Modeling the impact of universal tuberculosis molecular testing and timing of tuberculosis preventive treatment during antiretroviral therapy initiation in South Africa.

OBJECTIVES: Targeted universal tuberculosis (TB) testing can improve TB detection among people with HIV. This approach is being scaled up in South Africa through Xpert MTB/RIF Ultra testing for individuals starting antiretroviral therapy and annually thereafter. Clarity is needed on how Universal Xpert testing may affect TB preventive treatment (TPT) provision, and on whether TPT should be delayed until TB is ruled out. DESIGN: State-transition microsimulation. METHODS: We simulated a cohort of South African patients being screened for TB while entering HIV care. We compared clinical and cost outcomes between four TB screening algorithms: symptom-based, C-reactive protein-based, and Universal Xpert testing with either simultaneous or delayed TPT initiation. RESULTS: Prompt TB treatment initiation among simulated patients with TB increased from 26% (24-28%) under symptom screening to 53% (50-56%) with Universal Xpert testing. Universal Xpert testing led to increased TPT uptake when TPT initiation was simultaneous, but to approximately 50% lower TPT uptake if TPT was delayed. Universal Xpert with simultaneous TPT prevented incident TB compared to either symptom screening (median 17 cases averted per 5000 patients) or Universal Xpert with delayed TPT (median 23 averted). Universal Xpert with Simultaneous TPT cost approximately $39 per incremental TPT course compared to Universal Xpert with delayed TPT. CONCLUSIONS: Universal Xpert testing can promote timely treatment for newly diagnosed people with HIV who have active TB. Pairing universal testing with immediate TPT will improve the promptness, uptake, and preventive effects of TPT. Simultaneous improvements to TB care cascades are needed to maximize impact.

Pragmatic cluster-randomized trial of home-based preventive treatment for TB in Ethiopia and South Africa (CHIP-TB).

BACKGROUND: Each year, 1 million children develop TB resulting in over 200,000 child deaths. TB preventive treatment (TPT) is highly effective in preventing TB but remains poorly implemented for household child contacts. Home-based child contact management and TPT services may improve access to care. In this study, we aim to evaluate the effectiveness and cost-effectiveness of home-based contact management with TPT initiation in two TB high-burden African countries, Ethiopia and South Africa. METHODS: This pragmatic cluster randomized trial compares home-based versus facility-based care delivery models for contact management. Thirty-six clinics with decentralized TB services (18 in Ethiopia and 18 in South Africa) were randomized in a 1:1 ratio to conduct either home-based or facility-based contact management. The study will attempt to enroll all eligible close child contacts of infectious drug-sensitive TB index patients diagnosed and treated for TB by one of the study clinics. Child TB contact management, including contact tracing, child evaluation, and TPT initiation and follow-up, will take place in the child's home for the intervention arm and at the clinic for the control arm. The primary outcome is the cluster-level ratio of the number of household child contacts less than 15 years of age in Ethiopia and less than 5 years of age in South Africa initiated on TPT per index patient, comparing the intervention to the control arm. Secondary outcomes include child contact identification and the TB prevention continuum of care. Other implementation outcomes include acceptability, feasibility, fidelity, cost, and cost-effectiveness of the intervention. DISCUSSION: This implementation research trial will determine whether home-based contact management identifies and initiates more household child contacts on TPT than facility-based contact management. TRIAL REGISTRATION: NCT04369326 . Registered on April 30, 2020.

High Isoniazid Exposures When Administered with Rifapentine Once Weekly for Latent Tuberculosis in Individuals with Human Immunodeficiency Virus.

