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Background.  The effect of Xpert MTB/RIF (Xpert) scale-up on patient outcomes in low-income settings with a high tuberculosis (TB) burden has not been established. We sought to characterize the effectiveness of Xpert as implemented across different levels of the healthcare system in Uganda. Methods.  We reviewed laboratory records from 2012 to 2014 at 18 health facilities throughout Uganda. In 8 facilities, Xpert had been implemented onsite since 2012, and in 10 sites Xpert was available as an offsite referral test from another facility. We describe Xpert testing volumes by facility, Xpert and smear microscopy results, and downtime due to malfunction and cartridge stockouts. We compare TB treatment initiation as well as time to treatment between facilities implementing Xpert and those that did not. Results.  The median number of Xpert assays run at implementing facilities was 25/month (interquartile range [IQR], 10-63), amounting to 8% of total capacity. Among 1251 assays run for a new TB diagnosis, 19% were positive. Among 1899 patients with smear-negative presumptive TB, the proportion starting TB treatment was similar between Xpert facilities (11%; 95% confidence interval [CI], 9%-13%) and non-Xpert facilities (9%; 95% CI, 8%-11%; P = .325). In Xpert facilities, a positive Xpert preceded TB treatment initiation in only 12 of 70 (17%) smear-negative patients initiated on treatment. Conclusions.  Xpert was underutilized in Uganda and did not significantly increase the number of patients starting treatment for TB. Greater attention must be paid to appropriate implementation of novel diagnostic tests for TB if these new tools are to impact patient important outcomes.

Introduction: Pregnant women newly diagnosed with HIV during pregnancy are often lost to follow up and their adherence rates drop after delivery. We quantified changes in priorities related to isoniazid preventive therapy (IPT) and antiretrovira therapy (ART) among pregnant women living with HIV. Methods: We enrolled pregnant women recently diagnosed with HIV from 14 primary health clinics during pregnancy and followed them after delivery in Matlosana, South Africa. Best-worst scaling (BWS) was used to determine the women's priorities out of 11 attributes related to preventive therapy in the ante- versus postpartum periods. Aggregate BWS scores were calcuated based on the frequency with which participants selected each attribute as the best or worst among five options (across multiple choice sets). Individual BWS scores were also calculated and rescaled from 0 (always selected as worst) to 10 (always selected as best), and changes in BWS scores in the ante- versus postpartum periods were compared, using a paired t-test. Factors associated with the changes in BWS scores were examined in multiple linear regressions. Spearman's rho was used to compare the ranking of attributes. Results: Out of a total of 204 participants, 154 (75.5%) completed the survey in the postpartum at the median 15 (IQR: 11 to 27) weeks after delivery. Trust in healthcare providers was most highly prioritized both in the ante- (individual BWS Score = 7.34, SE = 0.13) and postpartum periods (BWS = 7.21 [+ or -] 0.11), followed by living a long life (BWS = 6.77 [+ or -] 0.09 in the ante- vs. BWS = 6.86 [+ or -] 0.10 in the postpartum). Prevention for infants' health was more prioritized in the post- (BWS = 6.54 [+ or -] 0.09) versus antepartum periods (BWS =6.11 [+ or -] 0.10) (p = 0.05). This change was associated with IPT initiation at enrolment (regression coefficient = 0.78 [+ or -] 0.33, p = 0.001). Difficulty in daily pill-uptake was significantly more prioritized in the postpartum (BWS = 5.03 [+ or -] 0.11) than in the antepartum (BWS = 4.43 [+ or -] 0.10) (p < 0.01). Transportation cost and worry about side effects of pills were least prioritized. Overall ranking of attributes was similar in both time periods (spearman's rho = 0.90). Conclusions: Comprehensive interventions to build trust in healthcare providers and support adherence may increase uptake of preventive therapy. Counselling needs to emphasize medication benefits for both maternal and infant health among HIV-positive pregnant women. Keywords: Pregnant women; preventive therapy; maternal priorities; preferences; HIV; TB; South Africa, 1 | INTRODUCTION In 2016, there were 10.4 million new cases of tuberculosis (TB) and 1.3 million deaths associated with it worldwide [1]. South Africa has some of the highest [...]

