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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

In the first preventative human immunodeficiency virus (HIV) vaccine study to be carried out in Africa, 40 HIV-seronegative Ugandan volunteers were randomly assigned to receive a canarypox vector containing HIV-1 clade B (env and gag-pro) antigens (ALVAC-HIV; n = 20), control vector containing the rabies virus glycoprotein G gene (n = 10), or saline placebo (n = 10). Cytotoxic T lymphocyte activity against target cells expressing clade A, B, and D antigens was assessed using standard chromium-release and confirmatory interferon-gamma enzyme-linked immunospot (ELISPOT) assays. Neutralizing antibody responses to cell line-adapted strains and primary isolates in all 3 clades were also tested. Twenty percent of vaccine recipients generated detectable cytolytic responses to either Gag or Env, and 45% had vaccine-induced HIV-specific CD8(+) T cell responses, as measured by the ELISPOT assay. In contrast, only 5% of the control group had vaccine-specific responses. Neutralizing antibodies against primary and laboratory-adapted HIV-1 clade B strains were seen in 10% and 15% of vaccine recipients, respectively, but responses against clades A and D were not detected. Although the immunogenicity of this clade B-based vaccine was low, ALVAC-HIV elicited CD8(+) T cell responses with detectable cross-activity against clade A and D antigens in a significant proportion of vaccine recipients.

Summary Background Little is known about how to implement antiretroviral treatment programmes in resource-limited countries. We assessed the UNAIDS/Uganda Ministry of Health HIV Drug Access Initiative—one of the first pilot antiretroviral programmes in Africa—in which patients paid for their medications at negotiated reduced prices. Methods We assessed patients' clinical and laboratory information from August, 1998, to July, 2000, from three of the five accredited treatment centres in Uganda, and tested a subset of specimens for phenotypic drug resistance. Findings 912 patients presented for care at five treatment centres. We assessed the care of 476 patients at three centres, of whom 399 started antiretroviral therapy. 204 (51%) received highly active antiretroviral therapy (HAART), 189 (47%) dual nucleoside reverse transcriptase inhibitors (2NRTI), and six (2%) NRTI monotherapy. Median baseline CD4 cell counts were 73 cells/μL (IQR 15–187); viral load was 193 817 copies/mL (37 013–651 716). The probability of remaining alive and in care was 0·63 (95% CI 0·58–0·67) at 6 months and 0·49 (0·43–0·55) at 1 year. Patients receiving HAART had greater virological responses than those receiving 2NRTI. Cox's proportional hazards models adjusted for viral load and regimen showed that a CD4 cell count of less than 50 cells/μL ( vs 50 cells/μL or more) was strongly associated with death (hazard ratio 2·93 [1·51–5·68], p=0·001). Among 82 patients with a viral load of more than 1000 copies/mL more than 90 days into therapy, phenotypic resistance to NRTIs was found for 47 (57%): 29 of 37 (78%) who never received HAART versus 18 of 45 (40%) who received HAART (p=0·0005). Interpretation This pilot programme successfully expanded access to antiretroviral drugs in Uganda. Identification and treatment of patients earlier in the course of their illness and increased use of HAART could improve probability of survival and decrease drug resistance.

Pleural tuberculosis (TB) was employed as a model to study T cell apoptosis at sites of active Mycobacterium tuberculosis (MTB) infection in human immunodeficiency virus (HIV)-coinfected (HIV/TB) patients and patients infected with TB alone. Apoptosis in blood and in pleural fluid mononuclear cells and cytokine immunoreactivities in plasma and in pleural fluid were evaluated. T cells were expanded at the site of MTB infection, irrespective of HIV status. Apoptosis of CD4 and non-CD4 T cells in the pleural space occurred in both HIV/TB and TB. Interferon (IFN)-gamma levels were increased in pleural fluid, compared with plasma. Spontaneous apoptosis correlated with specific loss of MTB-reactive, IFN-gamma-producing pleural T cells. Immunoreactivities of molecules potentially involved in apoptosis, such as tumor necrosis factor-alpha, Fas-ligand, and Fas, were increased in pleural fluid, compared with plasma. These data suggest that continued exposure of immunoreactive cells to MTB at sites of infection may initiate a vicious cycle in which immune activation and loss of antigen-responsive T cells occur concomitantly, thus favoring persistence of MTB infection.

