Variability of infectious aerosols produced during coughing by patients with pulmonary tuberculosis.

RATIONALE: Mycobacterium tuberculosis is transmitted by infectious aerosols, but assessing infectiousness currently relies on sputum microscopy that does not accurately predict the variability in transmission. OBJECTIVES: To evaluate the feasibility of collecting cough aerosols and the risk factors for infectious aerosol production from patients with pulmonary tuberculosis (TB) in a resource-limited setting. METHODS: We enrolled subjects with suspected TB in Kampala, Uganda and collected clinical, radiographic, and microbiological data in addition to cough aerosol cultures. A subset of 38 subjects was studied on 2 or 3 consecutive days to assess reproducibility. MEASUREMENTS AND MAIN RESULTS: M. tuberculosis was cultured from cough aerosols of 28 of 101 (27.7%; 95% confidence interval [CI], 19.9-37.1%) subjects with culture-confirmed TB, with a median 16 aerosol cfu (range, 1-701) in 10 minutes of coughing. Nearly all (96.4%) cultivable particles were 0.65 to 4.7 µm in size. Positive aerosol cultures were associated with higher Karnofsky performance scores (P = 0.016), higher sputum acid-fast bacilli smear microscopy grades (P = 0.007), lower days to positive in liquid culture (P = 0.004), stronger cough (P = 0.016), and fewer days on TB treatment (P = 0.047). In multivariable analyses, cough aerosol cultures were associated with a salivary/mucosalivary (compared with purulent/mucopurulent) appearance of sputum (odds ratio, 4.42; 95% CI, 1.23-21.43) and low days to positive (per 1-d decrease; odds ratio, 1.17; 95% CI, 1.07-1.33). The within-test (kappa, 0.81; 95% CI, 0.68-0.94) and interday test (kappa, 0.62; 95% CI, 0.43-0.82) reproducibility were high. CONCLUSIONS: A minority of patients with TB (28%) produced culturable cough aerosols. Collection of cough aerosol cultures is feasible and reproducible in a resource-limited setting.

Effectiveness of the standard WHO recommended retreatment regimen (category II) for tuberculosis in Kampala, Uganda: a prospective cohort study.

BACKGROUND: Each year, 10%-20% of patients with tuberculosis (TB) in low- and middle-income countries present with previously treated TB and are empirically started on a World Health Organization (WHO)-recommended standardized retreatment regimen. The effectiveness of this retreatment regimen has not been systematically evaluated. METHODS AND FINDINGS: From July 2003 to January 2007, we enrolled smear-positive, pulmonary TB patients into a prospective cohort to study treatment outcomes and mortality during and after treatment with the standardized retreatment regimen. Median time of follow-up was 21 months (interquartile range 12-33 months). A total of 29/148 (20%) HIV-uninfected and 37/140 (26%) HIV-infected patients had an unsuccessful treatment outcome. In a multiple logistic regression analysis to adjust for confounding, factors associated with an unsuccessful treatment outcome were poor adherence (adjusted odds ratio [aOR] associated with missing half or more of scheduled doses 2.39; 95% confidence interval (CI) 1.10-5.22), HIV infection (2.16; 1.01-4.61), age (aOR for 10-year increase 1.59; 1.13-2.25), and duration of TB symptoms (aOR for 1-month increase 1.12; 1.04-1.20). All patients with multidrug-resistant TB had an unsuccessful treatment outcome. HIV-infected individuals were more likely to die than HIV-uninfected individuals (p<0.0001). Multidrug-resistant TB at enrollment was the only common risk factor for death during follow-up for both HIV-infected (adjusted hazard ratio [aHR] 17.9; 6.0-53.4) and HIV-uninfected (14.7; 4.1-52.2) individuals. Other risk factors for death during follow-up among HIV-infected patients were CD4<50 cells/ml and no antiretroviral treatment (aHR 7.4, compared to patients with CD4≥200; 3.0-18.8) and Karnofsky score <70 (2.1; 1.1-4.1); and among HIV-uninfected patients were poor adherence (missing half or more of doses) (3.5; 1.1-10.6) and duration of TB symptoms (aHR for a 1-month increase 1.9; 1.0-3.5). CONCLUSIONS: The recommended regimen for retreatment TB in Uganda yields an unacceptable proportion of unsuccessful outcomes. There is a need to evaluate new treatment strategies in these patients.

