Impact of Option B+ Combination Antiretroviral Therapy on Mother-to-Child Transmission of HIV-1, Maternal and Infant Virologic Responses to Combination Antiretroviral Therapy, and Maternal and Infant Mortality Rates: A 24-Month Prospective Follow-Up Study at a Primary Health Care Clinic, in Harare, Zimbabwe.

We conducted a 24-month prospective follow-up study, at a primary health care clinic in Harare, Zimbabwe, to determine cumulative mother-to-child transmission of HIV-1 (MTCT) rate and the contributions of intrauterine (IU), intrapartum (IP), and postpartum (PP) to MTCT, as well as maternal and infant mortality rates in the era of Option B+ combination antiretroviral therapy (cART). Plasma for viral load (VL) quantitation was obtained from 475 mothers enrolled into the study. VL was quantified at enrolment and every 6 months thereafter up to 24 months using the Cepheid GeneXpert HIV-1 Quantitative test. Dried blood spots were collected from 453 infants at birth, 4-6 weeks, 3 months, and every 3 months thereafter up to 24 months. HIV-1 infant diagnosis was conducted using the Cepheid GeneXpert HIV-1 Qualitative test. Absolute, cumulative MTCT rates and mortality rate were calculated. Seven mothers (1.55%) transmitted HIV-1 infection to their infants by 24 months. Four infants (0.88%; 95% CI 0.26-2.33%), one infant (0.22%; 95% CI 0-1.4%), and two infants (0.44%; 95% CI 0.01-1.7%) were infected IU, IP, and PP, respectively. By 24 months, 88.94% of the mothers and 80% of the infants had undetectable VL. The maternal and infant mortality rates were 0.21% and 1.78%, respectively. In the first 24 months of life, IU transmission is the major route of MTCT. The cumulative MTCT rate of 1.55% and low maternal and infant mortality rates of 0.21% and 1.78%, respectively, contribute to growing evidence that Option B+ cART not only drastically reduces MTCT but also maternal and infant mortality.

Mother-to-child transmission of HIV-1 and infant mortality in the first six months of life, in the era of Option B Plus combination antiretroviral therapy.

OBJECTIVES: The aim of this study was to determine the contributions of intrauterine (IU), intrapartum (IP), and postpartum (PP) transmission to mother-to-child transmission of HIV-1 (MTCT) and infant mortality in the first 6 months of life, in the era of Option B Plus combination antiretroviral therapy. METHODS: Plasma for virus load (VL) quantitation was obtained from 451 women enrolled into the study. VL was quantified using the Cepheid GeneXpert HIV-1 quantitative test. Dried blood spots were collected from 453 infants at birth, 4-6 weeks, 3 months, and 6 months. HIV-1 infant diagnosis was conducted using the Cepheid GeneXpert HIV-1 qualitative test. Absolute and cumulative MTCT rates, and the mortality rate by 6 months were calculated. RESULTS: Seven mothers (1.55%) had transmitted HIV-1 infection to their infants by 6 months. Four infants (0.88%, 95% confidence interval (CI) 0.26-2.33%) were infected IU, one infant (0.22%, 95% CI 0-1.4%) was infected IP, and two infants (0.44%, 95% CI 0.01-1.7%) were infected PP. The infant mortality rate was 0.88% (95% CI 0.26-2.33%). CONCLUSIONS: In the first 6 months of life, in the era of Option B Plus combination antiretroviral therapy, IU transmission is the major route of MTCT. The cumulative MTCT rate of 1.55% in a breastfeeding population contributes to growing evidence that complete elimination of MTCT is possible.

Effect of Xpert MTB/RIF on clinical outcomes in routine care settings: individual patient data meta-analysis.