The first prophylactic human immunodeficiency virus type 1 (HIV-1) vaccine trial in Africa, with a clade B immunogen, is currently under way in Uganda, in a region where clades A and D are endemic. The use of a B clade vaccine is based on anticipated cross-recognition of endemic strains of HIV-1 in Uganda, but, in fact, little is known about the cytotoxic T lymphocyte (CTL) responses in that region. Seventeen HIV-1-infected volunteers from Kampala, Uganda, were studied to determine the immune responses elicited by natural infection with local HIV-1 strains. Despite the presence of broad cross-clade recognition, the CTL responses to the infecting viral clade were highest in most people. Recognition of nonendemic clade B antigens was similar to that of the coendemic local clade, and, in some instances, cross-recognition of clade B was greater. Nevertheless, the degree of cross-clade cellular responses we observed lends justification to the use of clade B-based immunogens in the current phase 1 vaccine trial in Uganda.

CXCR4, a coreceptor for T cell (T)-tropic HIV-1, is preferentially expressed on naive T cells, whereas CCR5, a coreceptor for macrophage (M)-tropic HIV-1, is preferentially expressed on previously activated memory T cells and the Th1 subset of CD4+ T cells. CCR4 is preferentially expressed on the Th2 subset of CD4+ T cells. A cross-sectional flow cytometry study was conducted to evaluate the expression of CXCR4, CCR5, and CCR4 on the peripheral blood CD4+ T cells from African HIV-1-infected and uninfected Ugandan adults. The plasma viral load in HIV-1-infected individuals was also examined. Upregulation of CCR4 and CCR5 expression but no decrease in CXCR4 expression on CD4+ T cells were obtained in peripheral blood from African adults with progression of the disease. Plasma HIV-1 viremia significantly and inversely correlated with the peripheral CD4+ T cell count but did not correlate with the degree of CCR4 and CCR5 expression on the peripheral CD4+ T cells in HIV-1-infected individuals. Our present data suggest an increase in percentage of activated memory CD4+ T cells in the advanced stage of HIV-1 infection among African adults. There was no evidence of a Th1 to Th2 shift in terms of chemokine receptor expression profile with advancing disease in the peripheral blood of these subjects.

Mycobacterium tuberculosis (MTB)-induced T cell responses are depressed in peripheral blood mononuclear cells of persons with newly diagnosed pulmonary tuberculosis (TB), and levels of interferon (IFN)-gamma remain low even after completion of antituberculous therapy. Loss of MTB-reactive T cells through apoptotic mechanisms could account for this prolonged T cell hyporesponsiveness. T cell apoptosis was studied in TB patients and healthy control subjects. Both spontaneous and MTB-induced apoptosis (in CD4 and non-CD4 T cells) from TB patients was increased when compared with healthy control subjects, whereas coculture with control antigen (candida) had no effect on T cell apoptosis in either group of study subjects. An inverse correlation existed between increased MTB-induced T cell apoptosis and IFN-gamma and interleukin (IL)-2 immunoreactivities. Successful antituberculous chemotherapy resulted in a 50% reduction in both spontaneous and MTB-induced apoptosis, which coincided with 3- and 8-fold increases in levels of MTB-stimulated IL-2 and IFN-gamma, respectively. These data indicate that apoptotic pathways are operant during active MTB infection and may contribute to deletion of MTB-reactive T cells and the immunopathogenesis of this disease.