Mycobacterium tuberculosis microbiologic and clinical treatment outcomes in a randomized trial of immediate versus CD4(+)-initiated antiretroviral therapy in HIV-infected adults with a high CD4(+) cell count.

In a prospective randomized, controlled trial in Uganda comparing the efficacy of antiretroviral therapy during tuberculosis therapy with the efficacy of tuberculosis therapy alone in HIV-infected patients with tuberculosis who have a CD4(+) cell count >350 cells/microL, it was found that antiretroviral therapy did not accelerate microbiologic, radiographic, or clinical responses to tuberculosis therapy: 18% of participants had sputum smears positive for Mycobacterium tuberculosis after 5 months of tuberculosis therapy, despite having had negative culture results. Trial registration. ClinicalTrials.gov identifier: NCT00078247 .

Evaluation of time to detection of Mycobacterium tuberculosis in broth culture as a determinant for end points in treatment trials.

Time to detection of Mycobacterium tuberculosis in broth culture was examined for utility as a treatment efficacy end point. Of 146 patients in a phase IIB trial, a decreased mean time to detection was found in 5 with treatment failure. Time to detection in an analysis-of-covariance model was associated with lung cavities, less intensive treatment, and differences in the bactericidal effects of treatment regimens.

Rapid detection of Mycobacterium tuberculosis and rifampin resistance by use of on-demand, near-patient technology.

Current nucleic acid amplification methods to detect Mycobacterium tuberculosis are complex, labor-intensive, and technically challenging. We developed and performed the first analysis of the Cepheid Gene Xpert System's MTB/RIF assay, an integrated hands-free sputum-processing and real-time PCR system with rapid on-demand, near-patient technology, to simultaneously detect M. tuberculosis and rifampin resistance. Analytic tests of M. tuberculosis DNA demonstrated a limit of detection (LOD) of 4.5 genomes per reaction. Studies using sputum spiked with known numbers of M. tuberculosis CFU predicted a clinical LOD of 131 CFU/ml. Killing studies showed that the assay's buffer decreased M. tuberculosis viability by at least 8 logs, substantially reducing biohazards. Tests of 23 different commonly occurring rifampin resistance mutations demonstrated that all 23 (100%) would be identified as rifampin resistant. An analysis of 20 nontuberculosis mycobacteria species confirmed high assay specificity. A small clinical validation study of 107 clinical sputum samples from suspected tuberculosis cases in Vietnam detected 29/29 (100%) smear-positive culture-positive cases and 33/39 (84.6%) or 38/53 (71.7%) smear-negative culture-positive cases, as determined by growth on solid medium or on both solid and liquid media, respectively. M. tuberculosis was not detected in 25/25 (100%) of the culture-negative samples. A study of 64 smear-positive culture-positive sputa from retreatment tuberculosis cases in Uganda detected 63/64 (98.4%) culture-positive cases and 9/9 (100%) cases of rifampin resistance. Rifampin resistance was excluded in 54/55 (98.2%) susceptible cases. Specificity rose to 100% after correcting for a conventional susceptibility test error. In conclusion, this highly sensitive and simple-to-use system can detect M. tuberculosis directly from sputum in less than 2 h.

Shortening treatment in adults with noncavitary tuberculosis and 2-month culture conversion.

