BACKGROUND: Among people living with HIV (PLHIV), more flexible and sensitive tuberculosis (TB) screening tools capable of detecting both symptomatic and subclinical active TB are needed to (1) reduce morbidity and mortality from undiagnosed TB; (2) facilitate scale-up of tuberculosis preventive therapy (TPT) while reducing inappropriate prescription of TPT to PLHIV with subclinical active TB; and (3) allow for differentiated HIV-TB care. METHODS AND FINDINGS: We used Botswana XPRES trial data for adult HIV clinic enrollees collected during 2012 to 2015 to develop a parsimonious multivariable prognostic model for active prevalent TB using both logistic regression and random forest machine learning approaches. A clinical score was derived by rescaling final model coefficients. The clinical score was developed using southern Botswana XPRES data and its accuracy validated internally, using northern Botswana data, and externally using 3 diverse cohorts of antiretroviral therapy (ART)-naive and ART-experienced PLHIV enrolled in XPHACTOR, TB Fast Track (TBFT), and Gugulethu studies from South Africa (SA). Predictive accuracy of the clinical score was compared with the World Health Organization (WHO) 4-symptom TB screen. Among 5,418 XPRES enrollees, 2,771 were included in the derivation dataset; 67% were female, median age was 34 years, median CD4 was 240 cells/μL, 189 (7%) had undiagnosed prevalent TB, and characteristics were similar between internal derivation and validation datasets. Among XPHACTOR, TBFT, and Gugulethu cohorts, median CD4 was 400, 73, and 167 cells/μL, and prevalence of TB was 5%, 10%, and 18%, respectively. Factors predictive of TB in the derivation dataset and selected for the clinical score included male sex (1 point), ≥1 WHO TB symptom (7 points), smoking history (1 point), temperature >37.5°C (6 points), body mass index (BMI) <18.5kg/m2 (2 points), and severe anemia (hemoglobin <8g/dL) (3 points). Sensitivity using WHO 4-symptom TB screen was 73%, 80%, 94%, and 94% in XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively, but increased to 88%, 87%, 97%, and 97%, when a clinical score of ≥2 was used. Negative predictive value (NPV) also increased 1%, 0.3%, 1.6%, and 1.7% in XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively, when the clinical score of ≥2 replaced WHO 4-symptom TB screen. Categorizing risk scores into low (<2), moderate (2 to 10), and high-risk categories (>10) yielded TB prevalence of 1%, 1%, 2%, and 6% in the lowest risk group and 33%, 22%, 26%, and 32% in the highest risk group for XPRES, XPHACTOR, TBFT, and Gugulethu cohorts, respectively. At clinical score ≥2, the number needed to screen (NNS) ranged from 5.0 in Gugulethu to 11.0 in XPHACTOR. Limitations include that the risk score has not been validated in resource-rich settings and needs further evaluation and validation in contemporary cohorts in Africa and other resource-constrained settings. CONCLUSIONS: The simple and feasible clinical score allowed for prioritization of sensitivity and NPV, which could facilitate reductions in mortality from undiagnosed TB and safer administration of TPT during proposed global scale-up efforts. Differentiation of risk by clinical score cutoff allows flexibility in designing differentiated HIV-TB care to maximize impact of available resources.