Background In highly resource-limited settings, many clinics lack same-day microbiological testing for active tuberculosis (TB). In these contexts, risk of pretreatment loss to follow-up is high, and a simple, easy-to-use clinical risk score could be useful. Methods and findings We analyzed data from adults tested for TB with Xpert MTB/RIF across 28 primary health clinics in rural South Africa (between July 2016 and January 2018). We used least absolute shrinkage and selection operator regression to identify characteristics associated with Xpert-confirmed TB and converted coefficients into a simple score. We assessed discrimination using receiver operating characteristic (ROC) curves, calibration using Cox linear logistic regression, and clinical utility using decision curves. We validated the score externally in a population of adults tested for TB across 4 primary health clinics in urban Uganda (between May 2018 and December 2019). Model development was repeated de novo with the Ugandan population to compare clinical scores. The South African and Ugandan cohorts included 701 and 106 individuals who tested positive for TB, respectively, and 686 and 281 randomly selected individuals who tested negative. Compared to the Ugandan cohort, the South African cohort was older (41% versus 19% aged 45 years or older), had similar breakdown of biological sex (48% versus 50% female), and had higher HIV prevalence (45% versus 34%). The final prediction model, scored from 0 to 10, included 6 characteristics: age, sex, HIV (2 points), diabetes, number of classical TB symptoms (cough, fever, weight loss, and night sweats; 1 point each), and >14-day symptom duration. Discrimination was moderate in the derivation (c-statistic = 0.82, 95% CI = 0.81 to 0.82) and validation (c-statistic = 0.75, 95% CI = 0.69 to 0.80) populations. A patient with 10% pretest probability of TB would have a posttest probability of 4% with a score of 3/10 versus 43% with a score of 7/10. The de novo Ugandan model contained similar characteristics and performed equally well. Our study may be subject to spectrum bias as we only included a random sample of people without TB from each cohort. This score is only meant to guide management while awaiting microbiological results, not intended as a community-based triage test (i.e., to identify individuals who should receive further testing). Conclusions In this study, we observed that a simple clinical risk score reasonably distinguished individuals with and without TB among those submitting sputum for diagnosis. Subject to prospective validation, this score might be useful in settings with constrained diagnostic resources where concern for pretreatment loss to follow-up is high., Author(s): Yeonsoo Baik 1,*, Hannah M. Rickman 1, Colleen F. Hanrahan 1, Lesego Mmolawa 2, Peter J. Kitonsa 3, Tsundzukana Sewelana 2, Annet Nalutaaya 3, Emily A. Kendall 3,4, Limakatso [...]

Introduction: The rapid and accurate diagnosis of HIV-associated tuberculosis (TB), timely initiation of curative or preventative treatment and assurance of favourable treatment outcomes is a complex process. The current system of monitoring and reporting TB diagnosis and treatment does not include several key aspects of the care cascade, and may obscure systematic bottlenecks, inefficiencies or sources of sub-optimal care. Methods: We critically reviewed the current World Health Organizations recommended system of monitoring and reporting, and identified the following key deficiencies that could limit the ability of healthcare workers to identify structural problems in the provision of TB/HIV care. Results: We identified the following key deficiencies in the current monitoring and evaluation system: (1) an emphasis on national-level reporting and programmatic analysis results in a loss of granularity; (2) the absence of a general framework to anchor indicators in relation to one another as well as the overall goals for TB/HIV collaborative activities; (3) de-linking of TB treatment indicators from those for screening and diagnosis; (4) few indicators are tied to suggested times for completion of an activity. We defined three distinct stages comprising the cascade of HIV-associated TB diagnosis and treatment: (1) Screening & Diagnosis, (2) Treatment and (3) Preventive Therapy. We detailed major steps within each stage, described potential sources of variability, and proposed data elements, process indicators, main outcomes, and retention calculations for each stage. Conclusions: This proposed framework of monitoring is novel in its focus on a cohort experience through the entire scope of the care cascade from screening and TB diagnosis through curative or preventive treatment. This approach can be applied to all settings at clinic, district or national level, and used to identify crucial areas for improvement in order to maximize health outcomes for all those affected by the dual epidemics of TB and HIV. Keywords: tuberculosis; HIV; monitoring; cascade of care, Introduction The rapid and accurate diagnosis of HIV-associated tuberculosis (TB), timely initiation of effective treatment (or preventative treatment) and assurance of favourable treatment outcomes is a complex multi-step process, often [...]

