Compliance with tuberculosis preventive therapy in a randomized placebo-controlled trial in 2736 HIV-infected Ugandans was measured using urinary isoniazid metabolite testing, clinic attendance, and self-report. Overall, 77% of urine tests were positive, subjects kept 85% of their scheduled visits while on therapy, and 69% reportedly never forgot to take their medication. Different strategies were used for constructing three composite compliance indices in active arms: (1) an unweighted index of the summed scores on scaled compliance measures; (2) a weighted index using weights obtained from a survey of experts on tuberculosis; and (3) a statistically weighted index using principal components analysis. Composite indices were evaluated for reliability, validity, and practical utility. Understanding of the regimen, study arm, subsequent follow-up, tuberculosis status, and urine spot-check result were associated with composite compliance scores. The unweighted index in this study performed as well as the weighted indices.

SETTING: TB Treatment Centre, Kampala, Uganda.OBJECTIVE: To evaluate the impact of human immunodeficiency virus (HIV) co-infection on the bacteriologic and radiographic presentation of pulmonary tuberculosis (TB) in Uganda, a nation with high rates of Mycobacterium tuberculosis and HIV infection.DESIGN: To compare baseline characteristics among HIV-infected and non-HIV-infected adults with initial newly-diagnosed episodes of culture-confirmed pulmonary TB screened for participation in a randomized prospective TB treatment trial.RESULTS: Negative and paucibacillary (very scanty or scanty) sputum acid fast bacilli (AFB) smears were more frequent in HIV-infected patients presenting with pulmonary TB (P = 0.007). More HIV-infected individuals also had sputum cultures that required 7-8 weeks incubation until positivity than non-HIV-infected patients (P < 0.01). Lower lung field and diffuse pulmonary infiltrates were more frequent among HN-infected patients. Rates of atypical X-ray presentations and cavitary disease were comparable between HIV-seropositive and -seronegative patients; however, atypical disease was more frequent in HIV-infected patients with small tuberculin reactions or tuberculin anergy(PPD = 0 mm).CONCLUSION: HIV co-infection was associated with a higher frequency of negative and paucibacillary sputum AFB smears. The differences in the diagnostic yields of microscopy and culture between HIV-infected and non-HIV-infected individuals were small and do not, in our opinion, significantly affect the utility of these important diagnostic tests in developing countries. Examining more than one sputum specimen and monitoring cultured specimens for a full 8 weeks may assist in optimizing the diagnostic yield. Upper lobe infiltrates and cavitary disease are still the most frequent radiographic presentations of pulmonary TB in HIV-infected and non-HIV-infected adults in countries with a high prevalence of TB.

SETTING:Prospective randomised clinical trial comparing the safety and efficacy of rifampicin- and thiacetazone-containing regimens in human immunodeficiency virus (HIV)-infected adults with pulmonary tuberculosis (TB) at the National Tuberculosis Treatment Centre, Kampala, Uganda.OBJECTIVE:To assess demographic, clinical and laboratory risk factors associated with toxicity during treatment with streptomycin, thiacetazone and isoniazid (STH) of HIV-1 infected adults with pulmonary TB.DESIGN:Nested case-control study of all subjects randomized to the STH treatment arm. Baseline demographic, clinical, microbiological, hematological and radiographic characteristics were compared between subjects who developed and those who did not develop adverse drug reactions (ADR).RESULTS:Of the 90 subjects randomized to STH, 13 developed ADR yielding an incidence rate of 19.6 events per 100 person years of observation (PYO). Eleven of the 13 ADR were cutaneous hypersensitivity reactions, including one fatal case of Stevens-Johnson syndrome. Eight of 13 patients who developed ADR were tuberculin anergic, compared to 12 of 77 patients who did not develop ADR (P < 0.001). An absolute lymphocyte count below 2000 cells/mm3 was also associated with ADR (P = 0.02).CONCLUSION:Initial anergy to tuberculin and lymphocytopenia, markers of advanced HIV infection and immunosuppression, were associated with increased risk for adverse drug reactions during STH chemotherapy.

