A systematic review of risk factors for mortality among tuberculosis patients in South Africa.

BACKGROUND: Tuberculosis (TB)-associated mortality in South Africa remains high. This review aimed to systematically assess risk factors associated with death during TB treatment in South African patients. METHODS: We conducted a systematic review of TB research articles published between 2010 and 2018. We searched BioMed Central (BMC), PubMed®, EBSCOhost, Cochrane, and SCOPUS for publications between January 2010 and December 2018. Searches were conducted between August 2019 and October 2019. We included randomised control trials (RCTs), case control, cross sectional, retrospective, and prospective cohort studies where TB mortality was a primary endpoint and effect measure estimates were provided for risk factors for TB mortality during TB treatment. Due to heterogeneity in effect measures and risk factors evaluated, a formal meta-analysis of risk factors for TB mortality was not appropriate. A random effects meta-analysis was used to estimate case fatality ratios (CFRs) for all studies and for specific subgroups so that these could be compared. Quality assessments were performed using the Newcastle-Ottawa scale or the Cochrane Risk of Bias Tool. RESULTS: We identified 1995 titles for screening, 24 publications met our inclusion criteria (one cross-sectional study, 2 RCTs, and 21 cohort studies). Twenty-two studies reported on adults (n = 12561) and two were restricted to children < 15 years of age (n = 696). The CFR estimated for all studies was 26.4% (CI 18.1-34.7, n = 13257 ); 37.5% (CI 24.8-50.3, n = 5149) for drug-resistant (DR) TB; 12.5% (CI 1.1-23.9, n = 1935) for drug-susceptible (DS) TB; 15.6% (CI 8.1-23.2, n = 6173) for studies in which drug susceptibility was mixed or not specified; 21.3% (CI 15.3-27.3, n = 7375) for people living with HIV/AIDS (PLHIV); 19.2% (CI 7.7-30.7, n = 1691) in HIV-negative TB patients; and 6.8% (CI 4.9-8.7, n = 696) in paediatric studies. The main risk factors associated with TB mortality were HIV infection, prior TB treatment, DR-TB, and lower body weight at TB diagnosis. CONCLUSIONS: In South Africa, overall mortality during TB treatment remains high, people with DR-TB have an elevated risk of mortality during TB treatment and interventions to mitigate high mortality are needed. In addition, better prospective data on TB mortality are needed, especially amongst vulnerable sub-populations including young children, adolescents, pregnant women, and people with co-morbidities other than HIV. Limitations included a lack of prospective studies and RCTs and a high degree of heterogeneity in risk factors and comparator variables. SYSTEMATIC REVIEW REGISTRATION: The systematic review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42018108622. This study was funded by the Bill and Melinda Gates Foundation (Investment ID OPP1173131) via the South African TB Think Tank.

Who is more likely to return for TB test results? A survey at three high-burden primary healthcare facilities in Cape Town, South Africa.

BACKGROUND: In low- and middle-income countries with a high burden of tuberculosis (TB), a large proportion of people who are tested for TB do not return to the health facility to collect their test results and initiate treatment, thus putting themselves at increased risk of adverse outcomes. METHODS: This prospective study aimed to identify predictors of returning to the primary health care (PHC) facility to collect TB test results. From 15 August to 15 December 2017, 1105 people who tested for pulmonary TB at three Cape Town PHC facilities were surveyed. Using multi-variate logistic regressions on an analysis sample of 1097 people, three groups of predictors were considered: (i) demographics, health and socio-economic status; (ii) costs and benefits; and (iii) behavioural factors. RESULTS: Forty-four percent of people tested returned to the PHC facility to collect their test results within the stipulated 2 days, and 68% returned before the end of the study period. Return was strongly and positively correlated with expecting a TB-positive result, cognitive avoidance and postponement behaviour. CONCLUSION: Interventions to improve pre-treatment loss to follow-up should target patients who think they do not have TB, and those with a history of postponement behaviour and cognitive avoidance.

Urine lipoarabinomannan for rapid tuberculosis diagnosis in HIV-infected adult outpatients in Khayelitsha.