BACKGROUND: Clinical scores to determine early (6-month) antiretroviral therapy (ART) mortality risk have not been developed for sub-Saharan Africa (SSA), home to 70% of people living with HIV. In the absence of validated scores, WHO eligibility criteria (EC) for ART care intensification are CD4 < 200/μL or WHO stage III/IV. METHODS: We used Botswana XPRES trial data for adult ART enrollees to develop CD4-independent and CD4-dependent multivariable prognostic models for 6-month mortality. Scores were derived by rescaling coefficients. Scores were developed using the first 50% of XPRES ART enrollees, and their accuracy validated internally and externally using South African TB Fast Track (TBFT) trial data. Predictive accuracy was compared between scores and WHO EC. RESULTS: Among 5553 XPRES enrollees, 2838 were included in the derivation dataset; 68% were female and 83 (3%) died by 6 months. Among 1077 TBFT ART enrollees, 55% were female and 6% died by 6 months. Factors predictive of 6-month mortality in the derivation dataset at p < 0.01 and selected for the CD4-independent score included male gender (2 points), ≥ 1 WHO tuberculosis symptom (2 points), WHO stage III/IV (2 points), severe anemia (hemoglobin < 8 g/dL) (3 points), and temperature > 37.5 °C (2 points). The same variables plus CD4 < 200/μL (1 point) were included in the CD4-dependent score. Among XPRES enrollees, a CD4-independent score of ≥ 4 would provide 86% sensitivity and 66% specificity, whereas WHO EC would provide 83% sensitivity and 58% specificity. If WHO stage alone was used, sensitivity was 48% and specificity 89%. Among TBFT enrollees, the CD4-independent score of ≥ 4 would provide 95% sensitivity and 27% specificity, whereas WHO EC would provide 100% sensitivity but 0% specificity. Accuracy was similar between CD4-independent and CD4-dependent scores. Categorizing CD4-independent scores into low (< 4), moderate (4-6), and high risk (≥ 7) gave 6-month mortality of 1%, 4%, and 17% for XPRES and 1%, 5%, and 30% for TBFT enrollees. CONCLUSIONS: Sensitivity of the CD4-independent score was nearly twice that of WHO stage in predicting 6-month mortality and could be used in settings lacking CD4 testing to inform ART care intensification. The CD4-dependent score improved specificity versus WHO EC. Both scores should be considered for scale-up in SSA.

Setting: Twenty-two clinics providing HIV care and treatment in Botswana where tuberculosis (TB) and HIV comorbidity is as high as 49%. Objectives: To assess eligibility of TB preventive treatment (TPT) at antiretroviral therapy (ART) initiation and at four follow-up visits (FUVs), and to describe the TB prevalence and associated factors at baseline and yield of TB diagnoses at each FUV. Design: A prospective study of routinely collected data on people living with HIV (PLHIV) enrolled into care for the Xpert((R)) MTB/RIF Package Rollout Evaluation Study between 2012 and 2015. Results: Of 6041 PLHIV initiating ART, eligibility for TPT was 69% (4177/6041) at baseline and 93% (5408/5815); 95% (5234/5514); 96% (4869/5079); and 97% (3925/4055) at FUV1, FUV2, FUV3, and FUV4, respectively. TB prevalence at baseline was 11% and 2%, 3%, 3% and 6% at each subsequent FUV. At baseline, independent risk factors for prevalent TB were CD4 <200 cells/mm(3) (aOR = 1.4, P = 0.030); anemia (aOR = 2.39, P < 0.001); cough (aOR = 11.21, P < 0.001); fever (aOR = 2.15, P = 0.001); and weight loss (aOR = 2.60, P = 0.002). Conclusion: Eligibility for TPT initiation is higher at visits post-ART initiation, while most cases of active TB were identified at ART initiation. Missed opportunities for TB further compromises TB control effort among PLHIV in Botswana.