SETTING:A study conducted by the Uganda-Case Western Reserve University Research Collaboration in Kampala, Uganda, a country with high incidence rates of tuberculosis (TB) and human immunodeficiency virus type 1 (HIV-1) infection.OBJECTIVE:To assess clinical, microbiologic and radiographic factors associated with risk for relapse in HIV-infected adults treated for initial episodes of pulmonary TB.DESIGN:Nested case-control study within a randomized prospective clinical trial comparing the safety and efficacy of thiacetazone- and rifampicin-containing regimens for TB treatment in HIV-infected adults.RESULTS:The analysis was based on 119 patients who completed therapy. Median follow-up for all subjects was 22.3 months. Ten patients relapsed a median of 12.7 months after the end of therapy; seven of these were initially treated with the thiacetazone (T)-containing regimen. Each relapse case was matched to four controls by length of follow-up after initial TB treatment. In a univariate analysis risk for relapse was associated with treatment with the T-containing regimen (OR = 4.2, P = 0.08), age > or = 30 yrs (OR = 2.9, P = 0.16), and irregular compliance (OR = 3.6, P = 0.1). Baseline anergy on Mantoux tuberculin skin testing, cavitary disease, radiographic extent of disease and sputum bacillary burden, two month culture negativity, and residual cavitary disease at the end of treatment did not differ between relapses and controls.CONCLUSION:Older HIV-1 infected patients, those with poor treatment compliance, and those being treated with T-containing regimens, may be at increased risk for relapse after TB treatment and require closer post-treatment surveillance. Risk for relapse in HIV-infected adults with pulmonary TB after treatment with a nine month rifampicin-containing regimen was low (3.1 per 100 person-years observation) compared with those treated with a thiacetazone-containing regimen (10.1 per 100 person-years observation).

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'0 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.

Infection with the human immunodeficiency virus (HIV) has changed both the epidemiology and natural history of tuberculosis. Despite a generally good response to effective antituberculous therapy, the prognosis remains poor. The objective of this analysis was to determine the independent predictors of survival in HIV-infected Ugandan adults with smear-positive pulmonary tuberculosis. A total of 191 HIV-infected Ugandan adults with smear-positive pulmonary tuberculosis were enrolled into a clinical trial of chemotherapy for tuberculosis. The subjects received either rifampin, isoniazid, and pyrazinamide for two months, followed by rifampin and isoniazid for six months (n = 101) or streptomycin, thiacetazone, and isoniazid for two months followed by thiacetazone and isoniazid for eight months (n = 90). After standard measurements were made at baseline, the group was followed at regular intervals for a mean of 16 months to determine survival. During the course of follow-up, 82 (43%) of the patients died, six within the first month of therapy. The one-year survival proportion was 68% with an estimated median survival of 26 months and did not differ according to treatment regimen. The hazard for death was biphasic, high early in the course of therapy, and then again after about one year. After controlling for the treatment regimen, four independent predictors of survival were found: anergy to purified protein derivative, atypical chest roentgenogram, previous HIV-related condition, and lymphopenia. In this cohort of Ugandan adults, four simple and inexpensive predictors of survival were found. These factors suggest that the degree of immunosuppression was a major determinant of survival.