Despite current efforts to combat HIV/AIDS through behavioural change, ingrained socio-cultural practices such as widow inheritance in south-western Uganda has not changed. Low education, unemployment, dowry, widows' socioeconomic demands and the inheritor's greed for the deceased's wealth, influence widow inheritance. Voluntary counselling and testing is needed for the widows and their inheritors; formal dowry should be removed from marriage and widow inheritance stripped of its sexual component.

1and new resources have become available. 2 Although expense, feasibility, and effective delivery remain formidable barriers, public health and technical agencies have started to re-examine their assumptions and to discuss use of antiretroviral drugs in poorly resourced environments. 3 Data lending support to use of antiretroviral treatment in poorly resourced regions are few. Even in well resourced countries, clinicians still do not have evidencebased answers to simple issues such as: when to start antiretrovirals, how to monitor their therapeutic and toxic effects, and in what sequence to use them. Answers to such issues are greatly needed to speed up delivery of antiretrovirals to the populations most in need of treatment. As a working group convened by the Rockefeller Foundation, we outline an urgent research agenda that attempts to identify gaps in knowledge and to prioritise issues affecting access to treatment for the tens of millions of adults living with HIV/AIDS in poorly resourced regions. Answers to many of these questions will also benefit patients in well resourced regions. We do not address the equally important issues about use of antiretrovirals in infants and children and of prevention of mother-to-child transmission. When should antiretroviral treatment be started? Use of antiretroviral treatment is straightforward in adults with symptomatic HIV-1 disease or CD4+ counts of 200 or less, 4–6 but whether asymptomatic adults with more

Objective: Design: Setting: Results: Conclusions: This study demonstrates that abstinence and use of condoms on their own may not be enough for HIV prevention among PLWHAs who desire children. Additional methods such as use of ART to reduce HIV infectiousness and sperm washing are needed. In the past 12 months 227 (60%) of the PLWHAs were sexually active. Of the sexually active 42 (19%) never used a condom, and 92 (40%) used condoms inconsistently, thus 134 (35%) of PLWHAs engaged in high risk sex. Two hundred and sixty five (70%) said that PLWHAs can have healthy children and 115 (30%) desired more children with 21 (10%) of the women in the reproductive age group reporting a pregnancy and 22 (17%) of the men reporting having caused a pregnancy. Only three (7%) of the pregnancies were unplanned. Desire for more children was a strong independent predictor of engaging in high risk sex (Adjusted Odds Ratio 2.44, 95% CI 1.35-4.42). Joint Clinical Research Centre, Kampala Uganda. Participants: Three hundred and eighty PLWHAs, 50% of whom had initiated antiretro viral therapy (ART). Main outcome measures: PLWHAs answered questions regarding sexual behaviour, number and type of sexual partners, symptoms of sexually transmitted infections, having been pregnant or causing a pregnancy, social demographic characteristics, consumption of alcohol, having biological children, desire for more children and use of condoms. A cross sectional study. To identify sexual behaviour and reproductive health needs of people living with HIV/AIDS (PLWHAs).

BACKGROUND: We sought to investigate renal function in previously untreated symptomatic human immunodeficiency virus (HIV)-infected adults with CD4(+) cell counts of or =60 but or =30 but

