, lamivudine, and nevirapine as part of a home-based HIV/AIDS care programme in rural Uganda. Case 1 A 31-year-old antiretroviral-naive woman with a baseline CD4 cell count of 195 cells/μl was initiated on stavudine, lamivudine, and nevirapine in March 2004. On day 14 of therapy, while receiving induction doses of 200 mg nevirapine per day, she was admitted to the local district hospital with a 5-day history of a generalized skin rash with bullae and mucosal ulcerations, diagnosed clinically as SJS. After a one-month hospitalization consisting of supportive treatment with intravenous fluids, steroids, and antimicrobial agents, she was discharged. ART was re-initiated with stavudine, lamivudine, and lopinavir/ritonavir. The patient continues to do well in August 2004. Case 2 The 8-year-old son of case 1, with a baseline CD4 cell count of 279 cells/μl and symptomatic AIDS was initiated on the same ART regimen as his mother in May 2004. Nevirapine was given at a dose of 4 mg/kg once a day for 14 days, then 4 mg/kg twice a day. On day 28 of ART, he was admitted to the district hospital with a 2-day history of a bullous rash, mucosal ulcerations, and fever diagnosed as SJS. Despite initial improvement with supportive therapy and steroids, on day 25 of hospitalization he developed fever, restlessness, and altered mental status, and died of probable sepsis. We are unaware of any previous reports of familial clustering of nevirapine hypersensitivity. A recent investigation associated HLA-DRB1*01 with an increased probability of nevirapine hepatoxicity and rash [6]. An increased risk of severe cutaneous reactions has been reported among siblings given other drugs, and genetic factors may increase the risk of adverse reactions [7]. For example, carbamazepine-associated dermatological reactions have been strongly associated with HLA-B*1502 among Han Chinese individuals; sensitivity of this allele for severe toxic epidermal necrolysis and SJS was 100%; specificity was 97% [8]. No specific guidelines currently exist regarding the use of nevirapine in first-degree relatives of individuals who have experienced nevirapine-associated adverse reactions. In Europe and North America, the experience with pediatric antiretroviral management remains limited compared with anticipated numbers of children needing ART in Africa. Very few parent–child pairs have received nevirapine, except in the context of the prevention of mother-to-child transmission interventions, in which infants normally receive only a single dose. To date, there have been no cases of serious hepatotoxicity, SJS, or other severe adverse events reported for single-dose nevirapine used for the prevention of mother-to-child transmission, based on clinical trial data available for over 3000 mother–infant pairs [9–12]. The scenario we report here will become more common as ART expansion continues, especially if these medications are provided to all clinically eligible family members of patients receiving care. Additional research is needed to investigate the degree to which serious nevirapine toxicities can be predicted on the basis of genetic factors or previous toxicity in first-degree relatives.