Setting: Tuberculosis Treatment Center, Kampala, Uganda.Objective: HIV-1 affects outcome in pulmonary tuberculosis (TB). Immune mechanisms triggered by Mycobacterium tuberculosis may lead to increased HIV expression and accelerated disease progression. This study was conducted to correlate serum levels of markers of immune activation with mortality and drug toxicity in HIV + TB.Design: Substudy of a randomized clinical trial of streptomycin-thiacetazone-isoniazid (STH) vs. rifampin-isoniazid-pyrazinamide (RHZ) in HIV + TB.Results: Neopterin greater than or equal to 14 ng/nJ, TNF-alpha receptors greater than or equal to 6.5 ng/ml, and negative skin test were independently associated with increased mortality (P < 0.01). Among STH-treated subjects, dermatologic toxicity and mortality were respectively 13- and 6.3-fold more likely to occur in subjects with elevated neopterin (P < 0.05), although these two adverse events occurred independently. Activation markers increased from baseline after 2 months of therapy with the less rapidly bactericidal STH regimen, whereas they declined in those treated with RHZ, suggesting a relationship with continued mycobacterial replication.Conclusions: Immune activation in HIV + TB is associated with shortened survival and increased risk of drug toxicity. HIV + TB patients with elevated serum neopterin should be treated with a rapidly-bactericidal drug regimen which does not include thiacetazone.

Among HIV-positive patients who received treatment for active tuberculosis, thiacetazone has been associated with cutaneous hypersensitivity and recurrent tuberculosis. No controlled trials have investigated the safety and efficacy of thiacetazone-containing regimens compared with alternative regimens among patients with HIV. In a randomised clinical trial of 191 HIV-positive patients with active pulmonary tuberculosis, we examined the safety and short-term efficacy of isoniazid, rifampicin, and pyrazinamide for two months followed by isoniazid and rifampicin for seven months (RHZ) compared with streptomycin, thiacetazone, and isoniazid for two months followed by thiacetazone and isoniazid for ten months (STH). Between May, 1990, and September, 1991, 191 HIV-positive adult Ugandan patients with acid-fast bacilli sputum smear-positive pulmonary tuberculosis (93% confirmed by culture) received either STH or RHZ. Subjects had a standard evaluation that included Mantoux skin test, complete blood count with differential white blood cell count, and chest radiography. After starting therapy, subjects were followed-up over one year for three outcomes: complications of anti-tuberculosis therapy, early sterilisation of cultures, and survival. Of 191 eligible subjects, 90 received STH and 101 received RHZ. The overall one-year survival was similar for STH and RHZ (65% vs 72%), but when controlled for baseline differences in Mantoux reaction size and absolute lymphocyte count, the relative risk of death for STH compared with RHZ was 1.57 (95% CI 1.0-2.48). Overall, 12 adverse drug reactions occurred in the STH arm (18.2 reactions per 100 person years [PYO]) compared with one in the RHZ arm (1.6 reactions per 100 PYO) for a relative risk of 11.7 (95% CI 1.52-90.0). 10 cutaneous reactions occurred in the STH arm (15.2 events per 100 PYO) compared with one event in the RHZ arm (1.6 events per 100 PYO) for a relative risk of 9.7 (95% CI: 1.24, 75.8). A greater proportion of RHZ patients compared with STH patients had sterilised their sputum within two months (74% vs 37%, p < 0.001). In developing countries, rifampicin-containing regimens should be given, when possible, to HIV-positive patients to reduce drug toxicity and to prolong survival.

Tuberculosis results in activation of T cells and macrophages that may harbor latent human immunodeficiency virus (HIV-1). Although such activation is beneficial to the host in terms of mycobacterial disease, it may be deleterious in terms of HIV-1. In Ugandan HIV-1-seropositive patients with pulmonary tuberculosis, antigen-induced blastogenesis and production of tumor necrosis factor-alpha (a cytokine that induces expression of HIV-1 in latently infected cells) were 3-10 times greater than in controls. The mean seruM beta2-Microglobulin level was 5.22 mg/L in recently diagnosed patients, significantly greater than levels in HIV-negative patients with tuberculosis or asymptomatic HIV-1-seropositive subjects. Beta2-microglobulin was significantly lower in subjects who had completed at least 2 months of antituberculous therapy. These observations suggest that HIV-1-associated tuberculosis is accompanied by immune activation that may result in increased HIV expression and accelerated progression to AIDS.