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Post COVID-19 condition (PCC), as defined by WHO, refers to a wide range of new, returning, or ongoing health problems in people who have had COVID-19, and it represents a rapidly emerging public health priority. We aimed to establish how this developing condition has affected patients in South Africa and which population groups are at risk.In this prospective cohort study, we used the DATCOV national hospital surveillance system to identify participants aged 18 years or older who had been hospitalised with laboratory-confirmed SARS-CoV-2 infection in South Africa. Participants underwent telephone follow-up assessment at 1 month and 3 months after hospital discharge. Participants were assessed using a standardised questionnaire for the evaluation of symptoms, functional status, health-related quality of life, and occupational status. We used negative binomial regression models to determine factors associated with PCC.Of 241 159 COVID-19 admissions reported to DATCOV between Dec 1, 2020, and Aug 23, 2021, 8309 were randomly selected for enrolment. Of the 3094 patients that we were able to contact, 2410 (77·9%) consented to participate in the study at 1 month after discharge. Of these, 1873 (77·7%) were followed up at 3 months after hospital discharge. Participants had a median age of 52 years (IQR 41-62) and 960 (51·3%) were women. At 3 months of follow-up, 1249 (66·7%) of 1873 participants reported new or persistent COVID-19-related symptoms, compared with 1978 (82·1%) of 2410 at 1 month after hospital discharge. The most common symptoms reported at 3 months were fatigue (50·3%), shortness of breath (23·4%), confusion or lack of concentration (17·5%), headaches (13·8%), and problems seeing or blurred vision (10·1%). On multivariable analysis, the factors associated with persistent symptoms after acute COVID-19 were being female (adjusted incident rate ratio 1·20, 95% CI 1·04-1·38) and admission to an intensive care unit (1·17, 1·01-1·37).Most participants in this cohort of individuals previously hospitalised with COVID-19 reported persistent symptoms 3 months after hospital discharge and a significant impact of PCC on their functional and occupational status. The large burden of PCC symptoms identified in this study emphasises the need for a national health strategy. This should include the development of clinical guidelines and training of health-care workers for identifying, assessing, and caring for patients affected by PCC; establishment of multidisciplinary health services; and provision of information and support to people who have PCC.BillMelinda Gates Foundation, UK Foreign, CommonwealthDevelopment Office, and Wellcome.

Summary Background Bedaquiline improves outcomes of patients with rifampicin-resistant and multidrug-resistant (MDR) tuberculosis; however, emerging resistance threatens this success. We did a cross-sectional and longitudinal analysis evaluating the epidemiology, genetic basis, and treatment outcomes associated with bedaquiline resistance, using data from South Africa (2015–19). Methods Patients with drug-resistant tuberculosis starting bedaquiline-based treatment had surveillance samples submitted at baseline, month 2, and month 6, along with demographic information. Culture-positive baseline and post-baseline isolates had phenotypic resistance determined. Eligible patients were aged 12 years or older with a positive culture sample at baseline or, if the sample was invalid or negative, a sample within 30 days of the baseline sample submitted for bedaquiline drug susceptibility testing. For the longitudinal study, the first surveillance sample had to be phenotypically susceptible to bedaquiline for inclusion. Whole-genome sequencing was done on bedaquiline-resistant isolates and a subset of bedaquiline-susceptible isolates. The National Institute for Communicable Diseases tuberculosis reference laboratory, and national tuberculosis surveillance databases were matched to the Electronic Drug-Resistant Tuberculosis Register. We assessed baseline resistance prevalence, mutations, transmission, cumulative resistance incidence, and odds ratios (ORs) associating risk factors for resistance with patient outcomes. Findings Between Jan 1, 2015, and July 31, 2019, 8041 patients had surveillance samples submitted, of whom 2023 were included in the cross-sectional analysis and 695 in the longitudinal analysis. Baseline bedaquiline resistance prevalence was 3·8% (76 of 2023 patients; 95% CI 2·9–4·6), and it was associated with previous exposure to bedaquiline or clofazimine (OR 7·1, 95% CI 2·3–21·9) and with rifampicin-resistant or MDR tuberculosis with additional resistance to either fluoroquinolones or injectable drugs (pre-extensively-drug resistant [XDR] tuberculosis: 4·2, 1·7–10·5) or to both (XDR tuberculosis: 4·8, 2·0–11·7). Rv0678 mutations were the sole genetic basis of phenotypic resistance. Baseline resistance could be attributed to previous bedaquiline or clofazimine exposure in four (5·3%) of 76 patients and to primary transmission in six (7·9%). Odds of successful treatment outcomes were lower in patients with baseline bedaquiline resistance (0·5, 0·3–1). Resistance during treatment developed in 16 (2·3%) of 695 patients, at a median of 90 days (IQR 62–195), with 12 of these 16 having pre-XDR or XDR. Interpretation Bedaquiline resistance was associated with poorer treatment outcomes. Rapid assessment of bedaquiline resistance, especially when patients were previously exposed to bedaquiline or clofazimine, should be prioritised at baseline or if patients remain culture-positive after 2 months of treatment. Preventing resistance by use of novel combination therapies, current treatment optimisation, and patient support is essential. Funding National Institute for Communicable Diseases of South Africa.