Objectives Polymorphisms in the cytochrome P450 (CYP) 2B6 gene have been shown to influence nevirapine plasma concentrations in HIV-infected European Caucasians. Although nevirapine is used extensively in Africa, the influence of CYP2B6 genotype on nevirapine exposure has not been assessed in this population. We aimed to determine the influence of CYP2B6 genotype at position 516 on nevirapine trough concentrations in HIV-infected patients in Kampala, Uganda. Additional polymorphisms in the CYP and multidrug resistance protein-1 (MDR-1) genes were also assessed for their impact on nevirapine concentrations. Methods The following genotypes were determined in all subjects using polymerase chain reaction–restriction fragment length polymorphism: CYP2B6 G516T, MDR-1 C3435T and G2677T, CYP3A4*1B and CYP3A5*3. Nevirapine plasma concentrations were determined using high-performance liquid chromatography in 23 HIV-infected patients who were generally healthy and had been taking nevirapine 200 mg twice daily for at least 14 days. Analysis of variance with post hoc testing was used to compare nevirapine concentrations among CYP2B6 genotype groups. Results The median nevirapine trough concentration in individuals homozygous for the variant allele (TT) was 7607 ng/mL vs 4181 and 5559 ng/mL for GG and GT individuals, respectively (GG vs TT median ratio=1.82; P=0.011). The mean ratio for TT vs GG individuals (95% confidence interval) was 1.51 (1.18, 1.84). No associations were observed between the other polymorphisms studied and nevirapine concentrations. Conclusions CYP2B6 G516T significantly influenced nevirapine trough concentrations in HIV-infected patients in Uganda. Additional studies in larger patient populations are necessary to further define the potential clinical impact of these preliminary findings.

OBJECTIVE: To measure nevirapine elimination in African adults undertaking a structured treatment interruption (STI) in the DART trial. DESIGN: Cohort (16 women, 5 men; median weight 61 kg) within a randomized trial of management strategies. METHODS: Plasma nevirapine was measured by validated high performance liquid chromatography at 0,1,2,3 and 4 weeks after stopping the drug in a subset of patients undertaking an STI. All patients continued lamivudine plus zidovudine/stavudine for a further 7 days. RESULTS: Two patients with no or low plasma nevirapine concentration at baseline were excluded. Geometric mean plasma concentration when nevirapine was stopped in the remaining 19 patients was 6421 ng/ml (range, 3724-9473). Nevirapine was detected in 15/18 (83%) patients at 1 week, and 5/19 (26%) patients at 2 weeks but was not found any samples collected after 2 weeks. Only one patient had > 100 ng/ml (limit of quantification) at 2 weeks (415 ng/ml, female). The median times to reach thresholds of 200, 100 and 20 ng/ml (limit of detection) were estimated to be 7.6 [interquartile range (IQR), 7.0-10.1], 9.3 (IQR, 8.7-13.0) and 13.2 (IQR, 12.3-18.4) days, respectively, with 3/19 (16%) and 14/19 (74%) estimated to have reached < 20 ng/ml by 7 and 14 days, respectively. CONCLUSION: Although elimination of nevirapine was faster than previously published after a single dose, the data suggest that an additional staggered period of 7-10 days with dual nucleotide reverse transcriptase inhibitor cover is necessary for African patients discontinuing nevirapine.

Tuberculosis (TB) enhances HIV-1 replication and the progression to AIDS in dually infected patients. We employed pleural TB as a model to understand the interaction of the host with HIV-1 during active TB, at sites of Mycobacterium tuberculosis (MTB) infection. HIV-1 replication was enhanced both in the cellular (pleural compared with blood mononuclear cells) and acellular (pleural fluid compared with plasma) compartments of the pleural space. Several potential mechanisms for expansion of HIV-1 in situ were found, including augmentation in expression of tumor necrosis factor (TNF)-alpha and the HIV-1 noninhibitory beta-chemokine (MCP-1), low presence of HIV-1 inhibitory beta-chemokines (MIP-1 alpha, MIP-1 beta, and RANTES [regulated on activation, normal T expressed and secreted]), and upregulation in expression of the HIV-1 coreceptor, CCR5, by pleural fluid mononuclear cells. Thus, at sites of MTB infection, conditions are propitious both for transcriptional activation of HIV-1 in latently infected mononuclear cells, and facilitation of viral infection of newly recruited cells. These mechanisms may contribute to enhanced viral burden and dissemination during TB infection.