Background Household contact investigation for people newly diagnosed with tuberculosis (TB) is poorly implemented, particularly in low- and middle-income countries. Conditional cash incentives may improve uptake. Methods We conducted a pragmatic, cluster-randomized, crossover trial of 2 TB contact investigation approaches (household-based and incentive-based) in 28 public primary care clinics in South Africa. Each clinic used 1 approach for 18 months, followed by a 6-month washout period, after which the opposite approach was used. Fourteen clinics were randomized to each approach. In the household-based arm, we conducted TB screening and testing of contacts at the household. In the incentive-based arm, both index patients and ≤10 of their close contacts (either within or outside the household) were given small cash incentives for presenting to study clinics for TB screening. The primary outcome was the number of people with incident TB who were diagnosed and started on treatment at study clinics. Results From July 2016 to January 2020, we randomized 28 clinics to each study arm, and enrolled 782 index TB patients and 1882 contacts in the household-based arm and 780 index patients and 1940 contacts in the incentive-based arm. A total of 1413 individuals started on TB treatment in the household-based arm and 1510 in the incentive-based arm. The adjusted incidence rate ratio of TB treatment initiation in the incentive- versus household-based arms was 1.05 (95% confidence interval:.97–1.13). Conclusions Incentive-based contact investigation for TB has similar effectiveness to traditional household-based approaches and may be a viable alternative or complementary approach to household-based investigation. [ABSTRACT FROM AUTHOR]

Background Adherence clubs, where groups of 25-30 patients who are virally suppressed on antiretroviral therapy (ART) meet for counseling and medication pickup, represent an innovative model to retain patients in care and facilitate task-shifting. This intervention replaces traditional clinical care encounters with a 1-hour group session every 2-3 months, and can be organized at a clinic or a community venue. We performed a pragmatic randomized controlled trial to compare loss from club-based care between community- and clinic-based adherence clubs. Methods and findings Patients on ART with undetectable viral load at Witkoppen Health and Welfare Centre in Johannesburg, South Africa, were randomized 1:1 to a clinic- or community-based adherence club. Clubs were held every other month. All participants received annual viral load monitoring and medical exam at the clinic. Participants were referred back to clinic-based standard care if they missed a club visit and did not pick up ART medications within 5 days, had 2 consecutive late ART medication pickups, developed a disqualifying (excluding) comorbidity, or had viral rebound. From February 12, 2014, to May 31, 2015, we randomized 775 eligible adults into 12 pairs of clubs-376 (49%) into clinic-based clubs and 399 (51%) into community-based clubs. Characteristics were similar by arm: 65% female, median age 38 years, and median CD4 count 506 cells/mm.sup.3 . Overall, 47% (95% CI 44%-51%) experienced the primary outcome of loss from club-based care. Among community-based club participants, the cumulative proportion lost from club-based care was 52% (95% CI 47%-57%), compared to 43% (95% CI 38%-48%, p = 0.002) among clinic-based club participants. The risk of loss to club-based care was higher among participants assigned to community-based clubs than among those assigned to clinic-based clubs (adjusted hazard ratio 1.38, 95% CI 1.02-1.87, p = 0.032), after accounting for sex, age, nationality, time on ART, baseline CD4 count, and employment status. Among those who were lost from club-based care (n = 367), the most common reason was missing a club visit and the associated ART medication pickup entirely (54%, 95% CI 49%-59%), and was similar by arm (p = 0.086). Development of an excluding comorbidity occurred in 3% overall of those lost from club-based care, and was not different by arm (p = 0.816); no deaths occurred in either arm during club-based care. Viral rebound occurred in 13% of those lost from community club-based care and 21% of those lost from clinic-based care (p = 0.051). In post hoc secondary analysis, among those referred to standard care, 72% (95% CI 68%-77%) reengaged in clinic-based care within 90 days of their club-based care discontinuation date. The main limitations of the trial are the lack of a comparison group receiving routine clinic-based standard care and the potential limited generalizability due to the single-clinic setting. Conclusions These findings demonstrate that overall loss from an adherence club intervention was high in this setting and that, importantly, it was worse in community-based adherence clubs compared to those based at the clinic. We urge caution in assuming that the effectiveness of clinic-based interventions will carry over to community settings, without a better understanding of patient-level factors associated with successful retention in care. Trial registration Pan African Clinical Trials Registry (PACTR201602001460157)., Author(s): Colleen F. Hanrahan 1,*, Sheree R. Schwartz 1, Mutsa Mudavanhu 2, Nora S. West 1, Lillian Mutunga 2, Valerie Keyser 2, Jean Bassett 2, Annelies Van Rie 3 Introduction [...]