Isoniazid pharmacokinetics are not yet well-described during once weekly, high-dose administrations with rifapentine (3HP) for latent tuberculosis infection (LTBI). Fewer data describe 3HP with dolutegravir-based antiretroviral therapy for the treatment of human immunodeficiency virus (HIV). The only prior report of 3HP with dolutegravir reported elevated isoniazid exposures. We measured the plasma isoniazid levels in 30 adults receiving 3HP and dolutegravir for the treatment of LTBI and HIV. The patients were genotyped to determine NAT2 acetylator status, and a population PK model was estimated by nonlinear mixed-effects modeling. The results were compared to previously reported data describing 3HP with dolutegravir, 3HP alone, and isoniazid with neither dolutegravir nor rifapentine. The isoniazid concentrations were adequately described by a one compartment model with a transit compartment absorption process. The isoniazid clearance for slow (8.33 L/h) and intermediate (12 L/h) acetylators were similar to previously reported values. Rapid acetylators (N = 4) had clearance similar to those of intermediate acetylators and much slower than typically reported, but the small sample size was limiting. The absorption rate was lower than usual, likely due to the coadministration with food, and it was faster among individuals with a low body weight. Low-body weight participants were also observed to have greater oral bioavailability. The isoniazid exposures were consistent with, or greater than, the previously reported "elevated" concentrations among individuals receiving 3HP and dolutegravir. The concentrations were substantially greater than those presented in previous reports among individuals receiving 3HP or isoniazid without rifapentine or dolutegravir. We discuss the implications of these findings and the possibility of a drug-drug interaction that is mediated by cellular transport. (This study has been registered at ClinicalTrials.gov under identifier NCT03435146 and has South African National Clinical Trial Registration no. DOH-27-1217-5770.).

Preventive Treatment for Household Contacts of Drug-Susceptible Tuberculosis Patients.

People who live in the household of someone with infectious pulmonary tuberculosis are at a high risk of tuberculosis infection and subsequent progression to tuberculosis disease. These individuals are prioritized for contact investigation and tuberculosis preventive treatment (TPT). The treatment of TB infection is critical to prevent the progression of infection to disease and is prioritized in household contacts. Despite the availability of TPT, uptake in household contacts is poor. Multiple barriers prevent the optimal implementation of these policies. This manuscript lays out potential next steps for closing the policy-to-implementation gap in household contacts of all ages.

Monocyte Transcriptional Responses to Mycobacterium tuberculosis Associate with Resistance to Tuberculin Skin Test and Interferon Gamma Release Assay Conversion.

Heavy exposure to Mycobacterium tuberculosis, the etiologic agent of tuberculosis (TB) and among the top infectious killers worldwide, results in infection that is cleared, contained, or progresses to disease. Some heavily exposed tuberculosis contacts show no evidence of infection using the tuberculin skin test (TST) and interferon gamma release assay (IGRA); yet the mechanisms underlying this "resister" (RSTR) phenotype are unclear. To identify transcriptional responses that distinguish RSTR monocytes, we performed transcriptome sequencing (RNA-seq) on monocytes isolated from heavily exposed household contacts in Uganda and gold miners in South Africa after ex vivo M. tuberculosis infection. Gene set enrichment analysis (GSEA) revealed several gene pathways that were consistently enriched in response to M. tuberculosis among RSTR subjects compared to controls with positive TST/IGRA testing (latent TB infection [LTBI]) across Uganda and South Africa. The most significantly enriched gene set in which expression was increased in RSTR relative to LTBI M. tuberculosis-infected monocytes was the tumor necrosis factor alpha (TNF-α) signaling pathway whose core enrichment (leading edge) substantially overlapped across RSTR populations. These leading-edge genes included candidate resistance genes (ABCA1 and DUSP2) with significantly increased expression among Uganda RSTRs (false-discovery rate [FDR], <0.1). The distinct monocyte transcriptional response to M. tuberculosis among RSTR subjects, including increased expression of the TNF signaling pathway, highlights genes and inflammatory pathways that may mediate resistance to TST/IGRA conversion and provides therapeutic targets to enhance host restriction of M. tuberculosis intracellular infection. IMPORTANCE After heavy M. tuberculosis exposure, the events that determine why some individuals resist TST/IGRA conversion are poorly defined. Enrichment of the TNF signaling gene set among RSTR monocytes from multiple distinct cohorts suggests an important role for the monocyte TNF response in determining this alternative immune outcome. These TNF responses to M. tuberculosis among RSTRs may contribute to antimicrobial programs that result in early clearance or the priming of alternative (gamma interferon-independent) cellular responses.

Resistance to Mycobacterium tuberculosis infection among highly TB exposed South African gold miners.