BACKGROUND: Decreasing tuberculosis (TB) mortality is constrained by diagnostic and treatment delays. The World Health Organization (WHO) recently actively recommended the point-of-care Alere Determine Lipoarabinomannan Ag assay (AlereLAM) to assist in the diagnosis of tuberculosis in specific HIV-infected outpatients. OBJECTIVES: The primary objective of this study was to compare time to ambulatory TB treatment in HIV-infected adults with CD4 ≤ 100 cells/µL before and after ('primary comparison groups') availability of AlereLAM. In pre-specified subgroups, we prospectively assessed AlereLAM-positive prevalence. METHOD: Clinicians prospectively performed AlereLAM in HIV-infected adults with TB symptoms and either CD4 ≤ 100 cells/µL or 'seriously ill' criteria. In a retrospective arm of equal duration, clinicians retrospectively collected data on HIV-infected adults with CD4 ≤ 100 cells/µL who initiated TB treatment. RESULTS: A total of 115 prospectively eligible adults (of whom 55 had CD4 ≤ 100 cells/µL) and 77 retrospectively eligible patients were included. In the primary comparison groups, the retrospective and prospective arms had similar age and sex distribution. With availability of AlereLAM, the time to TB treatment decreased from a median of 4 to 3 days (p = 0.0557). With availability of AlereLAM, same-day TB treatment initiation rose from 9.1% to 32.7% (p = 0.0006). In those with CD4 ≤ 100 only, those with 'seriously ill' criteria only, and in those meeting either, or both, of these criteria, AlereLAM was positive in 10.5%, 21.9%, 34.8% and 48.4% respectively. CONCLUSION: Availability of AlereLAM led to more patients initiating same-day TB treatment. Using both CD4 ≤ 100 and 'seriously ill' criteria gave the greatest yield. Results of this study have informed local policy design.

High Rates of Recurrent Tuberculosis Disease: A Population-level Cohort Study.

BACKGROUND: Retreatment tuberculosis (TB) disease is common in high-prevalence settings. The risk of repeated episodes of recurrent TB is unknown. We calculated the rate of recurrent TB per subsequent episode by matching individual treatment episodes over a period of 13 years. METHODS: All recorded TB episodes in Cape Town between 2003 and 2016 were matched by probabilistic linkage of personal identifiers. Among individuals with a first episode notified in Cape Town and who completed their prior treatment successfully we estimated the recurrence rate stratified by subsequent episode and HIV status. We adjusted person-time to background mortality by age, sex, and HIV status. RESULTS: A total of 292 915 TB episodes among 263 848 individuals were included. The rate of recurrent TB was 16.4 per 1000 person-years (95% CI, 16.2-16.6), and increased per subsequent episode (8.4-fold increase, from 14.6 to 122.7 per 1000 from episode 2 to 6, respectively). These increases were similar stratified by HIV status. Rates among HIV positives were higher than among HIV negatives for episodes 2 and 3 (2- and 1.5-fold higher, respectively), and the same thereafter. CONCLUSIONS: TB recurrence rates were high and increased per subsequent episode, independent of HIV status. This suggests that HIV infection is insufficient to explain the high burden of recurrence; it is more likely due to a high annual risk of infection combined with an increased risk of infection or progression to disease associated with a previous TB episode. The very high recurrence rates would justify increased TB surveillance of patients with >1 episode.

Ultrasound Shear Wave Elastography to Assess Tissue Mechanical Properties in Somatic Dysfunction: A Feasibility Study.

CONTEXT: Diagnosis of somatic dysfunction is based on subjective palpatory osteopathic assessments. This subjectivity has posed a challenge for researchers in studying osteopathic medicine. The development and use of radiological imaging techniques to objectively confirm or quantify muscle tissue stiffness associated with somatic dysfunction could be of benefit in osteopathic clinical practice, training, and further research. OBJECTIVES: To investigate the feasibility of ultrasound shear wave elastography (SWE) to quantify muscle tissue stiffness in somatic dysfunction before and after osteopathic manipulative treatment (OMT). METHODS: In this prospective study, we assessed lumbar spine somatic dysfunction in 20 adult patients before and after a single OMT session using standard osteopathic palpatory assessments by osteopathic physician faculty members in the Department of Osteopathic Principle and Practice at Rocky Vista University College of Osteopathic Medicine (Utah campus). Shear wave velocity (SWV, m/s) was measured in lumbar paraspinal muscle tissue using a commercial ultrasonography scanner on all participants immediately before and after OMT. In this study, OMT techniques targeted the iliocostalis lumborum and included the articulatory technique, balanced ligamentous tension, facilitated positional release, high-velocity, low-amplitude technique, muscle energy, myofascial release, and the Still technique at the discretion of the osteopathic physician. The difference in SWV between muscle tissues with and without dysfunction, and differences in SWV of dysfunctional tissue before and after OMT were examined using unpaired and paired t tests, as appropriate. The correlation between SWV measurements and osteopathic assessments was examined by the Spearman rank correlation. Intra- and interobserver reliability was analyzed using intraclass correlation coefficient. RESULTS: The difference in SWV between muscle tissues with and without somatic dysfunction was significant before OMT (mean [SD], 1.93 [0.44] vs 1.69 [0.19]; P=.03) and was not significant after OMT (mean [SD], 1.69 [0.19] vs 1.53 [0.31]; P=.05). The difference in SWV in the same tissue with somatic dysfunction before and after OMT was significant (mean [SD], 1.93 [0.44] vs 1.52 [0.3]; P<.001). The SWV value highly correlated with manual osteopathic assessments (r=0.72). Intra- and interobserver reliability for performing SWE in somatic dysfunction was good (intraclass correlation coefficient >0.80). CONCLUSIONS: The results of this study show that ultrasound SWE can objectively assess muscle tissue stiffness for diagnosis of somatic dysfunctions and for muscle tissue stiffness changes after OMT.

