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Background: Pulmonary tuberculosis (TB) in people living with HIV (PLH) frequently presents as sputum smear-negative. However, clinical trials of TB in adults often use smear-positive individuals to ensure measurable bacterial responses following initiation of treatment, thereby excluding HIV-infected patients from trials., Methods: In this prospective case cohort study, 118 HIV-seropositive TB patients were assessed prior to initiation of standard four-drug TB therapy and at several time points through 35 days. Sputum bacillary load, as a marker of treatment response, was determined serially by: smear microscopy, Xpert MTB/RIF, liquid culture, and colony counts on agar medium., Results: By all four measures, patients who were baseline smear-positive had higher bacterial loads than those presenting as smear-negative, until day 35. However, most smear-negative PLH had significant bacillary load at enrolment and their mycobacteria were cleared more rapidly than smear-positive patients. Smear-negative patients' decline in bacillary load, determined by colony counts, was linear to day 7 suggesting measurable bactericidal activity. Moreover, the decrease in bacterial counts was comparable to smear-positive individuals. Increasing cycle threshold values (Ct) on the Xpert assay in smear-positive patients to day 14 implied decreasing bacterial load., Conclusion: Our data suggest that smear-negative PLH can be included in clinical trials of novel treatment regimens as they contain sufficient viable bacteria, but allowances for late exclusions would have to be made in sample size estimations. We also show that increases in Ct in smear-positive patients to day 14 reflect treatment responses and the Xpert MTB/RIF assay could be used as biomarker for early treatment response.

Background: HIV-infected individuals have increased risk of developing obstructive lung disease (OLD). Studies from developed countries report high viral load, low CD4 counts, and anti-retroviral therapy (ART) to be associated with OLD; but these findings may not be generalizable to populations in resource-limited settings. Methods: We conducted a prospective cohort study of lung function in 730 HIV-infected black South African adults. Pre-bronchodilator spirometry was performed at enrollment and repeated annually for three years. Logistic regression models were used to identify factors associated with OLD, defined as FEV1/FVC<0.70, at enrollment. Excess annual declines in FEV1 and FVC were modelled as the product-term of follow-up time and exposures using random effects regression. Results: Median (IQR) age at enrollment was 36 (32–41) years, 85% were female and 30% ever-smoked with a median (IQR) exposure of 3 (1–6) pack-years. Median (IQR) CD4 count and viral load at enrollment were 372 (261–518) cells/mm3 and 2655 (91–13,548) copies/mL respectively. Overall, 25% were receiving ART at enrollment, 16% of whom reported at least 6 months of ART receipt. OLD was found in 35 (5%) at enrollment. Increasing age (aOR = 2.08 per 10-years [95%CI 1.22–3.57], p = 0.007), current smoking (aOR = 3.55 [95%CI 1.20–10.53], p = 0.02), and CRP (aOR = 1.01 per unit-increase [95%CI 1.00–1.03], p = 0.04) were significantly associated with OLD at enrollment; while increasing CD4 count (aOR = 1.02 per-100 cells/mm3 [95%CI 0.85–1.22], p = 0.82), viral load (aOR = 0.67 per log-increase [95%CI 0.43–1.10], p = 0.12) and receipt of ART (aOR = 0.57 [95%CI 0.18–1.75], p = 0.32) were not. The median (IQR) follow-up time was 18 (12–24) months. Participants with a history of tuberculosis (TB) had a 35 mL (95%CI 2–68, p = 0.03) and 57 mL (95%CI 19–96, p = 0.003) per year excess loss of FEV1 and FVC respectively. Conclusion: Prevalent OLD was associated with older age, current smoking and higher CRP levels, but not CD4 counts and ART, in HIV-infected South African adults. Better understanding of the long-term effects of TB, smoking and inflammation on lung function in HIV-infected populations is urgently needed. [ABSTRACT FROM AUTHOR]