BACKGROUND: Despite high exposure to Mycobacterium tuberculosis, a small proportion of South African goldminers resist TB infection. We determined, among long-service gold miners i) the proportion who were TB uninfected and ii) epidemiological factors associated with being uninfected. METHODS: We enrolled HIV-negative gold miners aged 33-60 years with ≥15 years' service and no history of TB or silicosis. Miners were defined as TB uninfected if i) QuantiFERON-TB Gold Plus (QFT-Plus) negative or ii) in a stricter definition, QFT-Plus-negative and zero-response on TST and as resisters if they were of Black/African ethnicity and negative on both tests. Logistic regression was used to identify epidemiological factors associated with being TB uninfected. RESULTS: Of 307 participants with a QFT-Plus result, median age was 48 years (interquartile range [IQR] 44-53), median time working underground was 24 years (IQR 18-28), 303 (99%) were male and 91 (30%) were QFT-Plus-negative. The odds of being TB uninfected was 52% lower for unskilled workers (adjusted odds ratio [aOR] 0.48; 95% confidence interval [CI] 0.27-0.85; p = 0.013). Among 281 participants of Black/African ethnicity, 71 (25%) were QFT-Plus negative. Miners with a BMI ≥30 were less likely to be TB uninfected (OR 0.38; 95% CI 0.18-0.80). Using the stricter definition, 44.3% (136/307) of all miners were classified as either TB uninfected (35; 26%) or infected, (101; 74%) and the associations remained similar. Among Black/African miners; 123 were classified as either TB uninfected (23; 19%) or infected (100; 81%) using the stricter definition. No epidemiological factors for being TB uninfected were identified. CONCLUSIONS: Despite high cumulative exposure, a small proportion of miners appear to be resistant to TB infection and are without distinguishing epidemiological characteristics.

Feasibility and effectiveness of HCV viraemia testing at harm reduction sites in Georgia: A prospective three-arm study.

BACKGROUND AND AIMS: In 2015, Georgia began a hepatitis C virus (HCV) elimination programme. Although screening programmes have been decentralized for high-risk groups, viraemic testing remains a bottleneck for people who inject drugs. Here, we describe two models of viraemic testing that aimed to address this gap. METHODS: We assigned eight harm reduction sites (HRS) to one of three arms (2,1:1): Xpert HCV viral load testing on-site, blood draw on-site with centralized HCV core antigen testing (HCVcAg), or standard-of-care (SOC) referral with viremia testing performed at treatment centres. RESULTS: 1671 HCV-seropositive participants were enrolled (Xpert, 37.1%; HCVcAg, 29.1%; referral, 33.8%). Participants were predominantly male (95.4%), mean age (IQR) 43 (37, 50) years and 1290 (77.2%) were currently injecting drugs. Significantly higher proportions of participants in the Xpert (100%) and HCVcAg (99.8%) arms received viraemia testing compared with the referral arm (91.3%) (Xpert vs referral, p < 0.0001; HCVcAg vs referral, p < 0.0001). Among viraemic participants, treatment uptake was similar (Xpert, 84.0%; HCVcAg, 79.5%; referral, 88.4%). The time between screening and sample collection for viraemia testing was significantly longer in the referral arm compared with both Xpert and HCVcAg arms (median 1 day compared with 0 days respectively), and the overall time between screening to treatment initiation was longer for the referral arm (median 67 days) compared with both Xpert and HCVcAg arms (median 57 and 50 days respectively). CONCLUSIONS: Point-of-care viraemia testing and blood drawn on-site for HCVcAg testing yielded more HCV-seropositive patients receiving viraemic testing within a shorter timeframe compared with referrals.

Annual Tuberculosis Preventive Therapy for Persons With HIV Infection : A Randomized Trial.