Summary Background The WHO End TB Strategy requires drug susceptibility testing and treatment of all people with tuberculosis, but second-line diagnostic testing with line-probe assays needs to be done in experienced laboratories with advanced infrastructure. Fewer than half of people with drug-resistant tuberculosis receive appropriate treatment. We assessed the diagnostic accuracy of the rapid Xpert MTB/XDR automated molecular assay (Cepheid, Sunnyvale, CA, USA) to overcome these limitations. Methods We did a prospective study involving individuals presenting with pulmonary tuberculosis symptoms and at least one risk factor for drug resistance in four sites in India (New Delhi and Mumbai), Moldova, and South Africa between July 31, 2019, and March 21, 2020. The Xpert MTB/XDR assay was used as a reflex test to detect resistance to isoniazid, fluoroquinolones, ethionamide, amikacin, kanamycin, and capreomycin in adults with positive results for Mycobacterium tuberculosis complex on Xpert MTB/RIF or Ultra (Cepheid). Diagnostic performance was assessed against a composite reference standard of phenotypic drug-susceptibility testing and whole-genome sequencing. This study is registered with ClinicalTrials.gov , number NCT03728725 . Findings Of 710 participants, 611 (86%) had results from both Xpert MTB/XDR and the reference standard for any drug and were included in analysis. Sensitivity for Xpert MTB/XDR detection of resistance was 94% (460 of 488, 95% CI 92–96) for isoniazid, 94% (222 of 235, 90–96%) for fluoroquinolones, 54% (178 of 328, 50–61) for ethionamide, 73% (60 of 82, 62–81) for amikacin, 86% (181 of 210, 81–91) for kanamycin, and 61% (53 of 87, 49–70) for capreomycin. Specificity was 98–100% for all drugs. Performance was equivalent to that of line-probe assays. The non-determinate rate of Xpert MTB/XDR (ie, invalid M tuberculosis complex detection) was 2·96%. Interpretation The Xpert MTB/XDR assay showed high diagnostic accuracy and met WHO's minimum target product profile criteria for a next-generation drug susceptibility test. The assay has the potential to diagnose drug-resistant tuberculosis rapidly and accurately and enable optimum treatment. Funding German Federal Ministry of Education and Research through KfW, Dutch Ministry of Foreign Affairs, and Australian Department of Foreign Affairs and Trade.

Contains fulltext : 291526.pdf (Publisher’s version ) (Closed access) Drug-resistant tuberculosis is a substantial health-care concern worldwide. Despite culture-based methods being considered the gold standard for drug susceptibility testing, molecular methods provide rapid information about the Mycobacterium tuberculosis mutations associated with resistance to anti-tuberculosis drugs. This consensus document was developed on the basis of a comprehensive literature search, by the TBnet and RESIST-TB networks, about reporting standards for the clinical use of molecular drug susceptibility testing. Review and the search for evidence included hand-searching journals and searching electronic databases. The panel identified studies that linked mutations in genomic regions of M tuberculosis with treatment outcome data. Implementation of molecular testing for the prediction of drug resistance in M tuberculosis is key. Detection of mutations in clinical isolates has implications for the clinical management of patients with multidrug-resistant or rifampicin-resistant tuberculosis, especially in situations when phenotypic drug susceptibility testing is not available. A multidisciplinary team including clinicians, microbiologists, and laboratory scientists reached a consensus on key questions relevant to molecular prediction of drug susceptibility or resistance to M tuberculosis, and their implications for clinical practice. This consensus document should help clinicians in the management of patients with tuberculosis, providing guidance for the design of treatment regimens and optimising outcomes. 01 april 2023

Background\ud The bedaquiline–pretomanid–linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear.\ud \ud Methods\ud We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated.\ud \ud Results\ud A total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline–pretomanid–linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups.\ud \ud Conclusions\ud A total of 84 to 93% of the participants across all four bedaquiline–pretomanid–linezolid treatment groups had a favorable outcome. The overall risk–benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486. opens in new tab.)

BACKGROUND: There are no data comparing the 6–9 month oral three-drug Nix regimen (bedaquiline, pretomanid and linezolid [BPaL]) to conventional regimens containing bedaquiline (B, BDQ) and linezolid (L, LZD).METHODS: Six-month post end-of-treatment outcomes were compared between Nix-TB (n = 109) and 102 prospectively recruited extensively drug-resistant TB patients who received an ˜18-month BDQ-based regimen (median of 8 drugs). A subset of patients received BDQ and LZD (n = 86), and a subgroup of these (n = 75) served as individually matched controls in a pairwise comparison to determine differences in regimen efficacy.RESULTS: Favourable outcomes (%) were significantly better with BPaL than with the B–L-based combination regimen (98/109, 89.9% vs. 56/86, 65.1%; adjusted relative risk ratio [aRRR] 1.35; P < 0.001) and in the matched pairwise analysis (67/75, 89.3% vs. 48/75, 64.0%; aRRR 1.39; P = 0.001), despite significantly higher baseline bacterial load and prior second-line drug exposure in the BPaL cohort. Time to culture conversion (P < 0.001), time to unfavourable outcome (P < 0.01) and time to death (P < 0.03) were significantly better or lower with BPaL than the B-L-based combinations.CONCLUSION: The BPaL regimen (and hence substitution of multiple other drugs by pretomanid and/or higher starting-dose LZD) may improve outcomes in drug-resistant TB patients with poor prognostic features. However, prospective controlled studies are required to definitively answer this question.