Xpert MTB/RIF Ultra and Xpert MTB/RIF for diagnosis of tuberculosis in an HIV-endemic setting with a high burden of previous tuberculosis: a two-cohort diagnostic accuracy study.

BACKGROUND: Xpert MTB/RIF Ultra (Ultra) is a new test for tuberculosis undergoing global roll-out. We assessed the performance of Ultra compared with Xpert MTB/RIF (Xpert) in an HIV-endemic setting where previous tuberculosis is frequent and current test performance is suboptimal. METHODS: In this two-cohort diagnostic accuracy study, we used sputum samples from patients in South Africa to evaluate the accuracy of Ultra and Xpert against a single culture reference standard. For the first cohort (cohort A), we recruited adults (aged ≥18 years) with symptoms of presumptive tuberculosis at Scottsdene clinic in Cape Town, South Africa. We collected three sputum samples from each patient in cohort A, two at the first visit of which one was tested using Xpert and the other was tested using culture, and one sample the next morning which was tested using Ultra. In a separate cohort of patients with presumptive tuberculosis and recent previous tuberculosis (≤2 years) who had submitted sputum samples to the National Health Laboratory Services (cohort B), decontaminated sediments were, after processing, randomly allocated (1:1) for testing with Ultra or Xpert. For both cohorts we calculated the sensitivity and specificity of Ultra and Xpert and evaluated the effects of different methods of interpreting Ultra trace results. FINDINGS: Between Feb 6, 2016, and Feb 2, 2018, we recruited 302 people into cohort A, all of whom provided sputum samples and 239 were included in the head-to-head analyses of Ultra and Xpert. For cohort B, we collected sputum samples from eligible patients who had submitted samples between Dec 6, 2016, and Dec 21, 2017, to give a cohort of 831 samples, of which 352 were eligible for inclusion in analyses and randomly assigned to Ultra (n=173) or Xpert (n=179). In cohort A, Ultra gave more non-actionable results (not positive or negative) than did Xpert (28 [10%] 275 vs 14 [5%] 301; p=0·011). In the head-to-head analysis, in smear-negative patients, sensitivity of Ultra was 80% (95% CI 64-90) and of Xpert was 73% (57-85; p=0·45). Overall, specificity of Ultra was lower than that of Xpert (90% [84-94] vs 99% [95-100]; p=0·001). In cohort B, overall sensitivity was 92% (81-98) for Xpert versus 86% (73-95; p=0·36) for Ultra and overall specificity was 69% (60-77) for Ultra versus 84% (78-91; p=0·005) for Xpert. Ultra specificity estimates improved after reclassification of results with the lowest Ultra-positive semiquantitation category (trace) to negative (15% [8-22]). In cohort A, the positive predictive value (PPV) for Ultra was 78% (67-87) and for Xpert was 96% (87-99; p=0·004); in cohort B, the PPV for Ultra was 50% (43-57) and for Xpert was 70% (61-78; p=0·014). Ultra PPV estimates in previously treated patients were low: at 15% tuberculosis prevalence, half of Ultra-positive patients with presumptive tuberculosis would be culture negative, increasing to approximately 70% in patients with recent previous tuberculosis. In cohort B, 21 (28%) of 76 samples that were Ultra positive were rifampicin indeterminate (all trace) and, like cohort A, most were culture negative (19 [90%] of 21). INTERPRETATION: In a setting with a high burden of previous tuberculosis, Ultra generated more non-actionable results and had diminished specificity compared with Xpert. In patients with recent previous tuberculosis, a quarter of Ultra-positive samples were indeterminate for rifampicin resistance and culture negative, suggesting that additional drug-resistance testing will probably be unsuccessful. Our data have implications for the handling of Ultra-positive results in patients with previous tuberculosis in high burden settings. FUNDING: South African Medical Research Council, the EDCTP2 program, and the Faculty of Medicine and Health Sciences, Stellenbosch University.