RATIONALE: Cavitary disease and delayed culture conversion have been associated with relapse. Combining patient characteristics and measures of bacteriologic response might allow treatment shortening with current drugs in some patients. OBJECTIVES: To assess whether treatment could be shortened from 6 to 4 months in patients with noncavitary tuberculosis whose sputum cultures converted to negative after 2 months. METHODS: This study was a randomized, open-label equivalence trial. HIV-uninfected adults with noncavitary tuberculosis were treated daily with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by 2 months of isoniazid and rifampin. After 4 months, patients with drug-susceptible TB whose sputum cultures on solid media were negative after 8 weeks of treatment were randomly assigned to continue treatment for 2 more months or to stop treatment. Patients were followed for relapse for 30 months after beginning treatment. MEASUREMENTS AND MAIN RESULTS: Enrollment was stopped by the safety monitoring committee after 394 patients were enrolled due to apparent increased risk for relapse in the 4-month arm. A total of 370 patients were eligible for per protocol analysis. Thirteen patients in the 4-month arm relapsed, compared with three subjects in the 6-month arm (7.0 vs. 1.6%; risk difference, 0.054; 95% confidence interval with Hauck-Anderson correction, 0.01-0.10). CONCLUSION: Shortening treatment from 6 to 4 months in adults with noncavitary disease and culture conversion after 2 months using current drugs resulted in a greater relapse rate. The combination of noncavitary disease and 2-month culture conversion was insufficient to identify patients with decreased risk for relapse.

Comparison of rapid tests for detection of rifampicin-resistant Mycobacterium tuberculosis in Kampala, Uganda.

BACKGROUND: Drug resistant tuberculosis (TB) is a growing concern worldwide. Rapid detection of resistance expedites appropriate intervention to control the disease. Several technologies have recently been reported to detect rifampicin resistant Mycobacterium tuberculosis directly in sputum samples. These include phenotypic culture based methods, tests for gene mutations and tests based on bacteriophage replication. The aim of the present study was to assess the feasibility of implementing technology for rapid detection of rifampicin resistance in a high disease burden setting in Africa. METHODS: Sputum specimens from re-treatment TB patients presenting to the Mulago Hospital National TB Treatment Centre in Kampala, Uganda, were examined by conventional methods and simultaneously used in one of the four direct susceptibility tests, namely direct BACTEC 460, Etest, "in-house" phage test, and INNO- Rif.TB. The reference method was the BACTEC 460 indirect culture drug susceptibility testing. Test performance, cost and turn around times were assessed. RESULTS: In comparison with indirect BACTEC 460, the respective sensitivities and specificities for detecting rifampicin resistance were 100% and 100% for direct BACTEC and the Etest, 94% and 95% for the phage test, and 87% and 87% for the Inno-LiPA assay. Turn around times ranged from an average of 3 days for the INNO-LiPA and phage tests, 8 days for the direct BACTEC 460 and 20 days for the Etest. All methods were faster than the indirect BACTEC 460 which had a mean turn around time of 24 days. The cost per test, including labour ranged from $18.60 to $41.92 (USD). CONCLUSION: All four rapid technologies were shown capable of detecting rifampicin resistance directly from sputum. The LiPA proved rapid, but was the most expensive. It was noted, however, that the LiPA test allows sterilization of samples prior to testing thereby reducing the risk of accidental laboratory transmission. In contrast the Etest was low cost, but slow and would be of limited assistance when treating patients. The phage test was the least reproducible test studied with failure rate of 27%. The test preferred by the laboratory personnel, direct BACTEC 460, requires further study to determine its accuracy in real-time treatment decisions in Uganda.

Rate and amplification of drug resistance among previously-treated patients with tuberculosis in Kampala, Uganda.

BACKGROUND: Drug-resistant Mycobacterium tuberculosis has emerged as a global threat. In resource-constrained settings, patients with a history of tuberculosis (TB) treatment may have drug-resistant disease and may experience poor outcomes. There is a need to measure the extent of and risk factors for drug resistance in such patients. METHODS: From July 2003 through November 2006, we enrolled 410 previously treated patients with TB in Kampala, Uganda. We measured the prevalence of resistance to first- and second-line drugs and analyzed risk factors associated with baseline and acquired drug resistance. RESULTS: The prevalence of multidrug-resistant TB was 12.7% (95% confidence interval [95% CI], 9.6%-16.3%). Resistance to second-line drugs was low. Factors associated with multidrug-resistant TB at enrollment included a history of treatment failure (odds ratio, 23.6; 95% CI, 7.7-72.4), multiple previous TB episodes (odds ratio, 15.6; 95% CI, 5.0-49.1), and cavities present on chest radiograph (odds ratio, 5.9; 95% CI, 1.2-29.5). Among a cohort of 250 patients, 5.2% (95% CI, 2.8%-8.7%) were infected with M. tuberculosis that developed additional drug resistance. Amplification of drug resistance was associated with existing drug resistance at baseline (P < .01) and delayed sputum culture conversion (P < .01). CONCLUSIONS: The burden of drug resistance in previously treated patients with TB in Uganda is sizeable, and the risk of generating additional drug resistance is significant. There is an urgent need to improve the treatment for such patients in low-income countries.

