Optimal treatment regimens for patients with extensively drug-resistant tuberculosis (XDR-TB) remain unclear. Long-term prospective outcome data comparing XDR-TB regimens with and without bedaquiline ...from an endemic setting are lacking.We prospectively followed-up 272 South African patients (49.3% HIV-infected; median CD4 count 169 cells·µL
) with newly diagnosed XDR-TB between 2008 and 2017. Outcomes were compared between those who had not received bedaquiline (pre-2013; n=204) and those who had (post-2013; n=68; 80.9% received linezolid in addition).The 24-month favourable outcome rate was substantially better in the bedaquiline
the non-bedaquiline group (66.2% (45 out of 68)
13.2% (27 out of 204); p<0.001). In addition, the bedaquiline group exhibited reduced 24-month rates of treatment failure (5.9%
26.0%; p<0.001) and default (1.5%
15.2%; p<0.001). However, linezolid was withdrawn in 32.7% (18 out of 55) of patients in the bedaquiline group because of adverse events. Admission weight >50 kg, an increasing number of anti-TB drugs and bedaquiline were independent predictors of survival (the bedaquiline survival effect remained significant in HIV-infected persons, irrespective of CD4 count).XDR-TB patients receiving a backbone of bedaquiline and linezolid had substantially better favourable outcomes compared to those not using these drugs. These data inform the selection of XDR-TB treatment regimens and roll-out of newer drugs in TB-endemic countries.
The global tuberculosis burden remains substantial, with more than 10 million people newly ill per year. Nevertheless, tuberculosis incidence has slowly declined over the past decade, and mortality ...has decreased by almost a third in tandem. This positive trend was abruptly reversed by the COVID-19 pandemic, which in many parts of the world has resulted in a substantial reduction in tuberculosis testing and case notifications, with an associated increase in mortality, taking global tuberculosis control back by roughly 10 years. Here, we consider points of intersection between the tuberculosis and COVID-19 pandemics, identifying wide-ranging approaches that could be taken to reverse the devastating effects of COVID-19 on tuberculosis control. We review the impact of COVID-19 at the population level on tuberculosis case detection, morbidity and mortality, and the patient-level impact, including susceptibility to disease, clinical presentation, diagnosis, management, and prognosis. We propose strategies to reverse or mitigate the deleterious effects of COVID-19 and restore tuberculosis services. Finally, we highlight research priorities and major challenges and controversies that need to be addressed to restore and advance the global response to tuberculosis.
The diagnosis of pleural tuberculosis (TB) is problematic. The comparative performance of newer same-day tools for pleural TB, including Xpert MTB/RIF Ultra (ULTRA), has hitherto not been ...comprehensively studied. Adenosine deaminase (ADA), IRISA-TB (interferon gamma ultrasensitive rapid immunosuspension assay), Xpert MTB/RIF, and ULTRA performance outcomes were evaluated in pleural fluid samples from 149 patients with suspected pleural TB. The reference standard was culture positivity (fluid, biopsy specimen, or sputum) and/or pleural biopsy histopathology (termed definite TB). Those designated as having non-TB were negative by microbiological testing and were not initiated on anti-TB treatment. To determine the effect of sample concentration, 65 samples underwent pelleting by centrifugation, followed by conventional Xpert MTB/RIF and ULTRA. Of the 149 patients, 49 had definite TB, 16 had probable TB (not definite but treated for TB), and 84 had non-TB. ULTRA sensitivity and specificity (95% confidence intervals CI) were similar to those of Xpert MTB/RIF sensitivity, 37.5% (25.3 to 51.2) versus 28.6% (15.9 to 41.2), respectively; specificity, 98.8% (96.5 to 100) versus 98.8% (96.5 to 100), respectively. Centrifugation did not significantly improve ULTRA sensitivity (29.5% versus 31.3%, respectively). Adenosine deaminase and IRISA-TB sensitivity were 84.4% (73.9 to 95.0) and 89.8% (81.3 to 98.3), respectively. However, IRISA-TB demonstrated significantly better specificity (96.4% versus 87.5%
= 0.034), positive predictive value (93.6% versus 80.9
= 0.028), and positive likelihood ratio (25.1 versus 6.8
= 0.032) than ADA. In summary, Xpert ULTRA has poor sensitivity for the diagnosis of pleural TB. Alternative assays (ADA and IRISA-TB) are significantly more sensitive, with IRISA-TB demonstrating a higher specificity and rule-in value than ADA in this high-TB-burden setting where HIV is endemic.
•Linezolid interruption occurred in one-third of patients on bedaquiline therapy.•Anaemia and peripheral neuropathy are the most commonly reported adverse events.•System-specific toxicities occurred ...at predictable time frames following treatment.•HIV co-infection and high bacteria load predispose to linezolid interruption.•Linezolid interruption does not predispose to having an unfavourable treatment outcome.