BACKGROUND: Patients with non-tuberculous mycobacteria (NTM) or Mycobacterium tuberculosis (MTB) pulmonary disease may have similar clinical presentation. The potential for misdiagnosis and inappropriate treatment exists in settings with limited testing capacity for Xpert(R) MTB/RIF (Xpert), phenotypic culture and NTM speciation. We describe treatment outcomes among people living with HIV (PLHIV) who received anti-tuberculosis treatment and were found to have NTM or MTB positive sputum cultures. METHODS: PLHIV attending one of the 22 participating HIV clinics, who screened positive for >/=1 tuberculosis (TB) symptoms (cough, fever, night sweats, or weight loss) were asked to submit sputa for culture and speciation from August 2012 to November 2014. The national intensified TB case finding algorithms were followed: initially symptomatic patients were evaluated by testing sputum samples using a smear (smear-based TB diagnostic algorithm) and, after GeneXpert instruments were installed, by testing with Xpert (Xpert-based TB diagnostic algorithm). Within the study period, TB diagnostic algorithms used for MTB did not include screening, diagnosis, and management of NTM. Despite MTB negative culture, some symptomatic patients, including those with NTM positive culture, received empirical anti-TB treatment at the discretion of treating clinicians. Per the World Health Organization treatment outcomes classification: died, treatment failure or loss-to-follow-up were classified as unfavorable (unsuccessful) outcome; cured and treatment completed were classified as favorable (successful) outcome. Empiric treatment was defined as initiating treatment without or before receiving a test result indicating MTB. We compare treatment outcomes and characteristics among patients with NTM or MTB positive culture who received anti-TB treatment. RESULTS: Among 314 PLHIV, who were found co-infected with TB, 146 cases had microbiological evidence; and for 131/146 MTB positive cultures were reported. One-hundred fifty-two of the 314 were clinically diagnosed with TB and treated empirically. Among those empirically treated for TB, 36/152 had culture results positive for NTM, and another 43/152 had culture results positive for MTB, reported after patients received empirical anti-TB treatment. Overall, MTB positive culture results were reported for 174 (131 plus 43) patients. Treatment outcomes were available for 32/36 NTM and 139/174 MTB; unfavorable outcomes were 12.5% and 8.7% for NTM and MTB, respectively, p = 0.514, respectively. For 34/36 tested NTM patients, all Xpert results indicated 'no MTB'. Among patients who initially received empiric anti-TB treatment and ultimately were found to have MTB positive culture, the unfavorable outcome was 11.8% (4/34), compared to 12.5% (4/32) of patients with NTM positive culture, Fisher's exact test p = 1.00. CONCLUSIONS: While the higher unfavorable outcome was non statistically significant, the impact of inappropriate treatment among NTM patients should not be overlooked. Our findings suggest that Xpert has the potential to rapidly rule-out NTM and avoid sub-optimal treatment; further research is needed to evaluate such potential.

Setting: Twenty-two human immunodeficiency virus (HIV) clinics in Botswana. Objective: To compare sputum collection rates, sputum quality and volume, and tuberculosis (TB) diagnosis rates before and after field efforts to improve sputum collection among individuals newly diagnosed with HIV with TB symptoms. Design: Newly diagnosed individuals living with HIV attending 22 HIV clinics in Botswana were screened for TB from August 2012 to March 2014. Starting in May 2013, a field intervention composed of the introduction of a tracking log for presumed TB patients, and patient instructions and sputum induction to improve sputum collection rates was implemented. Results: Prior to the intervention, sputum collection rates were 44.1% (384/870). Subsequently, sputum collection increased to 58.3% (579/993) (P < 0.001). Sputum quality and volume also improved. Although rates of TB diagnosis increased from 9.7% (84/870) to 12.5% (120/993), this difference was not significant (P = 0.143). Conclusion: Sputum collection rates among presumptive TB cases, as well as sputum quality and volume improved after implementation of the field intervention. To improve sputum collection rates, efforts at the program level should be ongoing.