The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen.We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631.Between March 28, 2016, and Jan 28, 2020, 1436 participants were screened and 588 were randomly assigned. Of 517 participants in the mITT population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the oral regimen had a favourable outcome: a difference of 11·0% (95% CI 2·9-19·0), adjusted for HIV status and randomisation protocol (p0·0001 for non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent in participants on the control regimen than in those on the oral regimen (18 [9%] vs four [2%], p=0·0015). Of 134 participants in the mITT population who were allocated to the 6-month regimen, 122 (91%) had a favourable outcome compared with 87 (69%) of 127 participants randomly assigned concurrently to the control regimen (adjusted difference 22·2%, 95% CI 13·1-31·2); six (4%) of 143 participants on the 6-month regimen had grade 3 or 4 hearing loss.Both bedaquiline-containing regimens, a 9-month oral regimen and a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy compared with a 9-month injectable-containing regimen, with fewer cases of hearing loss.USAID and Janssen ResearchDevelopment.

ObjectivesPatients with highly resistant tuberculosis have few treatment options. Bedaquiline, pretomanid and linezolid regimen (BPaL) is a new regimen shown to have favourable outcomes after six months. We present an economic evaluation of introducing BPaL against the extensively drug-resistant tuberculosis (XDR-TB) standard of care in three epidemiological settings.DesignCost-effectiveness analysis using Markov cohort model.SettingSouth Africa, Georgia and the Philippines.ParticipantsXDR-TB and multidrug-resistant tuberculosis (MDR-TB) failure and treatment intolerant patients.InterventionsBPaL regimen.Primary and secondary outcome measures(1) Incremental cost per disability-adjusted life years averted by using BPaL against standard of care at the Global Drug Facility list price. (2) The potential maximum price at which the BPaL regimen could become cost neutral.ResultsBPaL for XDR-TB is likely to be cost saving in all study settings when pretomanid is priced at the Global Drug Facility list price. The magnitude of these savings depends on the prevalence of XDR-TB in the country and can amount, over 5 years, to approximately US$ 3 million in South Africa, US$ 200 000 and US$ 60 000 in Georgia and the Philippines, respectively. In South Africa, related future costs of antiretroviral treatment (ART) due to survival of more patients following treatment with BPaL reduced the magnitude of expected savings to approximately US$ 1 million. Overall, when BPaL is introduced to a wider population, including MDR-TB treatment failure and treatment intolerant, we observe increased savings and clinical benefits. The potential threshold price at which the probability of the introduction of BPaL becoming cost neutral begins to increase is higher in Georgia and the Philippines (US$ 3650 and US$ 3800, respectively) compared with South Africa (US$ 500) including ART costs.ConclusionsOur results estimate that BPaL can be a cost-saving addition to the local TB programmes in varied programmatic settings.

There is a need for short and safe all-oral treatment of rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after treatment initiation for patients with rifampicin-resistant tuberculosis in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable group).Patients with rifampicin-resistant tuberculosis, aged 18 years or older, eligible for a short regimen starting treatment between Jan 1 and Dec 31, 2017, with a bedaquiline-containing or WHO recommended injectable-containing treatment regimen of 9-12 months, registered in the drug-resistant tuberculosis database (EDRWeb), and with known age, sex, HIV status, and national identification number were eligible for study inclusion; patients receiving linezolid, carbapenems, terizidone or cycloserine, delamanid, or para-aminosalicylic acid were excluded. Bedaquiline was given at a dose of 400 mg once daily for two weeks followed by 200 mg three times a week for 22 weeks. To compare regimens, patients were exactly matched on HIV and ART status, previous tuberculosis treatment history, and baseline acid-fast bacilli smear and culture result, while propensity score matched on age, sex, province of treatment, and isoniazid-susceptibility status. We did binomial linear regression to estimate adjusted risk differences (aRD) and 95% CIs for 24-month outcomes, which included: treatment success (ie, cure or treatment completion without evidence of recurrence) versus all other outcomes, survival versus death, disease free survival versus survival with treatment failure or recurrence, and loss to follow-up versus all other outcomes.Overall, 1387 (14%) of 10152 patients with rifampicin-resistant tuberculosis treated during 2017 met inclusion criteria; 688 in the bedaquiline group and 699 in the injectable group. Four patients (1%) had treatment failure or recurrence, 44 (6%) were lost to follow-up, and 162 (24%) died in the bedaquiline group, compared with 17 (2%), 87 (12%), and 199 (28%), respectively, in the injectable group. In adjusted analyses, treatment success was 14% (95% CI 8-20) higher in the bedaquiline group than in the injectable group (70% vs 57%); loss to follow-up was 4% (1-8) lower in the bedaquiline group (6% vs 12%); and disease-free survival was 2% (0-5) higher in the bedaquiline group (99% vs 97%). The bedaquiline group had 8% (4-11) lower risk of mortality during treatment (17·0% vs 22·4%), but there was no difference in mortality post-treatment.Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months. This finding supports the use of short bedaquiline-containing regimens in eligible patients.WHO Global TB Programme.For the French translation of the abstract see Supplementary Materials section.