Early virological response of zidovudine/lamivudine/abacavir for patients co-infected with HIV and tuberculosis in Uganda.

Triple nucleoside reverse transcriptase inhibitors are recommended as an alternative regimen for HIV-infected patients undergoing tuberculosis treatment in resource-limited settings. Few data exist on the efficacy of such regimens in tuberculosis patients. In 34 tuberculosis/HIV-co-infected patients treated with zidovudine/lamivudine/abacavir, 76% achieved HIV RNA less than 50 copies/ml at 24 weeks. No cases of hypersensitivity or immune reconstitution syndrome were observed. These data support the continuing evaluation of nucleoside-based antiretroviral regimens as an alternative treatment for this population.

Men's circumcision status and women's risk of HIV acquisition in Zimbabwe and Uganda.

OBJECTIVE: To assess whether male circumcision of the primary sex partner is associated with women's risk of HIV. DESIGN: Data were analyzed from 4417 Ugandan and Zimbabwean women participating in a prospective study of hormonal contraception and HIV acquisition. Most were recruited from family planning clinics; some in Uganda were referred from higher-risk settings such as sexually transmitted disease clinics. METHODS: Using Cox proportional hazards models, time to HIV acquisition was compared for women with circumcised or uncircumcised primary partners. Possible misclassification of male circumcision was assessed using sensitivity analysis. RESULTS: At baseline, 74% reported uncircumcised primary partners, 22% had circumcised partners and 4% had partners of unknown circumcision status. Median follow-up was 23 months, during which 210 women acquired HIV (167, 34, and 9 women whose primary partners were uncircumcised, circumcised, or of unknown circumcision status, respectively). Although unadjusted analyses indicated that women with circumcised partners had lower HIV risk than those with uncircumcised partners, the protective effect disappeared after adjustment for other risk factors [hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.69-1.53]. Subgroup analyses suggested a non-significant protective effect of male circumcision on HIV acquisition among Ugandan women referred from higher-risk settings: adjusted HR 0.16 (95% CI, 0.02-1.25) but little effect in Ugandans (HR, 1.33; 95% CI, 0.72-2.47) or Zimbabweans (HR, 1.12; 95% CI, 0.65-1.91) from family planning clinics. CONCLUSIONS: After adjustment, male circumcision was not significantly associated with women's HIV risk. The potential protection offered by male circumcision for women recruited from high-risk settings warrants further investigation.

Low-cost rapid detection of rifampicin resistant tuberculosis using bacteriophage in Kampala, Uganda.