Ultrasound Shear Wave Elastography to Assess Osteopathic Manipulative Treatment on the Iliocostalis Lumborum Muscle: A Feasibility Study.

OBJECTIVES: To investigate the feasibility of ultrasound shear wave elastography (SWE) in assessing iliocostalis lumborum muscle changes after osteopathic manipulative treatment (OMT). METHODS: Using a linear array ultrasound transducer (4-9 MHz), we prospectively measured the shear wave velocity (SWV) of bilateral iliocostalis lumborum muscles in 20 patients with low back somatic dysfunction and in 9 age-matched healthy volunteers. The SWV was measured in muscle relaxation and contraction in all participants and immediately before and after OMT in patients. We developed a muscle SWV rate [SWVcontraction - SWVrelaxation )/SWVrelaxation ] and an SWV improvement index [(SWVpre-OMT - SWVpost-OMT )/SWVpre-OMT ] for quantifying muscle contractibility and changes in muscle stiffness after OMT. Statistical analyses included an unpaired t test to analyze the difference in the muscle SWV between muscle relaxation and contraction and between somatic dysfunction and nonsomatic dysfunction in patients and healthy volunteers, a paired t test to examine the difference in the SWV and SWV rate before and after OMT, the intraclass correlation coefficient to test intraobserver and interobserver reliability, and Spearman rank correlation to analyze the correlation of changes in the SWV with manual osteopathic assessments. RESULTS: The mean ages of the patients with low back somatic dysfunction and the healthy volunteers were 28 and 26 years, respectively. The muscle SWV significantly differed between somatic dysfunction and nonsomatic dysfunction in patients and healthy volunteers, between muscle relaxation and contraction, and before and after OMT (P < .001). The SWV improvement index moderately correlated with manual osteopathic assessments (r = 0.68). The interobserver and intraobserver reliability for performing SWE was good (intraclass correlation coefficient, >0.8). CONCLUSIONS: Our results suggest that SWE is feasible for quantifying the change in muscle stiffness and contractibility after OMT.

HIV prevalence and determinants of loss-to-follow-up in adolescents and young adults with tuberculosis in Cape Town.

TB remains a leading cause of mortality and morbidity in sub-Saharan Africa, due to the HIV epidemic. As TB treatment is lengthy, the completion of the full course of treatment may be especially challenging for young people. We therefore aimed to identify the extent of and reasons underlying loss to follow-up from TB treatment among young people in Cape Town. Accordingly, we reviewed the outcomes of young people treated for TB in Cape Town during 2009-2013, across three age groups: younger adolescents (10-14 years); older adolescents; (15-19 years) and young adults (20-24 years). We employed logistic regression analysis to identify risk factors for loss from TB care. 23,737 patients aged 10-24 were treated for drug sensitive TB over the study period. Of these, the HIV co-infection prevalence was 18.5% for younger adolescents, 12.9% for older adolescents and 33.1% for young adults. From age 16, HIV prevalence increased disproportionately among young women: by age 22, over 50% of women were TB/HIV co-infected compared to 14% of men. TB treatment success (cure plus completion) was 84.4%, while 1.7% of patients died, 9.5% were lost-to follow-up and 0.4% failed treatment. Being an older adolescent (aOR 1.75 [95% CI: 1.38-2.21]) or young adult (aOR: 1.96 [95% CI: 1.57-2.45]) increased the risk of loss-to-follow up, relative to being a younger adolescent. Further risk factors for loss from TB care were male gender (aOR: 1.33 [95% CI:1.20-1.46]), being a TB/HIV co-infected young person (aOR 1.74 [95% CI: 1.57-1.93]) and having had prior treatment for TB (aOR 3.17 [95% CI 2.87-3.51]). We identified risk factors for loss to follow-up and highlighted the need to focus on HIV prevention and retention in TB care among young people. TB care tailored to the needs of young people could improve patient retention, similar to improved outcomes reported by youth friendly HIV clinics.