Background Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommend...

BackgroundThe WHO End TB Strategy requires universal drug susceptibility testing and treatment of all people with tuberculosis. However, available second-line diagnostic tools are cumbersome and require sophisticated laboratory infrastructure, and ultimately less than half of those with drug-resistant tuberculosis receive appropriate treatment. Xpert MTB/XDR was developed to help overcome these limitations.MethodsWe assessed the diagnostic accuracy of sputum-based Xpert MTB/XDR for isoniazid, fluoroquinolone, ethionamide and second-line injectable resistance detection in adults with an Xpert MTB/RIF or Ultra Mycobacterium tuberculosis-positive result against a composite reference standard of phenotypic drug-susceptibility testing and whole genome sequencing (NCT03728725). Participants with pulmonary tuberculosis symptoms and ≥1 risk factor for drug resistance were consecutively enrolled between four clinical sites in India, Moldova and South Africa.FindingsBetween 31 July 2019 and 21 March 2020, we enrolled 710 patients, of which 611 (86.1%) had results from index and composite reference standard tests and were included in analysis. The sensitivity of Xpert MTB/XDR was 94% for isoniazid, 95% for fluoroquinolones, 54% for ethionamide, 73% for amikacin, 86% for kanamycin, and 61% for capreomycin resistance detection. Specificity was 98-100% for all drugs. Performance was equivalent to line-probe assays. The non-determinate rate of Xpert MTB/XDR was 2·96%.InterpretationThis first prospective, multicentre clinical study of the Xpert MTB/XDR assay demonstrated high diagnostic test accuracy, meeting target product profile criteria for a next-generation drug susceptibility test.FundingGerman Federal Ministry of Education and Research through KfW, Dutch Ministry of Foreign Affairs, and Australian Department of Foreign Affairs and Trade.Research in contextEvidence before this studyThe World Health Organization (WHO) has highlighted the development of expanded, rapid molecular drug susceptibility tests as a key priority to tackle drug-resistant tuberculosis (TB). Prior to the Cepheid Xpert MTB/XDR assay, the only WHO-recommended rapid molecular assay for second-line resistance detection was the Bruker-Hain GenoType MTBDRsl line probe assay. However, the high complexity of DNA-based hybridization assays limits their use to central reference or regional-level laboratories where the appropriate infrastructure and user expertise can be ensured. In this context, the Xpert MTB/XDR assay is the only lower complexity, automated molecular assay for broader resistance detection suitable for use at lower levels of the laboratory network. We searched PubMed databases for articles evaluating the performance of the sputum-based assay using search terms (tuberculosis or TB) AND (Xpert OR GeneXpert OR cartridge) AND (second-line OR XDR OR “extensively drug-resistant”) AND (sputum OR sputa) AND (test OR assay OR diagnostic OR “point of care”) AND (performance OR accuracy OR sensitivity OR specificity OR diagnos*). The search was done on 8 Feb 2021 with no search date or language restrictions. Our search yielded 51 studies, of which only three reported on a sputum-based cartridge for expanded resistance detection. The first two studies described the assay design approach and reported initial performance metrics for a prototype version of the Xpert MTB/XDR assay. In the third study, the manufacturer demonstrated high performance for the final assay (sensitivity of 94–100% and a specificity of 100% for all drugs except for ethionamide) when compared with sequencing for 314 sputum specimens and sediments. This study was the first assessment of Xpert MTB/XDR assay diagnostic accuracy in a prospective patient cohort.Added value of this studyThis is the first clinical study of the diagnostic performance of the Xpert MTB/XDR assay for expanded drug resistance detection. This study was performed independent of the manufacturer in settings of intended use utilizing prospectively collected primary clinical samples. The study employed a comprehensive reference standard using both phenotypic drug susceptibility testing and whole genome sequencing separately, as well as in combination, which allowed a differentiated view of performance of the assay for resistance detection. Moreover, we compared the performance of the assay on direct sputum samples with the performance of the WHO-recommended Bruker-Hain MTBDRplus and MTBDRsl line probe assays on culture.Implications of all the available evidenceThe WHO End TB Strategy calls for early diagnosis and universal access to drug susceptibility testing. With a 10-color calibration to GeneXpert instruments, the Xpert MTB/XDR assay expands upon the drug detection landscape of the Xpert MTB/RIF and Ultra assays and overcomes the limitations of the Bruker-Hain line probe assays to offer an option for lower-level health care centres to conduct rapid, expanded drug susceptibility testing in follow-up to a TB-positive result using existing laboratory infrastructure. Data from this study demonstrates that the Xpert MTB/XDR assay has high performance for a diverse clinical population in the intended setting of use, providing national TB programmes with a valuable tool for expanded drug susceptibility testing for all persons with signs and symptoms of TB.