BACKGROUND: Resistance to anti-tuberculosis drugs is a serious public health problem. Multi-drug resistant tuberculosis (MDR-TB), defined as resistance to at least rifampicin and isoniazid, has been reported in all regions of the world. Current phenotypic methods of assessing drug susceptibility of M. tuberculosis are slow. Rapid molecular methods to detect resistance to rifampicin have been developed but they are not affordable in some high prevalence countries such as those in sub Saharan Africa. A simple multi-well plate assay using mycobacteriophage D29 has been developed to test M. tuberculosis isolates for resistance to rifampicin. The purpose of this study was to investigate the performance of this technology in Kampala, Uganda. METHODS: In a blinded study 149 M. tuberculosis isolates were tested for resistance to rifampicin by the phage assay and results compared to those from routine phenotypic testing in BACTEC 460. Three concentrations of drug were used 2, 4 and 10 microg/ml. Isolates found resistant by either assay were subjected to sequence analysis of a 81 bp fragment of the rpoB gene to identify mutations predictive of resistance. Four isolates with discrepant phage and BACTEC results were tested in a second phenotypic assay to determine minimal inhibitory concentrations. RESULTS: Initial analysis suggested a sensitivity and specificity of 100% and 96.5% respectively for the phage assay used at 4 and 10 microg/ml when compared to the BACTEC 460. However, further analysis revealed 4 false negative results from the BACTEC 460 and the phage assay proved the more sensitive and specific of the two tests. Of the 39 isolates found resistant by the phage assay 38 (97.4%) were found to have mutations predictive of resistance in the 81 bp region of the rpoB gene. When used at 2 mug/ml false resistant results were observed from the phage assay. The cost of reagents for testing each isolate was estimated to be 1.3 US dollars when testing a batch of 20 isolates on a single 96 well plate. Results were obtained in 48 hours. CONCLUSION: The phage assay can be used for screening of isolates for resistance to rifampicin, with high sensitivity and specificity in Uganda. The test may be useful in poorly resourced laboratories as a rapid screen to differentiate between rifampicin susceptible and potential MDR-TB cases.

Delayed-type hypersensitivity skin test reactivity and survival in HIV-infected patients in Uganda: should anergy be a criterion to start antiretroviral therapy in low-income countries?

Access to antiretroviral (ARV) drugs is improving in sub-Saharan Africa but still constrained by several clinical and logistical obstacles. There is a need to develop affordable markers to guide initiation of treatment. We present a prospective cohort study of 779 patients participating in a TB prophylaxis trial. We performed separate analyses for anergic and nonanergic subjects. Prognostic factors for anergic and nonanergic subjects differed between groups. Individuals with anergy and constitutional symptoms were at the highest risk of death. Incident tuberculosis and CD4 < 200 cells/muL at enrollment were the strongest risk factors for death. HIV disease is associated with substantial morbidity and mortality in this population. The burden caused by tuberculosis is particularly high. Anergy is a strong and independent predictor of death. World Health Organization criteria to start ARV may be strengthened with the addition of DTH testing, an inexpensive and readily available tool in sub-Saharan Africa.

Immune correlates of acute Mycobacterium tuberculosis infection in household contacts in Kampala, Uganda.

To determine immunologic and epidemiologic correlates of acute Mycobacterium tuberculosis infection in household contacts of infectious tuberculosis cases, we performed a prospective, community-based cohort study of index cases and their household contacts in Kampala, Uganda. Contacts were evaluated for tuberculin skin test (TST) conversion over two years. Interferon-gamma expression was measured using a whole blood assay after stimulating with M. tuberculosis culture-filtrate. In 222 contacts with a TST less than 5 mm at baseline, the one-year rate of TST conversion was 27%. The TST conversion was associated with the infectiousness of the index case and proximity of contact. Interferon-gamma levels at baseline were greater among TST converters compared with those who did not convert. The risk of TST conversion increased four-fold as the baseline interferon-gamma increased 10-fold, but only in contacts with BCG vaccination. In household contacts of tuberculosis, interferon-gamma responses to non-specific mycobacterial antigens may be used to make an early diagnosis of tuberculosis infection, especially in resource-limited settings where bacille Calmette-Guérin vaccination is commonly used.

Effect of tuberculosis preventive therapy on HIV disease progression and survival in HIV-infected adults.

