Pregnancy in Women With HIV in a Tuberculosis Preventive Therapy Trial.

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.

Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis: The COMRADE Randomized, Phase 2A Clinical Trial.

Rationale: Carbapenems are recommended for treatment of drug-resistant tuberculosis. Optimal dosing remains uncertain. Objectives: To evaluate the 14-day bactericidal activity of meropenem, at different doses, with or without rifampin. Methods: Individuals with drug-sensitive pulmonary tuberculosis were randomized to one of four intravenous meropenem-based arms: 2 g every 8 hours (TID) (arm C), 2 g TID plus rifampin at 20 mg/kg once daily (arm D), 1 g TID (arm E), or 3 g once daily (arm F). All participants received amoxicillin/clavulanate with each meropenem dose. Serial overnight sputum samples were collected from baseline and throughout treatment. Median daily fall in colony-forming unit (CFU) counts per milliliter of sputum (solid culture) (EBACFU0-14) and increase in time to positive culture (TTP) in liquid media were estimated with mixed-effects modeling. Serial blood samples were collected for pharmacokinetic analysis on Day 13. Measurements and Main Results: Sixty participants enrolled. Median EBACFU0-14 counts (2.5th-97.5th percentiles) were 0.22 (0.12-0.33), 0.12 (0.057-0.21), 0.059 (0.033-0.097), and 0.053 (0.035-0.081); TTP increased by 0.34 (0.21-0.75), 0.11 (0.052-0.37), 0.094 (0.034-0.23), and 0.12 (0.04-0.41) (log10 h), for arms C-F, respectively. Meropenem pharmacokinetics were not affected by rifampin coadministration. Twelve participants withdrew early, many of whom cited gastrointestinal adverse events. Conclusions: Bactericidal activity was greater with the World Health Organization-recommended total daily dose of 6 g daily than with a lower dose of 3 g daily. This difference was only detectable with solid culture. Tolerability of intravenous meropenem, with amoxicillin/clavulanate, though, was poor at all doses, calling into question the utility of this drug in second-line regimens. Clinical trial registered with www.clinicaltrials.gov (NCT03174184).

The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis.

Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability. Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5-1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise. Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified. Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.

Screening for Tuberculosis With Xpert MTB/RIF Assay Versus Fluorescent Microscopy Among Adults Newly Diagnosed With Human Immunodeficiency Virus in Rural Malawi: A Cluster Randomized Trial (Chepetsa).

BACKGROUND: Tuberculosis (TB) remains the leading cause of death among human immunodeficiency virus (HIV)-infected individuals globally. Screening for TB at the point of HIV diagnosis with a high-sensitivity assay presents an opportunity to reduce mortality. METHODS: We performed a cluster randomized trial of TB screening among adults newly diagnosed with HIV in 12 primary health clinics in rural Thyolo, Malawi. Clinics were allocated in a 1:1 ratio to perform either point-of-care Xpert MTB/RIF assay (Xpert) or point-of-care light-emitting diode fluorescence microscopy (LED-FM) for individuals screening positive for TB symptoms. Asymptomatic participants were offered isoniazid preventive therapy in both arms. Investigators, but not clinic staff or participants, were masked to allocation. Our primary outcome was the incidence rate ratio (RR) of all-cause mortality within 12 months of HIV diagnosis. RESULTS: Prevalent TB was diagnosed in 24 of 1001 (2.4%) individuals enrolled in clinics randomized to Xpert, compared with 10 of 841 (1.2%) in clinics randomized to LED-FM. All-cause mortality was 22% lower in the Xpert arm than in the LED-FM arm (6.7 vs 8.6 per 100 person-years; RR, 0.78 [95% confidence interval {CI}, .58-1.06]). A planned subgroup analysis suggested that participants with more advanced HIV (World Health Organization clinical stage 3 or 4) disease had lower mortality in clinics randomized to Xpert than to LED-FM (RR, 0.43 [95% CI, .22-.87]). CONCLUSIONS: In rural Malawi, using point-of-care Xpert MTB/RIF to test symptomatic patients for TB at the time of HIV diagnosis reduced all-cause 12-month mortality among individuals with advanced HIV. CLINICAL TRIALS REGISTRATION: NCT01450085.

Factors associated with pulmonary impairment in HIV-infected South African adults.

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.

A Phase 2 Randomized Trial of a Rifapentine plus Moxifloxacin-Based Regimen for Treatment of Pulmonary Tuberculosis.