Background We evaluated Nix-TB trial data (NCT02333799, N = 109) to provide dosing recommendations to potentially minimize linezolid toxicity in patients with extensively drug-resistant tuberculosis. . Methods A pharmacokinetic model and toxicodynamic models for peripheral neuropathy, hemoglobin, and platelets were developed. Simulations compared safety outcomes for daily linezolid of 1200 and 600 mg, with and without dose adjustments for toxicity. Severe neuropathy was based on symptom scores from the Brief Peripheral Neuropathy Screen. Severe anemia and thrombocytopenia were defined as ≥ grade 3 adverse events according to the NIAID Division of Microbiology and Infectious Disease Adult Toxicity table. Results Predicted concentration-time profiles were a major predictor in all toxicodynamic models. Simulations showed higher percentages of patients with severe neuropathy (median, 19%; 90% confidence interval [CI], 17%–22% vs 5%, 4%–7%) and severe anemia (15%, 12%–17% vs 1%, 0%–2%) between 1200 and 600 mg daily linezolid. No differences in severe thrombocytopenia were observed (median, 10% decrease in hemoglobin level after 4 weeks of treatment would have maximum sensitivity (82%) and specificity (84%) for predicting severe anemia. Reducing the dose from 1200 to 600 mg triggered by this marker may prevent 60% (90% CI, 45%–72%) of severe anemia. Conclusions Simple neuropathy symptom and hemoglobin monitoring may guide linezolid dosing to avoid toxicities, but prospective testing is needed to confirm the benefit-to-risk ratio.

Background: We compared outcomes up to 24 months after treatment initiation for rifampicin-resistant tuberculosis (RR-TB) patients in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable group). Methods: RR-TB patients eligible for a short regimen starting treatment between 1 January and 31 December 2017 with a bedaquiline-containing or WHO recommended injectable-containing treatment regimen of 9 to 12 months, registered with their national ID in the drug-resistant TB database and with known age, sex, and HIV status were eligible for study inclusion. To compare regimens, we exactly matched patients on HIV-infection, previous TB treatment history, baseline acid-fast bacilli smear and culture result, and propensity score matched patients on age, sex, and isoniazid susceptibility status, using logistic regression with generalized linear mixed models to estimate adjusted odds ratios (aOR) and 95% confidence intervals (95%CI). Results: Overall, 1,387 of the 10,152 RR-TB patients treated during 2017 met inclusion criteria, of whom 688 received the bedaquiline-containing regimen and 699 patients received the injectable-containing regimen. Four patients (0.6%) had treatment failure and/or recurrence, 44 (6.4%) were lost to follow-up, and 162 (23.5%) died in the bedaquiline group, compared to 17 (2.4%), 87 (12.4%), and 199 (28.5%), respectively, in the injectable group. Patients in the bedaquiline group had 1.8 (95%CI 1.4 to 2.4) times higher odds of treatment success at 24 months and 0.6 (0.4 to 0.8) times lower odds of loss to follow-up. This was consistent in stratified analyses on HIV-status, AFB smear positivity, and previous treatment history. The bedaquiline group had lower odds of mortality during treatment (0.5, 95%CI 0.4 to 0.7), but not post treatment (1.1, 95%CI 0.7 to 1.7). Conclusion: Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months compared to the injectable group. The analysis supports the use of short bedaquiline-containing regimens in eligible patients. Funding: WHO Global TB Programme. Declaration of Interest: We declare no competing interests. Ethical Approval: This analysis was approved by Human Research Ethics Committee, Medical of University of Witwatersrand (#M150340, March 2015).

Rifampicin has played a key role in drug sensitive TB (DS-TB) treatment due to its bactericidal and sterilizing capacity. Since the introduction of the short course treatment for DS-TB using rifampicin, isoniazid (INH), ethambutol, and pyrazinamide (RHEZ), the development of resistance to any of the components was inevitable. The Directly Observed Treatment Short-r-t Course (DOTS) strategy was widely adopted, including direct supervision of medicine administration, to help with adherence to therapy. Since the 1970s there was a lull in clinical research and development of new TB medications. But multidrug-resistant tuberculosis (MDR-TB) and Rifampicin-Resistant TB (RR-TB) have since become a public health issue. According to the World Health Organization’s latest report on tuberculosis (TB), there are over ten million cases of active TB disease annually. Of these cases, the best estimate is that, worldwide in 2017, 558,000 people developed TB that was resistant to rifampicin. The regimens to treat RR-TB until recently been long, have contained toxic medications and have been less effective than RHEZ. However in the last 5 years, growing evidence has demonstrated that shorter all-oral regimens can be effective and safe for RR-TB.