Treatment outcomes of patients with extensively drug-resistant tuberculosis (XDR-TB) are suboptimal and treatment options remain limited. Linezolid is associated with improved outcomes but also substantial toxicity, and details about the relationship between these are lacking from resource-poor HIV-endemic settings.
This was a prospective follow-up study of 63 South African XDR-TB patients (58.7% HIV-infected; median CD4 131 cells/μl) between 2014 and 2018. The frequency and severity of linezolid-associated adverse events and the impact on treatment outcomes were compared between linezolid interrupters and non-interrupters.
Twenty-two patients (34.9%) discontinued or underwent dose reduction due to presumed linezolid-associated toxicity. Anaemia (77.3% vs. 7.3%; p< 0.001), peripheral neuropathy (63.6% vs. 14.6%; p= 0.003), and optic neuritis (18.2% vs. 9.8%; p= 0.34) occurred more frequently in linezolid interrupters than in non-interrupters. Anaemia, peripheral neuropathy, and optic neuritis occurred at a median of 5, 18, and 23 weeks, respectively, after treatment initiation. Linezolid interruption was not associated with unfavourable outcomes but was strongly associated with HIV co-infection (adjusted hazard ratio 4.831, 95% confidence interval 1.526–15.297; p= 0.007) and bacterial load (culture days to positivity; adjusted hazard ratio 0.824, 95% confidence interval 0.732– 0.927; p= 0.001).
Linezolid-related treatment interruption is common, is strongly associated with HIV co-infection, and system-specific toxicity occurs within predictable time frames. These data inform the clinical management of patients with drug-resistant TB.
There are limited data about Xpert-Ultra performance in different settings, in HIV-infected persons, in those with a history of previous TB, and with trace readouts.
We evaluated the relative ...accuracy of Xpert-MTB/RIF and Xpert-Ultra in 272 selected but well-characterized archived sputum samples. Of these, 168 were culture-positive (64/168 smear-positive and 104/168 smear-negative), and 104 were culture-negative (102/104 from patients with previous TB and 2/104 from patients without a TB history). Assay-specific limit-of-detection (LOD) experiments were conducted using serial dilutions of Mycobacterium tuberculosis H37Rv.
Overall sensitivity (95%CI) in smear-negative culture-positive samples for Xpert-MTB/RIF and Xpert-Ultra were 71.2% (62.5–79.9) and 77% (68.9–85.1), respectively (and in HIV-infected persons: 63.5% (50–76.1) and 73.1% (61.1–85.2), respectively). The LOD for Xpert-Ultra was lower (9 versus 184 CFU/ml). There were a total of 9/272 (3.3%) Xpert Ultra trace readouts (6/104 5.8%) in smear-negative culture-positive persons, and 3/102 (3%) in culture-negative non-TB persons with a history of previous TB).
Xpert-Ultra had a lower LOD compared to Xpert-MTB/RIF. A small proportion of samples (<5%) from culture-negative patients but with a history of previous TB had a likely false-positive trace readout. These data inform the management of patients with suspected TB in endemic settings.
HIV self-testing has the potential to improve test access and uptake, but concerns remain regarding counselling and support during and after HIV self-testing. We investigated an oral HIV self-testing ...strategy together with a mobile phone/tablet application to see if and how it provided counselling and support, and how it might impact test access. This ethnographic study was nested within an ongoing observational cohort study in Cape Town, South Africa. Qualitative data was collected from study participants and study staff using 33 semi-structured interviews, one focus group discussion, and observation notes. The app provided information and guidance while also addressing privacy concerns. The flexibility and support provided by the strategy gave participants more control in choosing whom they included during testing. Accessibility concerns included smartphone access and usability issues for older and rural users. The adaptable access and support of this strategy could aid in expanding test access in South Africa.
Low-risk perception is an important barrier to the utilization of HIV services. In this context, offering an online platform for people to assess their risk of HIV and inform their decision to test ...can be impactful in increasing testing uptake. Using secondary data from the HIVSmart! quasirandomized trial, we aimed to identify predictors of HIV, develop a risk staging model for South African township populations, and validate it in combination with the HIVSmart! digital self-testing program.
Townships in Cape Town, South Africa.
Using Bayesian predictive projection, we identified predictors of HIV and constructed a risk assessment model that we validated in external data.
Our analyses included 3095 participants from the HIVSmart! trial. We identified a model of 5 predictors (being unmarried, HIV testing history, having had sex with a partner living with HIV, dwelling situation, and education) that performed best during external validation (area under the receiver operating characteristic curve, 89% credible intervals: 0.71, 0.68 to 0.72). The sensitivity of our HIV risk staging model was 91.0% (89.1% to 92.7%) and the specificity was 13.2% (8.5% to 19.8%) but increased when combined with a digital HIV self-testing program, the specificity was 91.6% (95.9% to 96.4%) and sensitivity remained similar at 90.9% (89.1% to 92.6%).