SUMMARYActive TB in HIV-1-infected subjects is associated with increased HIV-1-related immunodeficiency and mortality. We assessed plasma viral load in HIV-1-infected patients with pulmonary TB (HIV/TB) and non-TB symptomatic HIV-1-infected patients (HIV). HIV-1 load was higher in HIV/TB compared with HIV at higher CD4 counts (> 500/μl) (P < 0·01), but not at lower CD4 counts (< 500/μl). We also evaluated the status of HIV-1 gene expression in peripheral blood mononuclear cells (PBMC) and serum from HIV/TB and CD4-matched healthy HIV-infected patients (HIV/C) by reverse transcriptase-polymerase chain reaction over a range of CD4 (> 900/μl to

To describe the clinical response to antituberculosis therapy in HIV-1 disease, 49 HIV-1 positive Ugandan adults (mean age 29.4 years; 68% men) with active pulmonary tuberculosis (PTB) were studied in a trial of rifampicin containing short-course antituberculosisis regimens. At presentation, 18 patients were PPD non-reactors (PPD skin test induration2mm), ten patients (20%) had non-cavitary lung disease. The mean CD4 lymphocyte count at presentation was 339/microliters (+/- SD 275). Among patients with abnormal baseline clinical values, the median time to resolution of fever, weight gain of 10%, increase of haemoglobin to 10g/dl and of Karnofsky performance score (KPS) to 80 occurred before sputum smear and culture conversion. Short-term survival was associated with: baseline lymphocytes1200/microliters, (Odds ratio (OR) 17.5), CD4+ lymphocytes200/microliters (OR 9.8), cavitary lung disease, (OR 0.6), atypical chest radiograph, (OR 6.7), and PPD non-reactivity, (OR 13.5), PPD non-reactivity and non-cavitary disease were associated with significantly lower CD4 lymphocyte counts. Affordable serial measurements parallel the response to therapy and predict survival in HIV-associated PTB.Tuberculosis (TB) is the most often seen and serious opportunistic infection in HIV-1-infected individuals in developing countries. Infection with HIV-1 predisposes individuals to TB, both progressive primary and reactivation disease. To describe the clinical response to anti-TB therapy in HIV-1 disease, 49 HIV-1-positive Ugandan adults of mean age 29.4 years with active pulmonary TB (PTB) were studied in a trial of rifampicin containing short-course anti-TB regimens. At presentation, 18 patients were PPD skin test nonreactive, and 39 had cavitary lung disease. The mean CD4 lymphocyte count at presentation was 339/mcl. Among patients with abnormal baseline clinical values, the median time to resolution of fever, weight gain of 10%, increase of hemoglobin to 10 g/dl, and Karnofsky performance score (KPS) to 80 occurred before sputum smear and culture conversion. Short-term survival was associated with baseline lymphocytes of less than 1200/mcl, cavitary lung disease, atypical chest radiograph, and PPD nonreactivity. PPD nonreactivity and noncavitary disease were associated with significantly lower CD4 lymphocyte counts. Study findings demonstrate that the careful monitoring of clinical symptoms and simple, inexpensive, and widely available laboratory markers permit the satisfactory evaluation of early clinical response to anti-TB therapy in HIV-1-infected patients with pulmonary TB.