Background There is a dearth of comparative effectiveness research examining the implementation of different strategies for active tuberculosis (TB) case finding, particularly in rural settings, which represent 60% of the population of sub-Saharan Africa. Methods and findings We conducted a pragmatic, cluster-randomized comparative effectiveness trial of two TB case finding strategies (facility-based screening and contact tracing) in 56 public primary care clinics in two largely rural districts of Limpopo Province, South Africa. In the facility-based screening arm, sputum Xpert MTB/RIF was performed on all patients presenting (for any reason) with TB symptoms to 28 study clinics, and no contact tracing was performed. In the contact-tracing arm, contacts of patients with active TB were identified (via household tracing in 14 clinics and using small monetary incentives in the other 14 clinics), screened for TB symptoms, and offered Xpert MTB/RIF testing. The primary outcome was the number of newly identified patients with TB started on treatment. The analysis used multivariable Poisson regression adjusted for historical clinic-level TB case volumes and district. The trial was registered with ClinicalTrials.gov (NCT02808507). From July 18, 2017, to January 17, 2019, a total of 3,755 individuals started TB treatment across 56 study clinics in the 18-month period. Clinic characteristics and clinic-level averages of patient characteristics were similar across the two arms: 40/56 (71%) clinics were in a rural location, 2,136/3,655 (58%) patients were male, and 2,243 (61%) were HIV positive. The treatment initiation ratio comparing the yield of TB patients started on treatment in the facility-based arm compared to that from the contact-tracing arm was 1.04 (95% confidence interval [CI] 0.83-1.30, p = 0. 73). In the contact-tracing arm, 1,677 contacts of 788 new TB index patients were screened, yielding 12 new patients with TB. Prespecified subgroup analyses resulted in similar results, with estimated treatment initiation ratios of 0.96 (95% CI 0.64-1.27; p = 0.78) and 1.23 (95% CI 0.87-1.59; p = 0.29) among historically smaller and historically larger clinics, respectively. This ratio was 1.02 (95% CI 0.66-1.37; p = 0.93) and 1.08 (95% CI 0.74-1.42; p = 0.68) in the Vhembe and Waterberg districts, respectively. The estimated treatment initiation ratio was unchanged in sensitivity analyses excluding 24 records whose TB registration numbers could not be verified (1.03, 95% CI 0.82-1.29; p = 0.78) and excluding transfers-in (1.02, 95% CI 0.80-1.29; p = 0.71). Study limitations include the possibility of imbalance on cluster size owing to changes in catchment population over time and the inability to distinguish the independent effects of the two contact investigation strategies. Conclusions Contact tracing based on symptom screening and Xpert MTB/RIF testing did not increase the rate of treatment initiation for TB relative to the less resource-intensive approach of facility-based screening in this rural sub-Saharan setting. Trial registration ClinicalTrials.gov NCT02808507., Author(s): Colleen F. Hanrahan 1,*, Bareng A. S. Nonyane 2, Lesego Mmolawa 3, Nora S. West 2, Tsundzukani Siwelana 3, Limakatso Lebina 3, Neil Martinson 3, David W. Dowdy 1 [...]