"Life continues": Patient, health care and community care workers perspectives on self-administered treatment for rifampicin-resistant tuberculosis in Khayelitsha, South Africa.

BACKGROUND: Self-administered treatment (SAT), a differentiated model of care for rifampicin-resistant tuberculosis (RR-TB), might address adherence challenges faced by patients and health care systems. This study explored patient, health-care worker (HCW) and community care worker (CCW) perspectives on a SAT pilot programme in South Africa, in which patients were given medication to take at home with the optional support of a CCW. METHODS: We conducted a mixed-methods study from July 2016-June 2017. The quantitative component included semi-structured questionnaires with patients, HCWs and CCWs; the qualitative component involved in-depth interviews with patients enrolled in the pilot programme. Interviews were conducted in isiXhosa, translated, transcribed and manually coded. RESULTS: Overall, 27 patients, 12 HCWs and 44 CCWs were enrolled in the quantitative component; nine patients were also interviewed. Of the 27 patients who completed semi-structured questionnaires, 22 were HIV-infected and 17 received a monthly supply of RR TB treatment. Most HCWs and CCWs (10 and 32, respectively) understood the pilot programme; approximately half (n = 14) of the patients could not correctly describe the pilot programme. Overall, 11 and 41 HCWs and CCWs reported that the pilot programme promoted treatment adherence. Additionally, 11 HCWs reported that the pilot programme relieved pressure on the clinic. Key qualitative findings highlighted the importance of a support person and how the flexibility of SAT enabled integration of treatment into their daily routines and reduced time spent in clinics. The pilot programme was also perceived to allow patients more autonomy and made it easier for them to manage side-effects. CONCLUSION: The SAT pilot programme was acceptable from the perspective of patients, HCWs and CCWs and should be considered as a differentiated model of care for RR-TB, particularly in settings with high burdens of HIV, in order to ease management of treatment for patients and health-care providers.

HIV and TB co-infection in the ART era: CD4 count distributions and TB case fatality in Cape Town.

BACKGROUND: In Cape Town, the roll-out of antiretroviral therapy (ART) has increased over the last decade with an estimated coverage of 63% of HIV- positive patients in 2013. The influence of ART on the characteristics of the population of HIV-positive patients presenting to the primary care TB programme is unknown. In this study, we examined trends in CD4 count distribution, ART usage and treatment outcomes among HIV-positive TB patients in Cape Town from 2009 to 2013. METHODS: Data from the electronic TB register on all newly registered drug-sensitive TB patients ≥18 years were analyzed retrospectively. Descriptive statistics were used to compare baseline characteristics, the CD4 count distribution and TB treatment outcomes both by year of treatment and ART status at the start of TB treatment. Survival analyses were used to assess the change in mortality risk during TB treatment over time, stratified by ART status at start of TB treatment. RESULTS: 118,989 patients were treated over 5 years. HIV prevalence among TB patients decreased from 50.9% in 2009 to 49.0% in 2013. The absolute number of HIV-positive TB cases declined by 13.2% between 2010 and 2013. More patients entered the TB programme on ART in 2013 compared to 2009 (30.0% vs 9.9%). Among these, the CD4 count distribution showed a year by year shift to higher CD4 counts. In 2013, over 75% of ART-naïve TB patients still had a CD4 count < 350 cells/mm3. ART initiation among ART-naive patients increased from 37.0 to 77.7% and TB case fatality declined from 7.4 to 5.2% (p < 0.001). In multivariate analysis a decrease in TB mortality was most strongly associated with CD4 count (Adjusted HR 0.82 per increase of 50 cells/mm3, 95% CI: 0.81-0.83, p < 001) and the initiation of ART during TB treatment (Adjusted HR 0.39, 95% CI: 0.35-0.42, p < 0.001). CONCLUSION: Comprehensive changes in the ART and TB treatment programmes resulted in incremental increases in ART coverage for HIV-positive TB patients and a subsequent decrease in TB case fatality due to increased ART uptake in HIV-positive ART-naïve patients. However TB still remained a major presenting opportunistic infection with the majority of cases occurring at low CD4 counts.

The impact of the roll-out of rapid molecular diagnostic testing for tuberculosis on empirical treatment in Cape Town, South Africa.