BACKGROUND: The combination of rifapentine and moxifloxacin administered daily with other anti-tuberculosis drugs is highly active in mouse models of tuberculosis chemotherapy. The objective of this phase 2 clinical trial was to determine the bactericidal activity, safety, and tolerability of a regimen comprised of rifapentine, moxifloxacin, isoniazid, and pyrazinamide administered daily during the first 8 weeks of pulmonary tuberculosis treatment. METHODS: Adults with sputum smear-positive pulmonary tuberculosis were randomized to receive either rifapentine (approximately 7.5 mg/kg) plus moxifloxacin (investigational arm), or rifampin (approximately 10 mg/kg) plus ethambutol (control) daily for 8 weeks, along with isoniazid and pyrazinamide. The primary endpoint was sputum culture status at completion of 8 weeks of treatment. RESULTS: 121 participants (56% of accrual target) were enrolled. At completion of 8 weeks of treatment, negative cultures using Löwenstein-Jensen (LJ) medium occurred in 47/60 (78%) participants in the investigational arm vs. 43/51 (84%, p = 0.47) in the control arm; negative cultures using liquid medium occurred in 37/47 (79%) in the investigational arm vs. 27/41 (66%, p = 0.23) in the control arm. Time to stable culture conversion was shorter for the investigational arm vs. the control arm using liquid culture medium (p = 0.03), but there was no difference using LJ medium. Median rifapentine area under the concentration-time curve (AUC0-24) was 313 mcg*h/mL, similar to recent studies of rifapentine dosed at 450-600 mg daily. Median moxifloxacin AUC0-24 was 28.0 mcg*h/mL, much lower than in trials where rifapentine was given only intermittently with moxifloxacin. The proportion of participants discontinuing assigned treatment for reasons other than microbiological ineligibility was higher in the investigational arm vs. the control arm (11/62 [18%] vs. 3/59 [5%], p = 0.04) although the proportions of grade 3 or higher adverse events were similar (5/62 [8%] in the investigational arm vs. 6/59 [10%, p = 0.76] in the control arm). CONCLUSION: For intensive phase daily tuberculosis treatment in combination with isoniazid and pyrazinamide, a regimen containing moxifloxacin plus low dose rifapentine was at least as bactericidal as the control regimen containing ethambutol plus standard dose rifampin. TRIAL REGISTRATION: www.ClinicalTrials.gov NCT00728507.

Risk factors for developing active tuberculosis after the treatment of latent tuberculosis in adults infected with human immunodeficiency virus.

Tuberculosis is the leading cause of death among adults infected with human immunodeficiency virus (HIV), and rates of tuberculosis remain high even after preventive therapy. Among 908 HIV-infected adults in a trial of preventive treatment, we found self-reported alcohol consumption, low baseline CD4 count, high baseline viral load, and tuberculin skin test size >15 mm as independent risk factors for incident tuberculosis.

Preventing tuberculosis among HIV-infected pregnant women in Lesotho: the case for rolling out active case finding and isoniazid preventive therapy.

BACKGROUND: The Lesotho Ministry of Health issued guidelines on active case finding (ACF) for tuberculosis (TB) and isoniazid preventive therapy (IPT) in April 2011. ACF has been recommended in maternal and child health (MCH) settings globally, however, the feasibility of implementing IPT within MCH in countries with high concurrent HIV and TB epidemics is unknown. DESIGN/METHODS: The study evaluated the implementation of ACF and IPT guidelines in MCH settings in 2 health facilities in Lesotho. This descriptive prospective study analyzed data collected during routine services. Categorical data and continuous variables were summarized using descriptive statistics. The χ test or Wilcoxon rank-sum test was used to ascertain significant associations between categorical and continuous variables, respectively. RESULTS: Data from 160 HIV-positive and 640 HIV-negative women were reviewed. Within this study population, 99.8% of women were screened for TB, and 11.4% HIV-positive women compared with 2.3% HIV-negative women were reported to have symptoms of TB (P < 0.001). IPT was initiated in 124/158 (78.5%) HIV-positive pregnant women, 64.5% women completed a 6-month IPT regimen, 2 (1.6%) died of causes unrelated to IPT/TB, and 31.5% were lost to follow-up. Predictors of IPT initiation among HIV-positive women included gestational age at the first antenatal visit (unadjusted odds ratio, -0.93; 95% confidence interval: -0.88 to 0.98), and receipt of antiretroviral therapy for treatment rather than for prevention of mother-to-child transmission prophylaxis only (odds ratio, 4.59; 95% confidence interval: 1.32 to 15.93). CONCLUSIONS: Implementation of ACF and IPT is feasible within the MCH setting. Uptake of IPT during pregnancy among HIV-positive women was high, but with a high rate of loss to follow-up.

CD4 and viral load dynamics in antiretroviral-naïve HIV-infected adults from Soweto, South Africa: a prospective cohort.

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/mm(3) 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/mm(3) (IQR 351-675). The overall mean decline in CD4 count was 3.2 cells/mm (3) per annum [corrected].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.

New regimens to prevent tuberculosis in adults with HIV infection.

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.).