BACKGROUND: Tuberculosis preventive therapy for persons with HIV infection is effective, but its durability is uncertain. OBJECTIVE: To compare treatment completion rates of weekly isoniazid-rifapentine for 3 months versus daily isoniazid for 6 months as well as the effectiveness of the 3-month rifapentine-isoniazid regimen given annually for 2 years versus once. DESIGN: Randomized trial. (ClinicalTrials.gov: NCT02980016). SETTING: South Africa, Ethiopia, and Mozambique. PARTICIPANTS: Persons with HIV infection who were receiving antiretroviral therapy, were aged 2 years or older, and did not have active tuberculosis. INTERVENTION: Participants were randomly assigned to receive weekly rifapentine-isoniazid for 3 months, given either annually for 2 years or once, or daily isoniazid for 6 months. Participants were screened for tuberculosis symptoms at months 0 to 3 and 12 of each study year and at months 12 and 24 using chest radiography and sputum culture. MEASUREMENTS: Treatment completion was assessed using pill counts. Tuberculosis incidence was measured over 24 months. RESULTS: Between November 2016 and November 2017, 4027 participants were enrolled; 4014 were included in the analyses (median age, 41 years; 69.5% women; all using antiretroviral therapy). Treatment completion in the first year for the combined rifapentine-isoniazid groups (n = 3610) was 90.4% versus 50.5% for the isoniazid group (n = 404) (risk ratio, 1.78 [95% CI, 1.61 to 1.95]). Tuberculosis incidence among participants receiving the rifapentine-isoniazid regimen twice (n = 1808) or once (n = 1802) was similar (hazard ratio, 0.96 [CI, 0.61 to 1.50]). LIMITATION: If rifapentine-isoniazid is effective in curing subclinical tuberculosis, then the intensive tuberculosis screening at month 12 may have reduced its effectiveness. CONCLUSION: Treatment completion was higher with rifapentine-isoniazid for 3 months compared with isoniazid for 6 months. In settings with high tuberculosis transmission, a second round of preventive therapy did not provide additional benefit to persons receiving antiretroviral therapy. PRIMARY FUNDING SOURCE: The U.S. Agency for International Development through the CHALLENGE TB grant to the KNCV Tuberculosis Foundation.

Monocyte metabolic transcriptional programs associate with resistance to tuberculin skin test/interferon-γ release assay conversion.

After extensive exposure to Mycobacterium tuberculosis (Mtb), most individuals acquire latent Mtb infection (LTBI) defined by a positive tuberculin skin test (TST) or interferon-γ release assay (IGRA). To identify mechanisms of resistance to Mtb infection, we compared transcriptional profiles from highly exposed contacts who resist TST/IGRA conversion (resisters, RSTRs) and controls with LTBI using RNAseq. Gene sets related to carbon metabolism and free fatty acid (FFA) transcriptional responses enriched across 2 independent cohorts suggesting RSTR and LTBI monocytes have distinct activation states. We compared intracellular Mtb replication in macrophages treated with FFAs and found that palmitic acid (PA), but not oleic acid (OA), enhanced Mtb intracellular growth. This PA activity correlated with its inhibition of proinflammatory cytokines in Mtb-infected cells. Mtb growth restriction in PA-treated macrophages was restored by activation of AMP kinase (AMPK), a central host metabolic regulator known to be inhibited by PA. Finally, we genotyped AMPK variants and found 7 SNPs in PRKAG2, which encodes the AMPK-γ subunit, that strongly associated with RSTR status. Taken together, RSTR and LTBI phenotypes are distinguished by FFA transcriptional programs and by genetic variation in a central metabolic regulator, which suggests immunometabolic pathways regulate TST/IGRA conversion.

Comparing QuantiFERON-TB Gold Plus with QuantiFERON-TB Gold in-tube for diagnosis of latent tuberculosis infection among highly TB exposed gold miners in South Africa.

Background: QuantiFERON-TB-Gold-in-tube (QFT-GIT) is an interferon-gamma release assay (IGRA) used to diagnose latent tuberculosis infection. Limited data exists on performance of QuantiFERON-TB Gold-Plus (QFT-Plus), a next generation of IGRA that includes an additional antigen tube 2 (TB2) while excluding TB7.7 from antigen tube 1 (TB1), to measure TB specific CD4+ and CD8+ T lymphocytes responses. We compared agreement between QFT-Plus and QFT-GIT among highly TB exposed goldminers in South Africa. Methods: We enrolled HIV-negative goldminers in South Africa, aged ≥33 years with no prior history of TB disease or evidence of silicosis. Blood samples were collected for QFT-GIT and QFT-Plus. QFT-GIT was considered positive if TB1 tested positive; while QFT-Plus was positive if both or either TB1 or TB2 tested positive, as per manufacturer's recommendations. We compared the agreement between QFT-Plus and QFT-GIT using Cohen's Kappa. To assess the specific contribution of CD8+ T-cells, we used TB2-TB1 differential values as an indirect estimate. A cut-off value was set at 0.6. Logistic regression was used to identify factors associated with having TB2-TB1>0.6 difference on QFT-Plus. Results: Of 349 enrolled participants, 304 had QFT-Plus and QFT-GIT results: 205 (68%) were positive on both assays; 83 (27%) were negative on both assays while 16 (5%) had discordant results. Overall, there was 94.7% (288/304) agreement between QFT-Plus and QFT-GIT (Kappa = 0.87). 214 had positive QFT-Plus result, of whom 202 [94.4%, median interquartile range (IQR): 3.06 (1.31, 7.00)] were positive on TB1 and 205 [95.8%, median (IQR): 3.25 (1.53, 8.02)] were positive on TB2. A TB2-TB1>0.6 difference was observed in 16.4% (35/214), with some evidence of a difference by BMI; 14.9% (7/47), 9.8% (9/92) and 25.3% (19/75) for BMI of 18.5-24.9, 18.5-25 and >30 kg/m 2, respectively (P=0.03). Conclusion: In a population of HIV-negative goldminers, QFT-Plus showed high agreement with QFT-GIT, suggesting similar performance.