Infection with the human immunodeficiency virus (HIV) greatly increases the risk of reactivation tuberculosis. We evaluated the safety and efficacy of three preventive-therapy regimens in a setting where exposure to tuberculosis is common.We performed a randomized, placebo-controlled trial in 2736 HIV-infected adults recruited in Kampala, Uganda. Subjects with positive tuberculin skin tests (induration,or =5 mm) with purified protein derivative (PPD) were randomly assigned to one of four regimens: placebo (464 subjects), isoniazid daily for six months (536), isoniazid and rifampin daily for three months (556), or isoniazid, rifampin, and pyrazinamide daily for three months (462). Subjects with anergy (0 mm induration in reaction to PPD and candida antigens) were randomly assigned to receive either placebo (323 subjects) or six months of isoniazid (395). The medications were dispensed monthly and were self-administered.Among the PPD-positive subjects, the incidence of tuberculosis in the three groups that received preventive therapy was lower than the rate in the placebo group (P=0.002 by the log-rank test). The relative risk of tuberculosis with isoniazid alone, as compared with placebo, was 0.33 (95 percent confidence interval, 0.14 to 0.77); with isoniazid and rifampin, 0.40 (0.18 to 0.86); and with isoniazid, rifampin, and pyrazinamide, 0.51 (0.24 to 1.08). Among the subjects with anergy, the relative risk of tuberculosis was 0.83 (95 percent confidence interval, 0.34 to 2.04) with isoniazid as compared with placebo. Side effects were more common with the multidrug regimens, and particularly with the regimen containing pyrazinamide. Survival did not differ among the groups, but the subjects with anergy had a higher mortality rate than the PPD-positive subjects.A six-month course of isoniazid confers short-term protection against tuberculosis among PPD-positive, HIV-infected adults. Multidrug regimens with isoniazid and rifampin taken for three months also reduce the risk of tuberculosis.

Between July and October 1993, 570 19- to 22-year-old volunteers were screened for HIV-1, with a resulting seroprevalence rate of 18.3% (95% CI: 14.0%, 22.6%). A cohort of 249 HIV-1-noninfected military recruits in the Ugandan Peoples' Defense Forces was followed prospectively for up to 18 months to document rates of HIV-1 seroprevalence, seroconversion, and knowledge and attitudes related to vaccine acceptability. The HIV-1 seroincidence rate was 3.56 per 100 person-years (95% CI: 1.49, 5.62) over 309 person-years of observation. At the 3- and 12-month visits, subjects were interviewed on issues of acceptance and knowledge about vaccines, including anti-HIV vaccines in particular. More than 90% believe that HIV vaccines will not cause HIV infection, and if offered, 88% report that they would take the vaccine if they were not already infected. Nonvaccine prevention methods were considered less reliable; monogamy and condom use were considered effective by only 33.5% and 69.3% of the cohort respectively. After completing the vaccine acceptability questionnaire at the 12-month visit, subjects were offered an approved polyvalent meningococcal vaccine as an indicator of general vaccine acceptance. All subjects reported receiving at least one previous vaccination, and 95% willingly accepted the meningococcal vaccination. The Ugandan military is a stable population at substantial risk for HIV-1 infection and may be a suitable population for vaccine efficacy trials.

Demand for treatment with antiretroviral (ARV) drugs increased in Africa in the wake of the July 1996 AIDS Conference in Vancouver, during which combination ARV treatment including protease inhibitors was shown to dramatically improve the quality and length of life for people with AIDS. However, 1 year after the Vancouver Conference, ARV drugs remain scarce in Africa. Most people treated with antivirals in Africa try to acquire their drugs by ordering them through friends outside Africa or by travelling to Europe or the US. ARV treatment is becoming more complicated and treatment strategies change rapidly. The imbalance between the high price of ARV treatment and the scarcity of resources, competing health care needs, and the continent's weak health care systems all impede the introduction of large-scale ARV treatment in Africa. Nonetheless, if neither governments, organizations, nor industry provide ARV, HIV-infected people, their families, and physicians may try to obtain them through informal channels. Poor quality ARV may then be procured, sold at extremely high prices, and inadequately administered. Indications for ARV treatment, indications of ARV as preventive therapy, and requirements to introduce ARV are discussed.