Background Providing incentives to screen close contacts for tuberculosis (TB) is an alternative to household-based contact investigation. We aimed to characterize patients and contexts where this incentive-based strategy might be preferred. Methods This is a secondary analysis of a cluster randomized trial of TB contact investigation in Limpopo District, South Africa, conducted between 2016 and 2020. Twenty-eight clinics were randomly allocated to household-based vs incentive-based contact investigation. In the incentive-based arm, index participants and contacts received transport reimbursement and incentives for TB screening and microbiological diagnosis of contacts. We estimated differences in mean number of contacts per index participant with household-based vs incentive-based contact investigation overall and within subgroups of index participants. Results A total of 3776 contacts (1903 in the incentive-based and 1873 in the household-based arm) were referred by 2501 index participants. A higher proportion of contacts in the incentive-based than household-based arm were adults (72% vs 59%), reported chronic TB symptoms (25% vs 16%) or ever smoking (23% vs 11%). Index participants who walked or bicycled to a clinic referred 1.03 more contacts per index (95% confidence interval [CI],.48 to 1.57) through incentive-based than household-based investigation. Index participants living with >5 household members referred 0.48 more contacts per index (95% CI,.03 to.94) through household-based than incentive-based investigation. Conclusions Relative to household-based investigation, incentive-based investigation identifies contacts likely at higher risk for active TB. Incentive-based investigation may be more appropriate for index participants who can easily access clinics, versus household-based investigation for patients with large households. Clinical Trials Registration. NCT02808507. [ABSTRACT FROM AUTHOR]

HIV-positive pregnant women who are initiated on lifelong antiretroviral therapy (ART) and isoniazid preventive therapy (IPT) have lower adherence rates after delivery. We quantified maternal motivation to take preventive therapy before and after delivery among pregnant women newly diagnosed with HIV. We enrolled pregnant women (≥ 18 years) with a recent HIV diagnosis (< 6 months) at 14 public primary health clinics in Matlosana, South Africa and followed them in the postpartum period. Participants received eight choice tasks comparing two mutually exclusive sub-sets of seven possible benefits related to preventive therapy identified through literature reviews and key informant interviews. Data was analyzed using conditional logit regression in the antepartum versus postpartum periods. Coefficients are reported with 95% confidence intervals (CI). Sixty-five women completed surveys both at enrollment and in the postpartum period. All women were already on ART, while 21 (32%) were receiving IPT at enrollment. The mean CD4 count was 436 (± 246) cells/mm3. In the antepartum period, preventing HIV transmission to partners was the most important benefit (coefficients (ß) = 0.87, 95% CI 0.64, 1.11), followed by keeping healthy for family (ß = 0.75, 95% CI 0.52, 0.97). Such prioritization significantly decreased in the postpartum period (p < 0.001). Compared to other motivators, keeping a high CD4 count was least prioritized in the antepartum period (ß = 0.19, 95% CI − 0.04, 0.43) but was most prioritized in the postpartum period (ß = 0.39, 95% CI 0.21, 0.57). These results highlight that messages on family might be particularly salient in the antepartum period, and keeping CD4 count high in the postpartum period. Understanding maternal motivation may help to design targeted health promotion messages to HIV-positive women around the time of delivery. [ABSTRACT FROM AUTHOR]

Background: Hospital studies have demonstrated the usefulness of alternative sampling strategies to expectorated sputum and new diagnostics for the diagnosis of childhood tuberculosis (TB) but there is limited evidence of how these approaches work in the primary-care setting. Aim: To assess the feasibility and yield of a variety of sample types and diagnostic tests for childhood TB at a primary-care clinic. Methods: A prospective cohort of children (<10 years) with signs and symptoms of TB was enrolled at a primary-care clinic in Johannesburg, South Africa. Tuberculin skin testing (TST) and chest X-ray (CXR) were performed in all. In those unable to expectorate, one induced sputum (IS), one ambulatory gastric aspirate (GA) and two nasopharyngeal aspirates (NPA) were collected. Stool was collected from all. Samples were processed for smear microscopy, liquid culture and Xpert MTB/RIF. The Determine TB LAM Ag (LAM) test was used for HIV-positive children. Results: From July 2013-December 2014, 119 children were enrolled, 21 (18%) of whom were HIV-positive. TST was positive in 25/105 (24%) and 70/116 (70%) had a positive CXR. Four (3%) had confirmed TB, 101 (85%) unconfirmed TB and 15 (13%) unlikely TB. Of the 469 samples collected, smear microscopy was positive in none, Xpert was positive in four (<1%) and culture was positive in two (<1%). Three of 11 (27%) HIV-positive patients were positive by LAM. Treatment was commenced in 48/119 (40%). Conclusions: At primary-care, alternative sampling strategies proved feasible but resulted in a low diagnostic yield. Extensive efforts to bacteriologically diagnose children did not contribute to clinical management. [ABSTRACT FROM AUTHOR]