BACKGROUND: Undiagnosed tuberculosis (TB) remains the most common cause of HIV-related mortality. Xpert MTB/RIF (Xpert) is being rolled out globally to improve TB diagnostic capacity. However, previous Xpert impact trials have reported that health system weaknesses blunted impact of this improved diagnostic tool. During phased Xpert rollout in Botswana, we evaluated the impact of a package of interventions comprising (1) additional support for intensified TB case finding (ICF), (2) active tracing for patients missing clinic appointments to support retention, and (3) Xpert replacing sputum-smear microscopy, on early (6-month) antiretroviral therapy (ART) mortality. METHODS: At 22 clinics, ART enrollees > 12 years old were eligible for inclusion in three phases: a retrospective standard of care (SOC), prospective enhanced care (EC), and prospective EC plus Xpert (EC+X) phase. EC and EC+X phases were implemented as a stepped-wedge trial. Participants in the EC phase received SOC plus components 1 (strengthened ICF) and 2 (active tracing) of the intervention package, and participants in the EC+X phase received SOC plus all three intervention package components. Primary and secondary objectives were to compare all-cause 6-month ART mortality between SOC and EC+X and between EC and EC+X phases, respectively. We used adjusted analyses, appropriate for study design, to control for baseline differences in individual-level factors and intra-facility correlation. RESULTS: We enrolled 14,963 eligible patients: 8980 in SOC, 1768 in EC, and 4215 in EC+X phases. Median age of ART enrollees was 35 and 64% were female. Median CD4 cell count was lower in SOC than subsequent phases (184/muL in SOC, 246/muL in EC, and 241/muL in EC+X). By 6 months of ART, 461 (5.3%) of SOC, 54 (3.2%) of EC, and 121 (3.0%) of EC+X enrollees had died. Compared with SOC, 6-month mortality was lower in the EC+X phase (adjusted hazard ratio, 0.77; 95% confidence interval, 0.61-0.97, p = 0.029). Compared with EC enrollees, 6-month mortality was similar among EC+X enrollees. CONCLUSIONS: Interventions to strengthen ICF and retention were associated with lower early ART mortality. This new evidence highlights the need to strengthen ICF and retention in many similar settings. Similar to other trials, no additional mortality benefit of replacing sputum-smear microscopy with Xpert was observed. TRIAL REGISTRATION: Retrospectively registered: ClinicalTrials.gov (NCT02538952).

BACKGROUND: Xpert(R) MTB/RIF (Xpert) has high sensitivity for diagnosing tuberculosis (TB) compared to sputum-smear microscopy (smear) and can reduce time-to-diagnosis, time-to-treatment and potentially unfavorable patient-level treatment outcome. METHODS: People living with HIV (PLHIV) initiating antiretroviral therapy at 22 HIV clinics were enrolled and underwent systematic screening for TB (August 2012-November 2014). GeneXpert instruments were deployed following a stepped-wedge design at 13 centers from October 2012-June 2013. Treatment outcomes classified as an unfavorable outcome (died, treatment failure or loss-to-follow-up) or favorable outcome (cured and treatment completed). To determine outcome, smear was performed at month 5 or 6. Empiric treatment was defined as initiating treatment without/before receiving TB-positive results. Adjusting for intra-facility correlation, we compared patient-level treatment outcomes between patients screened using smear (smear arm)- and Xpert-based algorithms (Xpert arm). RESULTS: Among 6041 patients enrolled (smear arm, 1816; Xpert arm, 4225), 256 (199 per 2985 and 57 per 1582 person-years of follow-up in Xpert and smear arms, respectively; adjusted incidence rate ratio, 9.07; 95% confidence interval [CI]: 4.70-17.48; p < 0.001) received TB diagnosis and were treated. TB treatment outcomes were available for 203 patients (79.3%; Xpert, 157; smear, 46). Unfavorable outcomes were reported for 21.7% (10/46) in the smear and 13.4% (21/157) in Xpert arm (adjusted hazard ratio, 1.40; 95% CI: 0.75-2.26; p = 0.268). Compared to smear, in Xpert arm median days from sputum collection to TB treatment was 6 days (interquartile range [IQR] 2-17 versus 22 days [IQR] 3-51), p = 0.005; patients with available sputum test result had microbiologically confirmed TB in 59.0% (102/173) versus 41.9% (18/43), adjusted Odds Ratio [aOR], 2.00, 95% CI: 1.01-3.96, p = 0.048). In smear arm empiric treatment was 68.4% (39/57) versus 48.7% (97/199), aOR, 2.28, 95% CI: 1.24-4.20, p = 0.011), compared to Xpert arm. CONCLUSIONS: TB treatment outcomes were similar between the smear and Xpert arms. However, compared to the smear arm, more patients in the Xpert arm received a TB diagnosis, had a microbiologically confirmed TB, and had a shorter time-to-treatment, and had a lower empiric treatment. Further research is recommended to identify potential gaps in the Botswana health system and similar settings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02538952. Retrospectively registered on 2 September 2015.