Background: CD4 count is a proxy for the extent of immune deficiency and declines in CD4 count are a measure of disease progression. Decline in CD4 count is an important component: for estimating benefits of ARV treatment; for individual level counselling on the rapidity of untreated disease progression and prognosis; and can be used in planning demand for health services. Our objective is to report CD4 decline and changes in viral load (VL) in a group of HIV-infected adults enrolled in a randomized trial of preventive treatment for TB in South Africa where clade C infection predominates. Methods: HIV-infected, tuberculin skin test positive adults who were not eligible for antiretroviral (ARV) treatment were randomized to a trial of preventive treatment from 2003–2005. VL and CD4 count were assessed at enrollment and CD4 counts repeated at least annually. During follow-up, individuals whose CD4 counts decreased to <200 cells/mm3 were referred for antiretroviral therapy (ART) and were analytically censored. Results: 1106 ARV naïve adults were enrolled. Their median age was 30 years and male to female ratio was 1∶5. Median baseline CD4 count was 490 cells/mm3 (IQR 351–675). The overall mean decline in CD4 count was 61 cells/mm3 per annum. Adjusting for age, gender, baseline hemoglobin, smoking and alcohol use had little impact on the estimate of CD4 decline. However, VL at baseline had a major impact on CD4 decline. The percent decline in CD4 count was 13.3% (95% CI 12.0%, 14.7%), 10.6% (95% CI 8.8%, 12.4%), and 13.8% (95% CI 12.1%, 15.5%) per annum for baseline VLs of <10,000 (N = 314), 10,001–100,000 (N = 338), >100,000 (N = 122) copies/ml. Conclusions: Our data suggests that six and a half years will elapse for an individual's CD4 count to decline from 750 to 350 cells/mm3 in the absence of ART. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Background: Tuberculosis preventive therapy (TPT) is recommended for people with HIV infection, including during pregnancy. The effect of TPT exposure at conception and during pregnancy is poorly documented. Methods: We report pregnancy outcomes among South African women with HIV enrolled in a randomized trial of 4 TPT regimens (two 3-month regimens, rifapentine/isoniazid [3HP] or rifampin/isoniazid [3HR], isoniazid for 6 months, or isoniazid continuously). Descriptive statistics and risk ratios were assessed to examine relationships between study regimens and outcomes. Results: 216/896 women (24%) conceived during the study. Women who conceived were younger (27.9 vs 31.3 years) and had higher mean CD4 counts (589.1 vs 536.7). The odds of pregnancy were higher in women in the rifamycin-isoniazid arms than those in the isoniazid arms (3HP: relative risk [RR] 1.73, P = 0.001; 3HR:RR 1.55, P = 0.017) despite increased contraceptive use compared with the standard 6H therapy. Thirty-four women became pregnant while taking preventive treatment (8 rifamycin and 26 isoniazid monotherapy). Pregnancy outcomes in these women were as follows: 17 (50%) mother/baby healthy, 3 (9%) spontaneous abortions, 6 (18%) elective abortions, 1 (3%) premature delivery, 2 (6%) neonatal deaths [1 rifamycin-isoniazid and 1 isoniazid], and 5 (15%) unknown. Conclusions: Pregnancy was common in women who had received TPT and more frequent in women who had received rifamycin-isoniazid–based regimens. [ABSTRACT FROM AUTHOR]

Background: Treatment of latent tuberculosis in patients infected with the human immunodeficiency virus (HIV) is efficacious, but few patients around the world receive such treatment. We evaluated three new regimens for latent tuberculosis that may be more potent and durable than standard isoniazid treatment. Methods: We randomly assigned South African adults with HIV infection and a positive tuberculin skin test who were not taking antiretroviral therapy to receive rifapentine (900 mg) plus isoniazid (900 mg) weekly for 12 weeks, rifampin (600 mg) plus isoniazid (900 mg) twice weekly for 12 weeks, isoniazid (300 mg) daily for up to 6 years (continuous isoniazid), or isoniazid (300 mg) daily for 6 months (control group). The primary end point was tuberculosis-free survival. Results: The 1148 patients had a median age of 30 years and a median CD4 cell count of 484 per cubic millimeter. Incidence rates of active tuberculosis or death were 3.1 per 100 person-years in the rifapentine–isoniazid group, 2.9 per 100 person-years in the rifampin–isoniazid group, and 2.7 per 100 person-years in the continuous-isoniazid group, as compared with 3.6 per 100 person-years in the control group (P>0.05 for all comparisons). Serious adverse reactions were more common in the continuous-isoniazid group (18.4 per 100 person-years) than in the other treatment groups (8.7 to 15.4 per 100 person-years). Two of 58 isolates of Mycobacterium tuberculosis (3.4%) were found to have multidrug resistance. Conclusions: On the basis of the expected rates of tuberculosis in this population of HIV-infected adults, all secondary prophylactic regimens were effective. Neither a 3-month course of intermittent rifapentine or rifampin with isoniazid nor continuous isoniazid was superior to 6 months of isoniazid. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00057122.) [ABSTRACT FROM PUBLISHER]