BACKGROUND: Xpert MTB/RIF, the most widely used automated nucleic acid amplification test for tuberculosis, is available in more than 130 countries. Although diagnostic accuracy is well documented, anticipated improvements in patient outcomes have not been clearly identified. We performed an individual patient data meta-analysis to examine improvements in patient outcomes associated with Xpert MTB/RIF. METHODS: We searched PubMed, Embase, ClinicalTrials.gov, and the Pan African Clinical Trials Registry from inception to Feb 1, 2018, for randomised controlled trials (RCTs) comparing the use of Xpert MTB/RIF with sputum smear microscopy as tests for tuberculosis diagnosis in adults (aged 18 years or older). We excluded studies of patients with extrapulmonary tuberculosis, and studies in which mortality was not assessed. We used a two-stage approach for our primary analysis and a one-stage approach for the sensitivity analysis. To assess the primary outcome of cumulative 6-month all-cause mortality, we first performed logistic regression models (random effects for cluster randomised trials, with robust SEs for multicentre studies) for each trial, and then pooled the odds ratio (OR) estimates by a fixed-effects (inverse variance) or random-effects (Der Simonian Laird) meta-analysis. We adjusted for age and gender, and stratified by HIV status and previous tuberculosis-treatment history. The study protocol has been registered with PROSPERO, number CRD42014013394. FINDINGS: Our search identified 387 studies, of which five RCTs were eligible for analysis. 8567 adult clinic attendees (4490 [63·5%] of 7074 participants for whom data were available were HIV-positive) were tested for tuberculosis with Xpert MTB/RIF (Xpert group) versus sputum smear microscopy (sputum smear group), across five low-income and middle-income countries (South Africa, Brazil, Zimbabwe, Zambia, and Tanzania). The primary outcome (reported in three studies) occurred in 182 (4·5%) of 4050 patients in the Xpert group and 217 (5·3%) of 4093 patients in the smear group (pooled adjusted OR 0·88, 95% CI 0·68-1·14 [p=0·34]; for HIV-positive individuals OR 0·83, 0·65-1·05 [p=0·12]). Kaplan-Meier estimates showed a lower rate of death (12·73 per 100 person-years in the Xpert group vs 16·38 per 100 person-years in the sputum smear group) for HIV-positive patients (hazard ratio 0·76, 95% CI 0·60-0·97; p=0·03). The risk of bias was assessed as reasonable and the statistical heterogeneity across studies was low (I2<20% for the primary outcome). INTERPRETATION: Despite individual patient data analysis from five RCTs, we were unable to confidently rule in nor rule out an Xpert MTB/RIF-associated reduction in mortality among outpatients tested for tuberculosis. Reduction in mortality among HIV-positive patients in a secondary analysis suggests the possibility of population-level impact. FUNDING: US National Institutes of Health.

Effect of new tuberculosis diagnostic technologies on community-based intensified case finding: a multicentre randomised controlled trial.

BACKGROUND: Inadequate case detection results in high levels of undiagnosed tuberculosis in sub-Saharan Africa. Data for the effect of new diagnostic tools when used for community-based intensified case finding are not available, so we investigated whether the use of sputum Xpert-MTB/RIF and the Determine TB LAM urine test in two African communities could be effective. METHODS: In a pragmatic, randomised, parallel-group trial with individual randomisation stratified by country, we compared sputum Xpert-MTB/RIF, and if HIV-infected, the Determine TB LAM urine test (novel diagnostic group), with laboratory-based sputum smear microscopy (routine diagnostic group) for intensified case finding in communities with high tuberculosis and HIV prevalence in Cape Town, South Africa, and Harare, Zimbabwe. Participants were randomly assigned (1:1) to these groups with computer-generated allocation lists, using culture as the reference standard. In Cape Town, participants were randomised and tested at an Xpert-equipped mobile van, while in Harare, participants were driven to a local clinic where the same diagnostic tests were done. The primary endpoint was the proportion of culture-positive tuberculosis cases initiating tuberculosis treatment in each study group at 60 days. This trial is registered at ClinicalTrials.gov, number NCT01990274. FINDINGS: Between Oct 18, 2013, and March 31, 2015, 2261 individuals were screened and 875 (39%) of these met the criteria for diagnostic testing. 439 participants were randomly assigned to the novel group and 436 to the routine group. 74 (9%) of 875 participants had confirmed tuberculosis. If late culture-based treatment initiation was excluded, more patients with culture-positive tuberculosis were initiated on treatment in the novel group at 60 days (36 [86%] of 42 in the novel group vs 18 [56%] of 32 in the routine group). Thus the difference in the proportion initiating treatment between groups was 29% (95% CI 9-50, p=0·0047) and 53% more patients initiated therapy in the novel diagnostic group than in the routine diagnostic group. One culture-positive patient was treated based only on a positive LAM test. INTERPRETATION: Compared with traditional tools, Xpert-MTB/RIF for community-based intensified case finding in HIV and tuberculosis-endemic settings increased the proportion of patients initiating treatment. By contrast, urine LAM testing was not found to be useful for intensive case finding in this setting. FUNDING: European and Developing Countries Clinical Trials Partnership and South African Medical Research Council.