OBJECTIVE: To investigate the impact of introducing a rapid test as the first-line diagnostic test for drug-sensitive tuberculosis in Cape Town, South Africa. METHODS: Xpert® MTB/RIF (Xpert®), an automated polymerase-chain-reaction-based assay, was rolled out between 2011 and 2013. Data were available on 102 007 adults treated for pulmonary tuberculosis between 2010 and 2014. Tuberculosis notification rates per 100 000 population were calculated for each calendar year and for each year relative to the test roll-out locally, overall and by bacteriological confirmation. Empirical treatment was defined as treatment given without bacteriological confirmation by Xpert®, sputum smear microscopy or sputum culture. FINDINGS: Between 2010 and 2014, the proportion of human immunodeficiency virus (HIV)-negative patients treated empirically for tuberculosis declined from 23% (2445/10 643) to 11% (1149/10 089); in HIV-positive patients, it declined from 42% (4229/9985) to 27% (2364/8823). The overall tuberculosis notification rate decreased by 12% and 19% among HIV-negative and HIV-positive patients, respectively; the rate of bacteriologically confirmed cases increased by 1% and 3%, respectively; and the rate of empirical treatment decreased by 56% and 49%, respectively. These changes occurred gradually following the test's introduction and stabilized after 3 years. CONCLUSION: Roll-out of the rapid test in a setting with a high prevalence of pulmonary tuberculosis and HIV infection was associated with a halving of empirical treatment that occurred gradually after the test's introduction, possibly reflecting the time needed for full implementation. More than a quarter of HIV-positive patients with tuberculosis were still treated empirically, highlighting the diagnostic challenge in these patients.

Has universal screening with Xpert® MTB/RIF increased the proportion of multidrug-resistant tuberculosis cases diagnosed in a routine operational setting?

SETTING: Primary health services in Cape Town, South Africa where the introduction of Xpert® MTB/RIF (Xpert) enabled simultaneous screening for tuberculosis (TB) and drug susceptibility in all presumptive cases. STUDY AIM: To compare the proportion of TB cases with drug susceptibility tests undertaken and multidrug-resistant tuberculosis (MDR-TB) diagnosed pre-treatment and during the course of 1st line treatment in the previous smear/culture and the newly introduced Xpert-based algorithms. METHODS: TB cases identified in a previous stepped-wedge study of TB yield in five sub-districts over seven one-month time-points prior to, during and after the introduction of the Xpert-based algorithm were analysed. We used a combination of patient identifiers to identify all drug susceptibility tests undertaken from electronic laboratory records. Differences in the proportions of DST undertaken and MDR-TB cases diagnosed between algorithms were estimated using a binomial regression model. RESULTS: Pre-treatment, the probability of having a DST undertaken (RR = 1.82)(p<0.001) and being diagnosed with MDR-TB (RR = 1.42)(p<0.001) was higher in the Xpert-based algorithm than in the smear/culture-based algorithm. For cases evaluated during the course of 1st-line TB treatment, there was no significant difference in the proportion with DST undertaken (RR = 1.02)(p = 0.848) or MDR-TB diagnosed (RR = 1.12)(p = 0.678) between algorithms. CONCLUSION: Universal screening for drug susceptibility in all presumptive TB cases in the Xpert-based algorithm resulted in a higher overall proportion of MDR-TB cases being diagnosed and is an important strategy in reducing transmission. The previous strategy of only screening new TB cases when 1st line treatment failed did not compensate for cases missed pre-treatment.

Comparing Tuberculosis Diagnostic Yield in Smear/Culture and Xpert® MTB/RIF-Based Algorithms Using a Non-Randomised Stepped-Wedge Design.