Background The STREAM trial demonstrated that a 9–11-month “short” regimen had non-inferior efficacy and comparable safety to a 20+ month “long” regimen for the treatment of rifampicin-resistant tuberculosis. Imbalance in the components of the composite primary outcome merited further investigation. Methods Firstly, the STREAM primary outcomes were mapped to alternatives in current use, including WHO programmatic outcome definitions and other recently proposed modifications for programmatic or research purposes. Secondly, the outcomes were re-classified according to the likelihood that it was a Failure or Relapse (FoR) event on a 5-point Likert scale: Definite, Probable, Possible, Unlikely, and Highly Unlikely. Sensitivity analyses were employed to explore the impact of informative censoring. The protocol-defined modified intention-to-treat (MITT) analysis population was used for all analyses. Results Cure on the short regimen ranged from 75.1 to 84.2% across five alternative outcomes. However, between-regimens results did not exceed 1.3% in favor of the long regimen (95% CI upper bound 10.1%), similar to the primary efficacy results from the trial. Considering only Definite or Probable FoR events, there was weak evidence of a higher risk of FoR in the short regimen, HR 2.19 (95%CI 0.90, 5.35), p = 0.076; considering only Definite FoR events, the evidence was stronger, HR 3.53 (95%CI 1.05, 11.87), p = 0.030. Cumulative number of grade 3–4 AEs was the strongest predictor of censoring. Considering a larger effect of informative censoring attenuated treatment differences, although 95% CI were very wide. Conclusion Five alternative outcome definitions gave similar overall results. The risk of failure or relapse (FoR) may be higher in the short regimen than in the long regimen, highlighting the importance of how loss to follow-up and other censoring is accounted for in analyses. The outcome of time to FoR should be considered as a primary outcome for future drug-sensitive and drug-resistant TB treatment trials, provided sensitivity analyses exploring the impact of departures from independent censoring are also included.

Worldwide uptake of new drugs in the treatment of rifampicin-resistant tuberculosis (RR-TB) has been extremely low. In June 2018, ahead of the release of the updated WHO guidelines for the management of RR-TB, South Africa announced that bedaquiline (BDQ) would be provided to virtually all RR-TB patients on shorter or longer regimens. South Africa has been the global leader in accessing BDQ for patients with RR-TB, who now represent 60% of the global BDQ cohort. The use of BDQ within a shorter modified regimen has generated the programmatic data underpinning the most recent change in WHO guidelines endorsing a shorter, injectable-free regimen. Progressive policies on access to new drugs have resulted in improved favourable outcomes and a reduction in mortality among RR-TB patients in South Africa. This supported global policy change. The strategies underpinning these bold actions include close collaboration between the South African National TB Programme and partners, introduction of new TB diagnostic tools in closely monitored conditions and the use of locally generated programmatic evidence to inform country policy changes. In this paper, we summarise a decade´s work that led to the bold decision to use a modified, short, injectable-free regimen with BDQ and linezolid under carefully monitored programmatic conditions.

No abstract available.

Summary Background Bedaquiline and delamanid are the first drugs of new classes registered for tuberculosis treatment in 40 years. Each can prolong the QTc interval, with maximum effects occurring weeks after drug initiation. The cardiac safety and microbiological activity of these drugs when co-administered are not well-established. Our aim was to characterise the effects of bedaquiline, delamanid, or both on the QTc interval, longitudinally over 6 months of multidrug treatment, among patients with multidrug-resistant or rifampicin-resistant tuberculosis taking multidrug background therapy. Methods ACTG A5343 is a phase 2, open-label, randomised, controlled trial in which adults with multidrug-resistant or rifampicin-resistant tuberculosis receiving multidrug background treatment were randomly assigned 1:1:1 by centrally, computer-generated randomisation, by means of permuted blocks to receive bedaquiline, delamanid, or both for 24 weeks. Participants were enrolled at TASK in Cape Town and the South African Tuberculosis Vaccine Initiative in Worcester, both in South Africa, and Hospital Maria Auxiliadora in Peru. Individuals with QTc greater than 450 ms were excluded. HIV-positive participants received dolutegravir-based antiretroviral therapy. Clofazimine was disallowed, and levofloxacin replaced moxifloxacin. ECG in triplicate and sputum cultures were done fortnightly. The primary endpoint was mean QTcF change from baseline (averaged over weeks 8–24); cumulative culture conversation at week 8-24 was an exploratory endpoint. Analyses included all participants who initiated study tuberculosis treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov , NCT02583048 and is ongoing. Findings Between Aug 26, 2016 and July 13, 2018, of 174 screened, 84 participants (28 in each treatment group, and 31 in total with HIV) were enrolled. Two participants did not initiate study treatment (one in the delamanid group withdrew consent and one in the bedaquiline plus delamanid group) did not meet the eligibility criterion). Mean change in QTc from baseline was 12·3 ms (95% CI 7·8–16·7; bedaquiline), 8·6 ms (4·0–13·1; delamanid), and 20·7 ms (16·1–25·3) (bedaquiline plus delamanid). There were no grade 3 or 4 adverse QTc prolongation events and no deaths during study treatment. Cumulative culture conversion by week 8 was 21 (88%) of 24 (95% CI 71–97; bedaquiline), 20 (83%) of 24 (65–95; delamanid), and 19 (95%) of 20 (79–100; bedaquiline plus delamanid) and was 92% (77–99) for bedaquiline, 91% (76–99), for delamanid, and 95% (79–100) for bedaquiline plus delamanid at 24 weeks. Interpretation Combining bedaquiline and delamanid has a modest, no more than additive, effect on the QTc interval, and initial microbiology data are encouraging. This study provides supportive evidence for use of these agents together in patients with multidrug-resistant or rifampicin-resistant tuberculosis with normal baseline QTc values. Funding Division of AIDS, National Institutes of Health.