Outcomes of HIV-positive patients with non-tuberculous mycobacteria positive culture who received anti-tuberculous treatment in Botswana: Implications of using diagnostic algorithms without non-tuberculous mycobacteria.

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® 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.

Tuberculosis treatment outcomes among people living with HIV diagnosed using Xpert MTB/RIF versus sputum-smear microscopy in Botswana: a stepped-wedge cluster randomised trial.

BACKGROUND: Xpert® 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.

Pathways to care and outcomes among hospitalised HIV-seropositive persons with cryptococcal meningitis in South Africa.

INTRODUCTION: Cryptococcus causes 15% of AIDS-related deaths and in South Africa, with its high HIV burden, is the dominant cause of adult meningitis. Cryptococcal meningitis (CM) mortality is high, partly because patients enter care with advanced HIV disease and because of failure of integrated care following CM diagnosis. We evaluated pathways to hospital care, missed opportunities for HIV testing and initiation of care. METHODS: We performed a cross-sectional study at five public-sector urban hospitals. We enrolled adults admitted with a first or recurrent episode of cryptococcal meningitis. Study nurses conducted interviews, supplemented by a prospective review of medical charts and laboratory records. RESULTS: From May to October 2015, 102 participants were enrolled; median age was 40 years (interquartile range [IQR] 33.9-46.7) and 56 (55%) were male. In the six weeks prior to admission, 2/102 participants were asymptomatic, 72/100 participants sought care at a public-sector facility, 16/100 paid for private health care. The median time from seeking care to admission was 4 days (IQR, 0-27 days). Of 94 HIV-seropositive participants, only 62 (66%) knew their status and 41/62 (66%) had ever taken antiretroviral treatment. Among 13 participants with a known previous CM episode, none were taking fluconazole maintenance therapy. In-hospital management was mostly amphotericin B; in-hospital mortality was high (28/92, 30%). Sixty-four participants were discharged, 92% (59/64) on maintenance fluconazole, 4% (3/64) not on fluconazole and 3% (2/64) unknown. Twelve weeks post-discharge, 31/64 (48%) participants were lost to follow up. By 12 weeks post discharge 7/33 (21%) had died. Interviewed patients were asked if they were still on fluconazole, 11% (2/18) were not. CONCLUSIONS: Among hospitalised participants with CM, there were many missed opportunities for HIV care and linkage to ART prior to admission. Universal reflex CrAg screening may prompt earlier diagnosis of cryptococcal meningitis but there is a wider problem of timely linkage to care for HIV-seropositive people.

The effect of sputum quality and volume on the yield of bacteriologically-confirmed TB by Xpert MTB/RIF and smear.

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.

Patient costs incurred by people living with HIV/AIDS prior to ART initiation in primary healthcare facilities in Gauteng, South Africa.

PURPOSE: To quantify costs to patients of accessing HIV care prior to ART initiation. MATERIALS AND METHODS: Using a cross-sectional study design, costs incurred by HIV-positive patients prior to ART initiation were estimated at urban primary healthcare facilities in South Africa. Costs included direct costs, indirect (productivity) costs, carer and coping costs (value of assets sold and money borrowed). The percentage of individual income spent on healthcare was calculated and compared by patient income tertiles and CD4 count strata. RESULTS: 289 patients (69% female, mean age 37 (SD: 10) years, median CD4 317 (IQR: 138-494) cells/mm3) were interviewed. The total mean monthly cost of pre-ART care was US$15.71. Indirect costs accounted for $2.59 (16.49%) of this when time was valued using the patient's reported income. The mean monthly patient costs were $31.61, $12.78, $12.65 and $11.93 for those with a CD4 count <100, 101-350, 351-500 and >500 cells/mm3 respectively. The percentage of individual income spent on healthcare was 7.25% for those with a CD4 count <100 cells/mm3 and 4.05% for those with a CD4 count >500 cells/mm3. CONCLUSIONS: Despite the provision of charge-free services at public clinics, care prior to ART initiation can be costly, particularly for the poor and unemployed. Our study adds to the growing body of evidence that highlights the need to consider policies to reduce the economic barriers to HIV service access, particularly for low income or unwell patient groups, such as improving access to disability grants.