SETTING: Primary health services in Cape Town, South Africa. STUDY AIM: To compare tuberculosis (TB) diagnostic yield in an existing smear/culture-based and a newly introduced Xpert® MTB/RIF-based algorithm. METHODS: TB diagnostic yield (the proportion of presumptive TB cases with a laboratory diagnosis of TB) was assessed using a non-randomised stepped-wedge design as sites transitioned to the Xpert® based algorithm. We identified the full sequence of sputum tests recorded in the electronic laboratory database for presumptive TB cases from 60 primary health sites during seven one-month time-points, six months apart. Differences in TB yield and temporal trends were estimated using a binomial regression model. RESULTS: TB yield was 20.9% (95% CI 19.9% to 22.0%) in the smear/culture-based algorithm compared to 17.9% (95%CI 16.4% to 19.5%) in the Xpert® based algorithm. There was a decline in TB yield over time with a mean risk difference of -0.9% (95% CI -1.2% to -0.6%) (p<0.001) per time-point. When estimates were adjusted for the temporal trend, TB yield was 19.1% (95% CI 17.6% to 20.5%) in the smear/culture-based algorithm compared to 19.3% (95% CI 17.7% to 20.9%) in the Xpert® based algorithm with a risk difference of 0.3% (95% CI -1.8% to 2.3%) (p = 0.796). Culture tests were undertaken for 35.5% of smear-negative compared to 17.9% of Xpert® negative low MDR-TB risk cases and for 82.6% of smear-negative compared to 40.5% of Xpert® negative high MDR-TB risk cases in respective algorithms. CONCLUSION: Introduction of an Xpert® based algorithm did not produce the expected increase in TB diagnostic yield. Studies are required to assess whether improving adherence to the Xpert® negative algorithm for HIV-infected individuals will increase yield. In light of the high cost of Xpert®, a review of its role as a screening test for all presumptive TB cases may be warranted.

Temporal trends in TB notification rates during ART scale-up in Cape Town: an ecological analysis.

INTRODUCTION: Although antiretroviral therapy (ART) reduces individual tuberculosis (TB) risk by two-thirds, the population-level impact remains uncertain. Cape Town reports high TB notification rates associated with endemic HIV. We examined population trends in TB notification rates during a 10-year period of expanding ART. METHODS: Annual Cape Town TB notifications were used as numerators and mid-year Cape Town populations as denominators. HIV-stratified population was calculated using overall HIV prevalence estimates from the Actuarial Society of South Africa AIDS and Demographic model. ART provision numbers from Western Cape government reports were used to calculate overall ART coverage. We calculated rates per 100,000 population over time, overall and stratified by HIV status. Rates per 100,000 total population were also calculated by ART use at treatment initiation. Absolute numbers of notifications were compared by age and sub-district. Changes over time were described related to ART provision in the city as a whole (ART coverage) and by sub-district (numbers on ART). RESULTS: From 2003 to 2013, Cape Town's population grew from 3.1 to 3.7 million inhabitants, and estimated HIV prevalence increased from 3.6 to 5.2%. ART coverage increased from 0 to 63% in 2013. TB notification rates declined by 16% (95% confidence interval (CI), 14-17%) from a 2008 peak (851/100,000) to a 2013 nadir (713/100,000). Decreases were higher among the HIV-positive (21% (95% CI, 19-23%)) than the HIV-negative (9% (95% CI, 7-11%)) population. The number of HIV-positive TB notifications decreased mainly among 0- to 4- and 20- to 34-year-olds. Total population rates on ART at TB treatment initiation increased over time but levelled off in 2013. Overall median CD4 counts increased from 146 cells/µl (interquartile range (IQR), 66, 264) to 178 cells/µl (IQR 75, 330; p<0.001). Sub-district antenatal HIV seroprevalence differed (10-33%) as did numbers on ART (9-29 thousand). Across sub-districts, infant HIV-positive TB decreased consistently whereas adult decreases varied. CONCLUSIONS: HIV-positive TB notification rates declined during a period of rapid scale-up of ART. Nevertheless, both HIV-positive and HIV-negative TB notification rates remained very high. Decreases among HIV positives were likely blunted by TB remaining a major entry to the ART programme and occurring after delayed ART initiation.

A comparison of multidrug-resistant tuberculosis treatment commencement times in MDRTBPlus line probe assay and Xpert® MTB/RIF-based algorithms in a routine operational setting in Cape Town.