Objective Using data from four public sector clinics in South Africa, we sought to investigate provider- and patient-level outcomes, to understand how the 2012 tenofovir stock shortage affected the HIV care and monitoring of ART patients. Methods Prospective cohort analysis of ART-naive, non-pregnant, HIV-infected patients >18 years initiating first-line ART between 1 July 2011–31 March 2013. Linear regression was used for all outcomes (number of ART initiates, days between pharmacy visits, transfers, single-drug substitutions, treatment interruptions, missed pharmacy visits, loss to follow-up and elevated viral load). We fit splines to smooth curves with knots at the beginning (1 February 2012) and end (31 August 2012) of the stock shortage and displayed results graphically by clinic. Difference-in-difference models were used to evaluate the effect of the stock shortage on outcomes. Results Results suggest a potential shift in the management of patients during the shortage, mainly fewer average days between visits during the shortage vs. before or after at all four clinics, and a significant difference in the proportion of patients missing visits during vs. before (RD: 1.2%; 95% CI: 0.5%, 2.0%). No significant difference was seen in other outcomes. Conclusion While South Africa has made great strides to extend access to ART and increase the quality of the health services provided, patient care can be affected when stock shortages/outs occur. While our results show little effect on treatment outcomes, this most likely reflects the clinics’ ability to mitigate the crisis by continuing to keep patient care and treatment as consistent as possible.

Purpose of Review We review the international evolution of HIV and solid organ transplantation over 30 years. We emphasise recent developments in solid organ transplantation from HIV-infected to HIV-uninfected individuals, and their implications. Recent Findings In 2017, Johannesburg, South Africa, a life-saving partial liver transplant from an HIV-infected mother to her HIV-uninfected child was performed. This procedure laid the foundation not only for consideration of HIV-infected individuals as living donors, but also for the possibility that HIV-uninfected individuals could receive organs from HIV-infected donors. Summary Recent advances in this field are inclusion of HIV-infected individuals as living organ donors and the possibility of offering HIV-uninfected individuals organs from HIV-infected donors who are well-controlled on combination antiretroviral therapy (cART). The large number of HIV-infected individuals on cART is an unutilised source of otherwise eligible living organ donors. HIV-positive-to-HIV-negative organ transplantation has become a reality, providing possible new therapeutic options to address extreme organ shortages.

We sought to compare the effectiveness of two World Health Organization (WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant (RR/MDR) tuberculosis (TB): a standardised regimen of 9-12 months (the "shorter regimen") and individualised regimens of ≥20 months ("longer regimens").We collected individual patient data from observational studies identified through systematic reviews and a public call for data. We included patients meeting WHO eligibility criteria for the shorter regimen: not previously treated with second-line drugs, and with fluoroquinolone- and second-line injectable agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects meta-regression to calculate adjusted odds ratios and adjusted risk differences (aRDs) for failure or relapse, death within 12 months of treatment initiation and loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine studies of shorter regimens and 2717 out of 13 104 (20.7%) individuals from 53 studies of longer regimens. Treatment success was higher with the shorter regimen than with longer regimens (pooled proportions 80.0%

Background We assessed multidrug-resistant tuberculosis (MDR-TB) cases and their household contacts (HHCs) to inform the development of an interventional clinical trial. Methods We conducted a cross-sectional study of adult MDR-TB cases and their HHCs in 8 countries with high TB burdens. HHCs underwent symptom screenings, chest radiographies, sputum TB bacteriologies, TB infection (TBI) testing (tuberculin skin test [TST] and interferon gamma release assay [IGRA]), and human immunodeficiency virus (HIV) testing. Results From October 2015 to April 2016, 1016 HHCs from 284 MDR-TB cases were enrolled. At diagnosis, 69% of MDR-TB cases were positive for acid-fast bacilli sputum smears and 43% had cavitary disease; at study entry, 35% remained smear positive after a median MDR-TB treatment duration of 8.8 weeks. There were 9 HHCs that were diagnosed with TB prior to entry and excluded. Of the remaining 1007 HHCs, 41% were male and the median age was 25 years. There were 121 (12%) HHCs that had new cases of TB identified: 17 (2%) were confirmed, 33 (3%) probable, and 71 (7%) possible TB cases. The TBI prevalence (defined as either TST or IGRA positivity) was 72% and varied by age, test used, and country. Of 1007 HHCs, 775 (77%) were considered high-risk per these mutually exclusive groups: 102 (10%) were aged Conclusions The majority of HHCs in these high-burden countries were at high risk of TB disease and infection, yet few were receiving routine preventive therapy. Trials of novel, preventive therapies are urgently needed to inform treatment policy and practice.