PURPOSE: To determine whether tuberculosis (TB) preventive therapies alter the rate of disease progression to AIDS or death and to identify significant prognostic factors for HIV disease progression to AIDS. METHOD: In a randomized placebo-controlled trial in Kampala, Uganda, 2,736 purified protein derivative (PPD)-positive and anergic HIV-infected adults were randomly assigned to four and two regimens, respectively. PPD-positive patients were treated with isoniazid (INH) for 6 months (6H; n = 536), INH plus rifampicin for 3 months (3HR; n = 556), INH plus rifampicin plus pyrazinamide for 3 months (3HRZ; n = 462), or placebo for 6 months (n = 464). Anergic participants were treated with 6H (n = 395) or placebo (n = 323). RESULTS: During follow-up, 404 cases progressed to AIDS and 577 deaths occurred. The cumulative incidence of the AIDS progression was greater in the anergic cohort compared to the PPD-positive cohort (p < .0001). Among PPD-positive patients, the relative risk of the AIDS progression with INH alone was 0.95 (95% CI 0.68-1.32); with 3HR it was 0.83 (95% CI 0.59-1.17); and with 3HRZ it was 0.76 (95% CI 0.52-1.08), controlling for significant baseline predictors. Among anergic patients, the relative risk of the AIDS progression was 0.81 (95% CI 0.56-1.15). Survival was greater in the PPD-positive cohort compared to the anergic cohort (p = .0001). CONCLUSION: The number of signs or symptoms at baseline and anergic status are associated with increasing morbidity and mortality. Even though the tuberculosis preventive therapies were effective in reducing the incidence of TB for HIV-infected adults, their benefit of delaying HIV disease progression to AIDS was not observed.

Gender and HIV-associated pulmonary tuberculosis: presentation and outcome at one year after beginning antituberculosis treatment in Uganda.

BACKGROUND: Tuberculosis is responsible for more female deaths around the earth than any other infectious disease. Reports have suggested that responses to tuberculosis may differ between men and women. We investigated gender related differences in the presentation and one year outcomes of HIV-infected adults with initial episodes of pulmonary tuberculosis in Uganda. METHODS: We enrolled and followed up a cohort of 105 male and 109 female HIV-infected adults on treatment for initial episodes of culture-confirmed pulmonary tuberculosis between March 1993 and March 1995. A favorable outcome was defined as being cured and alive at one year while an unfavorable outcome was not being cured or dead. Subjects were followed-up by serial medical examinations, complete blood counts, serum beta2 microglobulin, CD4+ cell counts, sputum examinations, and chest x-rays. RESULTS: Male patients were older, had higher body mass indices, and lower serum beta2 microglobulin levels than female patients at presentation. At one year, there was no difference between male and female patients in the likelihood of experiencing a favorable outcome (RR 1.02, 95% CI 0.89-1.17). This effect persisted after controlling for symptoms, serum beta2 microglobulin, CD4+ cell count, and severity of disease on chest x-ray (OR 1.07, 95% CI 0.54-2.13) with a repeated measures model. CONCLUSIONS: While differences existed between males and females with HIV-associated pulmonary tuberculosis at presentation, the outcomes at one year after the initiation of tuberculosis treatment were similar in Uganda. Women in areas with a high HIV and tuberculosis prevalence should be encouraged to present for screening at the first sign of tuberculosis symptoms.

Treatment outcomes of new tuberculosis patients hospitalized in Kampala, Uganda: a prospective cohort study.

BACKGROUND: In most resource limited settings, new tuberculosis (TB) patients are usually treated as outpatients. We sought to investigate the reasons for hospitalisation and the predictors of poor treatment outcomes and mortality in a cohort of hospitalized new TB patients in Kampala, Uganda. METHODS AND FINDINGS: Ninety-six new TB patients hospitalised between 2003 and 2006 were enrolled and followed for two years. Thirty two were HIV-uninfected and 64 were HIV-infected. Among the HIV-uninfected, the commonest reasons for hospitalization were low Karnofsky score (47%) and need for diagnostic evaluation (25%). HIV-infected patients were commonly hospitalized due to low Karnofsky score (72%), concurrent illness (16%) and diagnostic evaluation (14%). Eleven HIV uninfected patients died (mortality rate 19.7 per 100 person-years) while 41 deaths occurred among the HIV-infected patients (mortality rate 46.9 per 100 person years). In all patients an unsuccessful treatment outcome (treatment failure, death during the treatment period or an unknown outcome) was associated with duration of TB symptoms, with the odds of an unsuccessful outcome decreasing with increasing duration. Among HIV-infected patients, an unsuccessful treatment outcome was also associated with male sex (P = 0.004) and age (P = 0.034). Low Karnofsky score (aHR = 8.93, 95% CI 1.88 - 42.40, P = 0.001) was the only factor significantly associated with mortality among the HIV-uninfected. Mortality among the HIV-infected was associated with the composite variable of CD4 and ART use, with patients with baseline CD4 below 200 cells/µL who were not on ART at a greater risk of death than those who were on ART, and low Karnofsky score (aHR = 2.02, 95% CI 1.02 - 4.01, P = 0.045). CONCLUSION: Poor health status is a common cause of hospitalisation for new TB patients. Mortality in this study was very high and associated with advanced HIV Disease and no use of ART.