"To speak or not to speak": A qualitative analysis on the attitude and willingness of women to start conversations about voluntary medical male circumcision with their partners in a peri-urban area, South Africa.

INTRODUCTION: Voluntary medical male circumcision (VMMC) reduces the risk of HIV infection in heterosexual men and has long-term indirect protection for women, yet VMMC uptake in South Africa remains low (49.8%) in men (25-49 years). We explored the attitude and willingness of women to start conversations on VMMC with their sexual partners in a South African peri-urban setting to increase VMMC uptake. METHODS: Thirty women with median age of 30 years (inter-quartile range 26-33 years) were interviewed in a language of their choice. Key questions included: types of approach to use, gender roles, benefits and barriers to introducing the topic of VMMC, and perceptions of VMMC. Interviews were digitally-recorded, transcribed, and translated. Through a standard iterative process, a codebook was developed (QSR NVIVO 10 software) and inductive thematic analysis applied. RESULTS: Most women were willing talk to their sexual partners about circumcision, but indicated that the decision to circumcise remained that of their sexual partner. Women felt that they should encourage their partners, show more interest in circumcision, be patient, speak in a caring and respectful tone, choose a correct time when their partner was relaxed and talk in a private space about VMMC. Using magazine/newspaper articles, pamphlets or advertisements were identified as tools that could aid their discussion. Substantial barriers to initiating conversations on VMMC included accusations by partner on infidelity, fear of gender-based violence, cultural restrictions and hesitation to speak to a mature partner about circumcision. CONCLUSIONS: Women need to ensure that before talking to their partner about circumcision, the environment and approach that they use are conducive. Female social network forums could be used to educate women on conversation techniques, skills to use when talking to their partners and how to address communication challenges about circumcision. Involvement of women in VMMC awareness campaigns could encourage circumcision uptake among men.

Correction to: Small contribution of gold mines to the ongoing tuberculosis epidemic in South Africa: a modeling-based study.

The original article [1] did not contain comprehensive information regarding two authors' affiliations that may be considered a potential competing interest.

Geospatial distribution of Mycobacterium tuberculosis genotypes in Africa.

OBJECTIVE: To investigate the distribution of Mycobacterium tuberculosis genotypes across Africa. METHODS: The SITVIT2 global repository and PUBMED were searched for spoligotype and published genotype data respectively, of M. tuberculosis from Africa. M. tuberculosis lineages in Africa were described and compared across regions and with those from 7 European and 6 South-Asian countries. Further analysis of the major lineages and sub-lineages using Principal Component analysis (PCA) and hierarchical cluster analysis were done to describe clustering by geographical regions. Evolutionary relationships were assessed using phylogenetic tree analysis. RESULTS: A total of 14727 isolates from 35 African countries were included in the analysis and of these 13607 were assigned to one of 10 major lineages, whilst 1120 were unknown. There were differences in geographical distribution of major lineages and their sub-lineages with regional clustering. Southern African countries were grouped based on high prevalence of LAM11-ZWE strains; strains which have an origin in Portugal. The grouping of North African countries was due to the high percentage of LAM9 strains, which have an origin in the Eastern Mediterranean region. East African countries were grouped based on Central Asian (CAS) and East-African Indian (EAI) strain lineage possibly reflecting historic sea trade with Asia, while West African Countries were grouped based on Cameroon lineage of unknown origin. A high percentage of the Haarlem lineage isolates were observed in the Central African Republic, Guinea, Gambia and Tunisia, however, a mixed distribution prevented close clustering. CONCLUSIONS: This study highlighted that the TB epidemic in Africa is driven by regional epidemics characterized by genetically distinct lineages of M. tuberculosis. M. tuberculosis in these regions may have been introduced from either Europe or Asia and has spread through pastoralism, mining and war. The vast array of genotypes and their associated phenotypes should be considered when designing future vaccines, diagnostics and anti-TB drugs.