This is the first validated digital HIV risk assessment tool developed for South African township populations and the first study to evaluate the added value of a risk assessment tool with an app-based HIV self-testing program. Study findings are relevant for application of digital programs to improve utilization of HIV testing services.
Up to one third of HIV-infected individuals with suspected TB are sputum-scarce. The Alere Determine™ TB LAM Ag lateral flow strip test can be used to diagnose TB in HIV-infected patients with ...advanced immunosuppression. However, how urine LAM testing should be incorporated into testing algorithms and in the context of specific patient sub-groups remains unclear.
This study represents a post hoc sub-group analysis of data from a randomized multi-center parent study. The study population consisted of hospitalized HIV-infected patients with suspected TB who were unable to produce sputum and who underwent urine LAM testing. The diagnostic utility of urine LAM for TB in this group was compared to the performance of urine LAM in patients who did produce a sputum sample in the parent study.
There were a total of 187 and 2341 patients in the sputum-scarce and sputum-producing cohorts, respectively. 80 of the sputum-scarce patients underwent testing with urine LAM. In comparison to those who did produce sputum, sputum-scarce patients had a younger age, a lower Karnofsky performance score, and a lower weight and BMI at admission. A greater proportion of sputum-scarce patients were urine LAM positive, compared to those who were able to produce sputum (31% vs. 21%, p = 0.04). A higher proportion of sputum-scarce patients died within 8 weeks of admission (32% vs. 24%, p = 0.013). We inferred that 19% of HIV-infected sputum-scarce patients suspected of TB were diagnosed with tuberculosis by urine LAM testing, with an estimated positive predictive value of 63% (95% CI 43-82%).
Urine LAM testing can effectively identify tuberculosis in HIV-infected patients who are at a higher risk of mortality yet are unable to generate a sputum sample for diagnostic testing. Our findings support the use of urine LAM testing in sputum-scarce hospitalized HIV-infected patients, and its incorporation into diagnostic algorithms for this patient population.
The emergence of programmatically incurable tuberculosis threatens to destabilise control efforts. The aim of this study was to collect prospective patient-level data to inform treatment and ...containment strategies.
In a prospective cohort study, 273 South African patients with extensively drug-resistant tuberculosis, or resistance beyond extensively drug-resistant tuberculosis, were followed up over a period of 6 years. Transmission dynamics, infectiousness, and drug susceptibility were analysed in a subset of patients from the Western Cape using whole-genome sequencing (WGS; n=149), a cough aerosol sampling system (CASS; n=26), and phenotypic testing for 18 drugs (n=179).
Between Oct 1, 2008, and Oct 31, 2012, we enrolled and followed up 273 patients for a median of 20·3 months (IQR 9·6-27·8). 203 (74%) had programmatically incurable tuberculosis and unfavourable outcomes (treatment failure, relapse, default, or death despite treatment with a regimen based on capreomycin, aminosalicylic acid, or both). 172 (63%) patients were discharged home, of whom 104 (60%) had an unfavourable outcome. 54 (31%) home-discharged patients had failed treatment, with a median time to death after discharge of 9·9 months (IQR 4·2-17·4). 35 (20%) home-discharged cases were smear-positive at discharge. Using CASS, six (23%) of 26 home-discharged cases with data available expectorated infectious culture-positive cough aerosols in the respirable range (<5 μm), and most reported inter-person contact with suboptimal protective mask usage. WGS identified 17 (19%) of the 90 patients (with available sequence data) that were discharged home before the diagnosis of 20 downstream cases of extensively drug-resistant tuberculosis with almost identical sequencing profiles suggestive of community-based transmission (five or fewer single nucleotide polymorphisms different and with identical resistance-encoding mutations for 14 drugs). 11 (55%) of these downstream cases had HIV co-infection and ten (50%) had died by the end of the study. 22 (56%) of 39 isolates in patients discharged home after treatment failure were resistant to eight or more drugs. However, five (16%) of 31 isolates were susceptible to rifabutin and more than 90% were likely to be sensitive to linezolid, bedaquiline, and delamanid.
More than half of the patients with programmatically incurable tuberculosis were discharged into the community where they remained for an average of 16 months, were at risk of expectorating infectious cough aerosols, and posed a threat of transmission of extensively drug-resistant tuberculosis. Urgent action, including appropriate containment strategies, is needed to address this situation. Access to delamanid, bedaquiline, linezolid, and rifabutin, when appropriate, must be accelerated along with comprehensive drug susceptibility testing.
UK Medical Research Council, South African Medical Research Council, South African National Research Foundation, European & Developing Countries Clinical Trials Partnership, Oppenheimer Foundation, Newton Fund, Biotechnology and Biological Sciences Research Council, King Abdullah University of Science & Technology.
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