This pilot study was conducted at the Joint Clinical Research Centre (JCRC) in Kampala, Uganda, where tuberculosis (TB) is an epidemic health problem aggravated by the HIV-1 pandemic.To evaluate the feasibility of a larger phase III trial utilizing rifabutin as a substitute for rifampicin in short-course therapy for pulmonary TB.Single-blind randomized trial in 50 patients with new onset smear- and culture-positive pulmonary tuberculosis and HIV-1 infection. Comparison of daily, intermittently supervised 6-month treatment regimens of rifabutin versus rifampicin, together with isoniazid, ethambutol and pyrazinamide.Rifabutin- and rifampicin-containing regimens had comparable efficiency. However, rifabutin-treated patients had significantly more rapid clearance of acid-fast bacilli from sputum at 2 months (P0.05, Fisher exact test) and over the entire study period (P0.05, logrank test) than rifampicin-treated patients. The presence of cavitary disease was associated with a longer sputum conversion time for patients treated with either regimen. No major adverse events requiring dosage reduction or withdrawal of any study medication were seen in either treatment group. Mean absolute peripheral blood CD4 T lymphocyte counts increased by 28% from week 0 to week 12 in all subjects (334-427/microliters, respectively). An unexpected finding was the isolation of Mycobacterium africanum from 49% of the sputum cultures. This is the first report indicating a high prevalence of M. africanum in human TB in Uganda.Short-course antituberculosis regimens containing rifabutin or rifampicin are both safe and efficacious in the treatment of HIV-1 associated tuberculosis. Rifabutin-containing regimens were associated with earlier sputum smear and culture conversion.

Synthetic peptides comprising the predicted principal neutralizing determinant (PND) in new African and North American HIV-1 clones were tested in ELISA for reactivity with ninety six serum samples from asymptomatic donors in six selected localities in Uganda. Irrespective of the geographical origin of the samples, the majority of the test sera cross-reacted at high intensities with the peptides derived from the North American clone, BRT3.6 (Group B), the Ugandan clone, CUG045, (Group C), and the Romanian clone, FRMA (Group F). The frequency of reactivity of the peptides from BRT3.6, CUG045, and FRMA were within the ranges of 57-100%, 50-100%, and 57-100%, respectively, for the sera collected from these disparate localities. In contrast to these findings, the V3 peptides derived from the other Ugandan isolates showed a more restricted pattern of reactivity with the same serum samples: AUG06c (1-63%), DUG23c (2%), and DUG044 (38-87%). The results from ELISA inhibition assay indicated that the V3 peptide from BRT 3.6, CUG045, and FRMA express closely related antigenic specificities quite distinct from those in AUG06c and DUG044. The residues comprising the PND in BRT 3.6, CUG045, and FRMA appear to be well conserved in the HIV-1 subtypes prevalent in the selected Ugandan locales.In Uganda, health workers collected serum samples from 96 asymptomatic HIV-1 infected blood donors in Ishaka and Mbarara (southwest), Kisenyi and Kampala (central), and Lugazi and Jinja (east) so researchers working in a biochemistry laboratory at The City University of New York could describe the relative reactivity of the V3 loop from HIV-1 subtypes A, B, C, D, and F, as well as study the antigenic relationships within the PND encoded in the divergent HIV-1 subtypes. Regardless of geographic origin, the V3 peptides from most of the sera (at least 50%) collected in Uganda cross-reacted at high frequencies with the peptides derived from the novel North American clone (BRT3.6), the Ugandan clone (CUG045), and the Romanian clone (FRMA). The frequency of reactivity of these peptides with the test sera ranged from 57% to 100% for BRT3.6, from 50% to 100% for CUG045, and from 57% to 100% for FRMA. The V3 peptides from other Ugandan isolates (AUG06c, DUG044, and DUG23c) were less reactive with the same serum samples than BRT3.6, CUG045, and FRMA: 1-63%, 38-87%, and 2%, respectively. This finding suggests that the antigenic determinants expressed in AUG06c, DUG044, and DUG23c may not represent the PND encoded in most HIV-1 strains afflicting the Ugandan communities. The V3 peptides from BRT3.6, CUG045, and FRMA express closely related antigenic specificities altogether different from those in AUG06c and DUG044. The HIV-1 subtypes present in the selected Ugandan sites appear to effectively conserve the residues making up the PND in BRT3.6, CUG045, and FRMA.

Summary 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 μL. 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 μL [−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.