Introduction: the World Health Organization endorsed (2010) the use of Xpert MTB/RIF and countries are shifting from smear microscopy (smear)-based to Xpert MTB/RIF-based tuberculosis (TB) diagnostic algorithms. As with smear, sputum quality may predict the likelihood of obtaining a bacteriologically-confirmed TB when using Xpert MTB/RIF. Methods: from 08/12-11/2014, all people living with HIV were recruited at 22 clinics. For patients screened positive using the four TB symptoms their sputa were tested by Xpert MTB/RIF and smear. Laboratorians assessed and recorded sputum appearance and volume. The yield of bacteriologically-positive sputum evaluated using Xpert MTB/RIF and smear, likelihood-ratios were calculated. Results: among 6,041 patients enrolled 2,296 were presumptive TB, 1,305 (56.8%) had > 1 sputa collected and 644/1,305 (49.3%) had both Xpert MTB/RIF and smear results. Since >1 sputa collected from 644 patients 954 sputa were tested by Xpert MTB/RIF and smear. Bacteriologically-positive sputum was two-fold higher with Xpert MTB/RIF 11.4% versus smear 5.3%, p < 0.001. Sputum appearance and quantity were not predictive of bacteriologically-positive results, except volume of 2ml to < 3ml, tested by Xpert MTB/RIF LR+= 1.26 (95% CI, 1.05–1.50). Conclusion: Xpert MTB/RIF test yield to bacteriologically-positive sputum was superior to smear. Sputum quality and quantity, however, were not consistently predictive of bacteriologically-positive results by Xpert MTB/RIF or smear.

BACKGROUND: Non-tuberculous mycobacteria (NTM) can cause pulmonary infection and disease especially among people living with HIV (PLHIV). PLHIV with NTM disease may clinically present with one of the four symptoms consistent with tuberculosis (TB). We describe the prevalence of NTM and Mycobacterium tuberculosis complex (MTBC) isolated among PLHIV who presented for HIV care and treatment. METHODS: All PLHIV patients presenting for HIV care and treatment services at 22 clinical sites in Botswana were offered screening for TB and were recruited. Patients who had >/=1 TB symptom were asked to submit sputa for Xpert MTB/RIF and culture. Culture growth was identified as NTM and MTBC using the SD-Bioline TB Ag MPT64 Kit and Ziehl Neelsen microscopy. NTM and MTBC isolates underwent species identification by the Hain GenoType CM and AS line probe assays. RESULTS: Among 16, 259 PLHIV enrolled 3068 screened positive for at least one TB symptom. Of these, 1940 submitted >/=1 sputum specimen, 427 (22%) patients had >/=1 positive-culture result identified phenotypically for mycobacterial growth. Of these 247 and 180 patients were identified as having isolates were NTM and MTBC, respectively. Of the 247 patients identified with isolates containing NTM; 19 were later excluded as not having NTM based on additional genotypic testing. Among the remaining 408 patients 228 (56%, 95% confidence interval, 46-66%) with NTM. M. intracellulare was the most common isolated (47.8%). Other NTMs commonly associated with pulmonary disease included M. malmoense (3.9%), M. avium (2.2%), M. abscessus (0.9%) and M. kansasii (0.4%). After excluding NTM isolates that were non-speciated and M. gordonae 154 (67.5%) of the NTM isolates were potential pathogens. CONCLUSIONS: In the setting of HIV care and treatment, over-half (56%) of a positive sputum culture among PLHIV with TB symptoms was NTM. Though we were not able to distinguish in our study NTM disease and colonization, the study suggests culture and species identification for PLHIV presenting with TB symptoms remains important to facilitate NTM diagnosis and hasten time to appropriate treatment.