Using mHealth to improve tuberculosis case identification and treatment initiation in South Africa: Results from a pilot study.

BACKGROUND: Tuberculosis (TB) incidence in South Africa is among the highest globally. Initial loss to follow-up (ILFU), defined as not starting on TB treatment within 28 days of testing positive, is undermining control efforts. We assessed the feasibility, acceptability, and potential of a mHealth application to reduce ILFU. METHODS: An mHealth application was developed to capture patients TB investigation data, provide results and monitor treatment initiation. This was implemented in two primary health clinics (PHC) in inner-city Johannesburg. Feasibility was assessed by comparing documentation of personal details, specimen results for same individuals during implementation period (paper register and Mhealth application). Effectiveness was assessed by comparing proportion of patients with results within 48 hours, and proportion started on treatment within 28 days of testing TB positive during pre- implementation (paper register) and implementation (mHealth application) periods. In-depth interviews with patients and providers were conducted to assess acceptability of application. RESULTS: Pre-implementation, 457 patients were recorded in paper registers [195 (42.7%) male, median age 34 years (interquartile range IQR (28-40), 45 (10.5%) sputum Xpert positive]. During implementation, 319 patients were recorded in paper register and the mHealth application [131 (41.1%) male, median age 32 years (IQR 27-38), 33 (10.3%) sputum Xpert positive]. The proportion with complete personal details: [mHealth 95.0% versus paper register 94.0%, (p = 0.54)] and proportion with documented results: [mHealth 97.4% versus paper register 97.8%, (p = 0.79)] were not different in the two methods. The proportion of results available within 48 hours: [mHealth 96.8% versus paper register 68.6%), (p <0.001)], and the proportion on treatment within 28 days [mHealth 28/33 (84.8%) versus paper register 30/44 (68.2%), (p = 0.08)] increased during implementation but was not statistically significant. In-depth interviews showed that providers easily integrated the mHealth application into routine TB investigation and patients positively received the delivery of results via text message. Time from sputum collection to TB treatment initiation decreased from 4 days (pre-implementation) to 3 days but was not statistically significant. CONCLUSIONS: We demonstrated that implementation of the mHealth application was feasible, acceptable to health care providers and patients, and has potential to reduce the time to TB treatment initiation and ILFU in PHC settings.

Performance of verbal autopsy methods in estimating HIV-associated mortality among adults in South Africa.

INTRODUCTION: Verbal autopsy (VA) can be integrated into civil registration and vital statistics systems, but its accuracy in determining HIV-associated causes of death (CoD) is uncertain. We assessed the sensitivity and specificity of VA questions in determining HIV status and antiretroviral therapy (ART) initiation and compared HIV-associated mortality fractions assigned by different VA interpretation methods. METHODS: Using the WHO 2012 instrument with added ART questions, VA was conducted for deaths among adults with known HIV status (356 HIV positive and 103 HIV negative) in South Africa. CoD were assigned using physician-certified VA (PCVA) and computer-coded VA (CCVA) methods and compared with documented HIV status. RESULTS: The sensitivity of VA questions in detecting HIV status and ART initiation was 84.3% (95% CI 80 to 88) and 91.0% (95% CI 86 to 95); 283/356 (79.5%) HIV-positive individuals were assigned HIV-associated CoD by PCVA, 166 (46.6%) by InterVA-4.03, 201 (56.5%) by InterVA-5, and 80 (22.5%) and 289 (81.2%) by SmartVA-Analyze V.1.1.1 and V.1.2.1. Agreement between PCVA and older CCVA methods was poor (chance-corrected concordance [CCC] <0; cause-specific mortality fraction [CSMF] accuracy ≤56%) but better between PCVA and updated methods (CCC 0.21-0.75; CSMF accuracy 65%-98%). All methods were specific (specificity 87% to 96%) in assigning HIV-associated CoD. CONCLUSION: All CCVA interpretation methods underestimated the HIV-associated mortality fraction compared with PCVA; InterVA-5 and SmartVA-Analyze V.1.2.1 performed better than earlier versions. Changes to VA methods and classification systems are needed to track progress towards targets for reducing HIV-associated mortality.