Background: Many individuals at risk for HIV may be reached through active TB case finding interventions in areas with highly prevalent co-epidemics of TB/HIV., Methods: We analyzed data from a cluster-randomized trial of 2 TB case finding strategies: facility-based screening and contact investigation of newly identified TB cases. In both arms, on-site rapid HIV testing was offered to all contacts older than 18 months who did not self-report HIV-positive status. Those who were HIV infected were referred appropriately. All contacts 15 years and older were included in this analysis., Results: Among 2179 contacts identified, 50% (1092) accepted HIV testing and counselling, of whom 6.3% (68) tested HIV-positive. Contacts who were unemployed [adjusted prevalence ratio (aPR) 1.14, 95% confidence interval (CI): 1.04 to 1.25], had not been to a clinic (aPR 1.09, 95% CI: 1.02 to 1.18) or HIV tested (aPR 1.25, 95% CI: 1.14 to 1.39) 6 months before, and those reporting gastrointestinal symptoms (aPR 1.22, 95% CI: 0.98 to 1.52) and genitourinary symptoms (aPR 1.30, 95% CI: 1.17 to 1.45) were significantly associated with accepting HIV testing. Women [adjusted odds ratio (aOR) 2.19, 95% CI: 1.26 to 3.81], individuals with a past history of tuberculosis (aOR 1.96, 95% CI: 0.93 to 4.14), and those not HIV tested 6 months before (aOR 2.20, 95% CI: 1.28 to 3.79) were significantly associated with testing HIV-positive., Conclusion: Offering HIV testing in the context of active tuberculosis case finding represents an opportunity to identify a large proportion of previously undiagnosed individuals with HIV in a population that might otherwise not seek testing.

Introduction: Globally, multidrug resistant tuberculosis (MDR-TB) remains underdiagnosed. The Genotype MTBDRplus®, a rapid drug susceptibility testing (DST) assay used to detect resistance to isoniazid and rifampicin in the diagnosis of MDR-TB, has good diagnostic accuracy, but its impact on patient outcomes in routine practice is unproven. We assessed the clinical impact of routine DST using MTBDRplus in a single health district in South Africa., Methods: Data were collected on all adult pulmonary TB patients registered at 25 public health clinics in the periods before and after introduction of an expanded DST algorithm using MTBDRplus version 1.0., Results: We collected data on 1176 TB patients before implementation and 1177 patients afterwards. In the before period, measured MDR-TB prevalence among new cases was 0.7% (95% CI1.4-3.1%), and among retreatment cases 6.2% (95% CI:3.5-8.8%), versus 3.7% (95% CI:2.4-5.0, p<0.01) and 6.6% (95% CI:3.8-9.4%, p = 0.83) respectively after MTBDRplus introduction. The median times from sputum collection to MDR treatment in the before and after periods were 78 days (IQR:52-93) and 62 days (IQR:32-86, p = 0.05), respectively. Among MDR-TB cases, 27% (95%CI:10-44) in the before period converted sputum cultures to negative by 8 months following treatment initiation, while 52% (95%CI:38-66) converted in the intervention period (p = 0.04)., Conclusions: The expanded use of MTBDRplus DST resulted in a substantial increase in the proportion of new cases identified as MDR-TB; though time to MDR treatment was reduced, it was still over two months. Culture conversion for MDR-TB patients improved after introduction of MTBDRplus. This work illustrates the mixture of successes and challenges resulting from increased access to rapid DST in a setting with a high TB burden.