BACKGROUND: In 2011, the Botswana National Tuberculosis Program adopted World Health Organization guidelines and introduced Xpert MTB/RIF (Xpert) assay to support intensified case finding among people living with HIV enrolling in care. An evaluation was designed to assess performance under operational conditions to inform the national Xpert scale-up. METHODS: Xpert was implemented from August 2012 through November 2014 with 13 GeneXpert instruments (GeneXpert) deployed in a phased approach over nine months: nine centralized laboratory and four point-of-care (POC) peripheral clinics. Clinicians and laboratorians were trained on the four-symptom tuberculosis screening algorithm and Xpert testing. We documented our experience with staff training and GeneXpert performance. Test results were extracted from GeneXpert software; unsuccessful tests were analysed in relation to testing sites and trends over time. RESULTS: During 276 instrument-months of operation a total of 3,630 tests were performed, of which 3,102 (85%) were successful with interpretable results. Mycobacterium tuberculosis complex was detected for 447 (14%); of these, 36 (8%) were rifampicin resistant. Of all 3,630 Xpert tests, 528 (15%) were unsuccessful; of these 361 (68%) were classified as "error", 119 (23%) as "invalid" and 48 (9%) as "no result". The total number of recorded error codes was 385 and the most common reasons were related to sample processing (211; 55%) followed by power supply (77; 20%) and cartridge/module related (54; 14%). Cumulative incidence of unsuccessful test was similar between POC (17%, 95% CI: 11-25%) and centralized laboratory-based GeneXpert instruments (14%, 95% CI: 11-17%; p = 0.140). CONCLUSIONS: Xpert introduction was successful in the Botswana setting. The incidence of unsuccessful test was similar by GeneXpert location (POC vs. centralized laboratory). However, unsuccessful test incidence (15%) in our settings was higher than previously reported and was mostly related to improper sample processing. Ensuring adequate training among Xpert testing staff is essential to minimize errors.

BACKGROUND: Effective treatment for drug-susceptible tuberculosis (TB) rapidly renders patients non-infectious, long before conversion of sputum acid-fast smear or culture to negative. Multidrug-resistant TB (MDR-TB) patients on treatment are currently assumed to remain infectious for months. While the resources required for prolonged hospitalization are a barrier to the scale-up of MDR-TB treatment, the safety of community treatment is clear. OBJECTIVES: To estimate the impact of treatment on infectiousness among MDR-TB patients. METHODS: A series of five human-to-guinea pig TB transmission studies was conducted to test various interventions for infection control. Guinea pigs in adjacent chambers were exposed to exhaust air from a hospital ward occupied by mostly sputum smear- and culture-positive MDR-TB patients. The guinea pigs then underwent tuberculin skin testing for infection. Only the control groups of guinea pigs from each study (no interventions used) provide the data for this analysis. The number of guinea pigs infected in each study is reported and correlated with Mycobacterium tuberculosis drug susceptibility relative to treatment. RESULTS: Despite exposure to presumably infectious MDR-TB patients, infection percentages among guinea pigs ranged from 1% to 77% in the five experiments conducted. In one experiment in which guinea pigs were exposed to 27 MDR-TB patients newly started on effective treatment for 3 months, there was minimal transmission. In four other experiments with greater transmission, guinea pigs had been exposed to patients with unsuspected extensively drug-resistant tuberculosis who were not on effective treatment. CONCLUSIONS: In this model, effective treatment appears to render MDR-TB patients rapidly non-infectious. Further prospective studies on this subject are needed.