BACKGROUND: Xpert MTB/RIF was introduced as a screening test for all presumptive tuberculosis cases in primary health services in Cape Town, South Africa. STUDY AIM: To compare multidrug-resistant tuberculosis (MDR-TB) treatment commencement times in MDRTBPlus Line Probe Assay and Xpert MTB/RIF-based algorithms in a routine operational setting. METHODS: The study was undertaken in 10 of 29 high tuberculosis burden primary health facilities, selected through stratified random sampling. An observational study was undertaken as facilities transitioned to the Xpert MTB/RIF-based algorithm. MDR-TB diagnostic data were collected from electronic laboratory records and treatment data from clinical records and registers. Kaplan Meier time-to-event analysis was used to compare treatment commencement time, laboratory turnaround time and action delay between algorithms. A facility-level paired analysis was done: the median time-to-event was estimated per facility in each algorithm and mean differences between algorithms compared using a paired t-test. Cox proportional hazards regression was used to assess the effect of patient-level variables on treatment commencement time. The difference between algorithms was compared using the hazard ratio. RESULTS: The median treatment commencement time in the Xpert MTB/RIF-based algorithm was 17 days (95% CI 13 to 22 days), with a median laboratory turnaround time (to result available in the laboratory) of <1 day (95% CI<1 to 1 day). There was a decrease of 25 days (95% CI 17 to 32 days, p<0.001) in median MDR-TB treatment commencement time in the Xpert MTB/RIF-based algorithm. We found no significant effect on treatment commencement times for the patient-level variables assessed. CONCLUSION: MDR-TB treatment commencement time was significantly reduced in the Xpert MTB/RIF-based algorithm. Changes in the health system may have contributed. However, an unacceptable level of delay remains. Health system and patient factors contributing to delay need to be evaluated and addressed to optimise test benefits.

Impact of ART on TB case fatality stratified by CD4 count for HIV-positive TB patients in Cape Town, South Africa (2009-2011).

OBJECTIVE: To identify determinants of tuberculosis (TB) case fatality including the impact of antiretroviral therapy (ART) at different CD4 thresholds for HIV-positive adult and adolescent TB patients. METHODS: Through a retrospective analysis of the electronic TB database, we identified the HIV status of newly registered patients aged ≥15 years. Multivariable Cox proportional hazard models were used to determine the risk factors for TB case fatality in these patients. RESULTS: In 2009, 2010, and 2011, 25,841, 26,104, and 25,554 newly registered adult TB patients were treated in primary health care clinics in Cape Town, of whom 49.7%, 50.4%, and 50.9% were HIV positive. ART uptake increased over 3 years from 43% to 64.9%, and case fatality of the HIV-positive patients decreased from 7.0% to 5.8% (P < 0.001). Female gender, increasing age, retreatment TB, low CD4 counts, and extrapulmonary TB were associated with increased case fatality, whereas patients on ART had a substantial decrease in case fatality. The difference in case fatality between patients on ART and not on ART was most pronounced at low CD4 counts with the positive influence of ART noted up to a CD4 count threshold of 350 cells per cubic millimeter (P < 0.001). Despite improvements in ART uptake, in 2011, 21% of the patients with CD4 counts <350 cells per cubic millimeter did not start ART during TB treatment. CONCLUSION: This study showed a relatively poor uptake of ART among severely immune-compromised TB patients. Patients with CD4 counts <350 cells per cubic millimeter were shown to clearly benefit from ART during TB treatment, and ART initiation should be prioritized for this category of patients.

GeneXpert MTB/RIF version G4 for identification of rifampin-resistant tuberculosis in a programmatic setting.

A recent Cochrane review estimated GeneXpert MTB/RIF specificity for rifampin resistance as 98% (95% confidence interval [CI], 97 to 99), based on results from earlier test versions. The measured positive predictive value of the new generation test from programmatic implementation in Cape Town, South Africa, was 99.5% (95% CI, 98.5 to 100), confirming excellent specificity.

Improving access and quality of care in a TB control programme.

OBJECTIVES: To use a quality improvement approach to improve access to and quality of tuberculosis (TB) diagnosis and care in Cape Town. METHODS: Five HIV/AIDS/sexually transmitted infections/TB (HAST) evaluations were conducted from 2008 to 2010, with interviews with 99 facility managers and a folder review of over 850 client records per evaluation cycle. The data were used in a local quality improvement process: sub-district workshops identified key weaknesses and facility managers drew up action plans. Lessons learnt and successful strategies were shared at quarterly district-wide HIV/TB meetings. RESULTS: Geographical access was good, but there were delays in treatment commencement times. Access for high-risk clients improved significantly with intensified TB case finding made routine in both the HIV counselling and testing and antiretroviral treatment (ART) services (p<0.01 for both). Access for children in contact with an infectious case has improved but is still low (42% investigated and treated). Quality of care was mostly high at baseline (adherence to treatment protocols 95%). Measurement of body mass index improved from 20% to 62%. The assessment of contraception improved from 27% to 58%. Care for co-infected clients showed improved use of customised HIV stationery and increased assessment for ART eligibility. CONCLUSIONS: The HAST audit contributed to the improved TB cure rates by supplementing routine information and involving sub-district managers, facility managers and facility staff in a quality improvement process that identified local opportunities for programme strengthening.