Incidence and predictors of mortality and the effect of tuberculosis immune reconstitution inflammatory syndrome in a cohort of TB/HIV patients commencing antiretroviral therapy.

BACKGROUND: Tuberculosis-HIV (TB-HIV) coinfection remains an important cause of mortality in antiretroviral therapy (ART) programs. In a cohort of TB-HIV-coinfected patients starting ART, we examined the incidence and predictors of early mortality. METHODS: Consecutive TB-HIV-coinfected patients eligible for ART were enrolled in a cohort study at the Mulago National Tuberculosis and Leprosy Program clinic in Kampala, Uganda. Predictors of mortality were assessed using Cox proportional hazards analysis. RESULTS: Three hundred and two patients [median CD4 count 53 cells/µL (interquartile range, 20-134)] were enrolled. Fifty-three patients died, 36 (68%) of these died within the first 6 months of TB diagnosis. Male sex [hazard (HR): 2.19; 95% confidence interval (CI): 1.19 to 4.03; P = 0.011], anergy to tuberculin skin test [HR: 2.59 (1.10 to 6.12); P = 0.030], a positive serum cryptococcal antigen result at enrollment (HR: 4.27; 95% CI: 1.50 to 12.13; P = 0.006) and no ART use (HR: 4.63; 95% CI: 2. 37 to 9.03; P < 0.001) were independent predictors of mortality by multivariate analysis. Six (10%) patients with TB immune reconstitution inflammatory syndrome died, and in most, an alternative contributing cause of death was identified. CONCLUSIONS: Mortality among these TB-HIV-coinfected patients was high particularly when presenting with advanced HIV disease and not starting ART, reinforcing the need for timely and joint treatment for both infections. Screening for a concomitant cryptococcal infection and antifungal treatment for patients with cryptococcal antigenemia may further improve clinical outcome.

Tuberculosis treatment in HIV infected Ugandans with CD4 counts>350 cells/mm reduces immune activation with no effect on HIV load or CD4 count.

BACKGROUND: Both HIV and TB cause a state of heightened immune activation. Immune activation in HIV is associated with progression to AIDS. Prior studies, focusing on persons with advanced HIV, have shown no decline in markers of cellular activation in response to TB therapy alone. METHODOLOGY: This prospective cohort study, composed of participants within a larger phase 3 open-label randomized controlled clinical trial, measured the impact of TB treatment on immune activation in persons with non-advanced HIV infection (CD4>350 cells/mm3) and pulmonary TB. HIV load, CD4 count, and markers of immune activation (CD38 and HLA-DR on CD4 and CD8 T cells) were measured prior to starting, during, and for 6 months after completion of standard 6 month anti-tuberculosis (TB) therapy in 38 HIV infected Ugandans with smear and culture confirmed pulmonary TB. RESULTS: Expression of CD38, and co-expression of CD38 and HLA-DR, on CD8 cells declined significantly within 3 months of starting standard TB therapy in the absence of anti-retroviral therapy, and remained suppressed for 6 months after completion of therapy. In contrast, HIV load and CD4 count remained unchanged throughout the study period. CONCLUSION: TB therapy leads to measurable decreases in immune activation in persons with HIV/TB co-infection and CD4 counts>350 cells/mm3.