OBJECTIVE: While 6- to 12-month courses of isoniazid for tuberculosis prevention are considered safe in pregnant women, the effects of longer-term isoniazid prophylaxis or isoniazid in combination with antiretroviral therapy (ART) are not established in human-immunodeficiency-virus-(HIV-) infected women who experience pregnancy during the course of therapy. DESIGN: Nested study of pregnancy outcomes among HIV-infected women participating in a placebo-controlled, TB-prevention trial using 36 months daily isoniazid. Pregnancy outcomes were collected by interview and record review. RESULTS: Among 196 pregnant women, 103 (52.6%) were exposed to isoniazid during pregnancy; all were exposed to antiretroviral drugs. Prior to pregnancy they had received a median of 341 days (range 1-1095) of isoniazid. We observed no isoniazid-associated hepatitis or other severe isoniazid-associated adverse events in the 103 women. Pregnancy outcomes were 132 term live births, 42 premature births, 11 stillbirths, 8 low birth weight, 6 spontaneous abortions, 4 neonatal deaths, and 1 congenital abnormality. In a multivariable model, neither isoniazid nor ART exposure during pregnancy was significantly associated with adverse pregnancy outcome (adjusted odds ratios 0.6, 95% CI: 0.3-1.1 and 1.8, 95% CI 0.9-3.6, resp.). CONCLUSIONS Long-term isoniazid prophylaxis was not associated with adverse pregnancy outcomes, such as preterm delivery, even in the context of ART exposure.

RATIONALE: Drug-resistant tuberculosis transmission in hospitals threatens staff and patient health. Surgical face masks used by patients with tuberculosis (TB) are believed to reduce transmission but have not been rigorously tested. OBJECTIVES: We sought to quantify the efficacy of surgical face masks when worn by patients with multidrug-resistant TB (MDR-TB). METHODS: Over 3 months, 17 patients with pulmonary MDR-TB occupied an MDR-TB ward in South Africa and wore face masks on alternate days. Ward air was exhausted to two identical chambers, each housing 90 pathogen-free guinea pigs that breathed ward air either when patients wore surgical face masks (intervention group) or when patients did not wear masks (control group). Efficacy was based on differences in guinea pig infections in each chamber. MEASUREMENTS AND MAIN RESULTS: Sixty-nine of 90 control guinea pigs (76.6%; 95% confidence interval [CI], 68-85%) became infected, compared with 36 of 90 intervention guinea pigs (40%; 95% CI, 31-51%), representing a 56% (95% CI, 33-70.5%) decreased risk of TB transmission when patients used masks. CONCLUSIONS: Surgical face masks on patients with MDR-TB significantly reduced transmission and offer an adjunct measure for reducing TB transmission from infectious patients.

BACKGROUND: Participant non-adherence and loss to follow-up can compromise the validity of clinical trial results. An assessment of these issues was made in a 3-year tuberculosis prevention trial among HIV-infected adults in Botswana. METHODS AND FINDINGS: Between 11/2004-07/2006, 1995 participants were enrolled at eight public health clinics. They returned monthly to receive bottles of medication and were expected to take daily tablets of isoniazid or placebo for three years. Non-adherence was defined as refusing tablet ingestion but agreeing to quarterly physical examinations. Loss to follow-up was defined as not having returned for appointments in ≥60 days. Between 10/2008-04/2009, survey interviews were conducted with 83 participants identified as lost to follow-up and 127 identified as non-adherent. As a comparison, 252 randomly selected adherent participants were also surveyed. Multivariate logistic regression analysis was used to identify associations with selected risk factors. Men had higher odds of being non-adherent (adjusted odds ratio (AOR), 2.24; 95% confidence interval [95%CI] 1.24-4.04) and lost to follow-up (AOR 3.08; 95%CI 1.50-6.33). Non-adherent participants had higher odds of reporting difficulties taking the regimen or not knowing if they had difficulties (AOR 3.40; 95%CI 1.75-6.60) and lower odds associated with each year of age (AOR 0.95; 95%CI 0.91-0.98), but other variables such as employment, distance from clinic, alcohol use, and understanding study requirements were not significantly different than controls. Among participants who were non-adherent or lost to follow-up, 40/210 (19.0%) reported that they stopped the medication because of work commitments and 33/210 (15.7%) said they thought they had completed the study. CONCLUSIONS: Men had higher odds of non-adherence and loss to follow-up than women. Potential interventions that might improve adherence in trial participants may include:targeting health education for men, reducing barriers, clarifying study expectations, educating employers about HIV/AIDS to help reduce stigma in the workplace, and encouraging employers to support employee health. TRIAL REGISTRATION: ClinicalTrials.gov NCT00164281.