Drug-resistant tuberculosis in high-risk groups, Zimbabwe.

To estimate prevalence of multidrug-resistant tuberculosis (MDR TB) in Harare, Zimbabwe, in 2012, we performed microbiologic testing on acid-fast bacilli smear-positive sputum samples from patients previously treated for TB. Twenty (24%) of 84 specimens were consistent with MDR TB. A national drug-resistance survey is needed to determine MDR TB prevalence in Zimbabwe.

Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial.

BACKGROUND: The Xpert MTB/RIF test for tuberculosis is being rolled out in many countries, but evidence is lacking regarding its implementation outside laboratories, ability to inform same-day treatment decisions at the point of care, and clinical effect on tuberculosis-related morbidity. We aimed to assess the feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing at primary-care health-care facilities in southern Africa. METHODS: In this pragmatic, randomised, parallel-group, multicentre trial, we recruited adults with symptoms suggestive of active tuberculosis from five primary-care health-care facilities in South Africa, Zimbabwe, Zambia, and Tanzania. Eligible patients were randomly assigned using pregenerated tables to nurse-performed Xpert MTB/RIF at the clinic or sputum smear microscopy. Participants with a negative test result were empirically managed according to local WHO-compliant guidelines. Our primary outcome was tuberculosis-related morbidity (measured with the TBscore and Karnofsky performance score [KPS]) in culture-positive patients who had begun anti-tuberculosis treatment, measured at 2 months and 6 months after randomisation, analysed by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT01554384. FINDINGS: Between April 12, 2011, and March 30, 2012, we randomly assigned 758 patients to smear microscopy (182 culture positive) and 744 to Xpert MTB/RIF (185 culture positive). Median TBscore in culture-positive patients did not differ between groups at 2 months (2 [IQR 0-3] in the smear microscopy group vs 2 [0·25-3] in the MTB/RIF group; p=0·85) or 6 months (1 [0-3] vs 1 [0-3]; p=0·35), nor did median KPS at 2 months (80 [70-90] vs 90 [80-90]; p=0·23) or 6 months (100 [90-100] vs 100 [90-100]; p=0·85). Point-of-care MTB/RIF had higher sensitivity than microscopy (154 [83%] of 185 vs 91 [50%] of 182; p=0·0001) but similar specificity (517 [95%] 544 vs 540 [96%] of 560; p=0·25), and had similar sensitivity to laboratory-based MTB/RIF (292 [83%] of 351; p=0·99) but higher specificity (952 [92%] of 1037; p=0·0173). 34 (5%) of 744 tests with point-of-care MTB/RIF and 82 (6%) of 1411 with laboratory-based MTB/RIF failed (p=0·22). Compared with the microscopy group, more patients in the MTB/RIF group had a same-day diagnosis (178 [24%] of 744 vs 99 [13%] of 758; p<0·0001) and same-day treatment initiation (168 [23%] of 744 vs 115 [15%] of 758; p=0·0002). Although, by end of the study, more culture-positive patients in the MTB/RIF group were on treatment due to reduced dropout (15 [8%] of 185 in the MTB/RIF group did not receive treatment vs 28 [15%] of 182 in the microscopy group; p=0·0302), the proportions of all patients on treatment in each group by day 56 were similar (320 [43%] of 744 in the MTB/RIF group vs 317 [42%] of 758 in the microscopy group; p=0·6408). INTERPRETATION: Xpert MTB/RIF can be accurately administered by a nurse in primary-care clinics, resulting in more patients starting same-day treatment, more culture-positive patients starting therapy, and a shorter time to treatment. However, the benefits did not translate into lower tuberculosis-related morbidity, partly because of high levels of empirical-evidence-based treatment in smear-negative patients. FUNDING: European and Developing Countries Clinical Trials Partnership, National Research Foundation, and Claude Leon Foundation.