People living with the human immunodeficiency virus (HIV) (PLHIV) are at high risk for tuberculosis (TB), and TB is a major cause of death in PLHIV. Preventing TB in PLHIV is therefore a key priority. Early initiation of antiretroviral therapy (ART) in asymptomatic PLHIV has a potent TB preventive effect, with even more benefits in those with advanced immunodeficiency. Applying the most recent World Health Organization recommendations that all PLHIV initiate ART regardless of clinical stage or CD4 cell count could provide a considerable TB preventive benefit at the population level in high HIV prevalence settings. Preventive therapy can treat tuberculous infection and prevent new infections during the course of treatment. It is now established that isoniazid preventive therapy (IPT) combined with ART among PLHIV significantly reduces the risk of TB and mortality compared with ART alone, and therefore has huge potential benefits for millions of sufferers. However, despite the evidence, this intervention is not implemented in most low-income countries with high burdens of HIV-associated TB. HIV and TB programme commitment, integration of services, appropriate screening procedures for excluding active TB, reliable drug supplies, patient-centred support to ensure adherence and well-organised follow-up and monitoring that includes drug safety are needed for successful implementation of IPT, and these features would also be needed for future shorter preventive regimens. A holistic approach to TB prevention in PLHIV should also include other important preventive measures, such as the detection and treatment of active TB, particularly among contacts of PLHIV, and control measures for tuberculous infection in health facilities, the homes of index patients and congregate settings.

New anti-tuberculosis regimens that are shorter, simpler, and less toxic than those that are currently available are needed as part of the global effort to address the tuberculosis epidemic. We aimed to investigate the bactericidal activity and safety profile of combinations of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide in the first 8 weeks of treatment of pulmonary tuberculosis.; In this multicentre, open-label, partially randomised, phase 2b trial, we prospectively recruited patients with drug-susceptible or rifampicin-resistant pulmonary tuberculosis from seven sites in South Africa, two in Tanzania, and one in Uganda. Patients aged 18 years or older with sputum smear grade 1+ or higher were eligible for enrolment, and a molecular assay (GeneXpert or MTBDRplus) was used to confirm the diagnosis of tuberculosis and to distinguish between drug-susceptible and rifampicin-resistant tuberculosis. Patients who were HIV positive with a baseline CD4 cell count of less than 100 cells per uL were excluded. Patients with drug-susceptible tuberculosis were randomly assigned (1:1:1) using numbered treatment packs with sequential allocation by the pharmacist to receive 56 days of treatment with standard tuberculosis therapy (oral isoniazid, rifampicin, pyrazinamide, and ethambutol; HRZE), or pretomanid (oral 200 mg daily) and pyrazinamide (oral 1500 mg daily) with either oral bedaquiline 400 mg daily on days 1-14 then 200 mg three times per week (B; load; PaZ) or oral bedaquiline 200 mg daily (B; 200; PaZ). Patients with rifampicin-resistant tuberculosis received 56 days of the B; 200; PaZ regimen plus moxifloxacin 400 mg daily (BPaMZ). All treatment groups were open label, and randomisation was not stratified. Patients, trial investigators and staff, pharmacists or dispensers, laboratory staff (with the exception of the mycobacteriology laboratory staff), sponsor staff, and applicable contract research organisations were not masked. The primary efficacy outcome was daily percentage change in time to sputum culture positivity (TTP) in liquid medium over days 0-56 in the drug-susceptible tuberculosis population, based on non-linear mixed-effects regression modelling of log; 10; (TTP) over time. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov, NCT02193776, and all patients have completed follow-up.; Between Oct 24, 2014, and Dec 15, 2015, we enrolled 180 patients with drug-susceptible tuberculosis (59 were randomly assigned to B; load; PaZ, 60 to B; 200; PaZ, and 61 to HRZE) and 60 patients with rifampicin-resistant tuberculosis. 57 patients in the B; load; PaZ group, 56 in the B; 200; PaZ group, and 59 in the HRZE group were included in the primary analysis. B; 200; PaZ produced the highest daily percentage change in TTP (5·17% [95% Bayesian credibility interval 4·61-5·77]), followed by B; load; PaZ (4·87% [4·31-5·47]) and HRZE group (4·04% [3·67-4·42]). The bactericidal activity in B; 200; PaZ and B; load; PaZ groups versus that in the HRZE group was significantly different. Higher proportions of patients in the B; load; PaZ (six [10%] of 59) and B; 200; PaZ (five [8%] of 60) groups discontinued the study drug than in the HRZE group (two [3%] of 61) because of adverse events. Liver enzyme elevations were the most common grade 3 or 4 adverse events and resulted in the withdrawal of ten patients (five [8%] in the B; load; PaZ group, three [5%] in the B; 200; PaZ group, and two [3%] in the HRZE group). Serious treatment-related adverse events affected two (3%) patients in the B; load; PaZ group and one (2%) patient in the HRZE group. Seven (4%) patients with drug-susceptible tuberculosis died and four (7%) patients with rifampicin-resistant tuberculosis died. None of the deaths were considered to be related to treatment.; B; 200; PaZ is a promising regimen to treat patients with drug-susceptible tuberculosis. The bactericidal activity of both these regimens suggests that they have the potential to shorten treatment, and the simplified dosing schedule of B; 200; PaZ could improve treatment adherence in the field. However, these findings must be investigated further in a phase 3 trial assessing treatment outcomes.; TB Alliance, UK Department for International Development, Bill & Melinda Gates Foundation, US Agency for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, and the Federal Ministry for Education and Research of Germany.

In Uganda and other sub-Saharan African countries women’s gender roles center on marriage and motherhood. According to these roles women’s duties include caring for other members of the household tending to household chores and caring for the sick. Women are expected to consult with their husbands and obey their husbands’ decisions in all matters. A man’s primary role is to be the head of the family. Men are expected to bring in income to pay for shelter food and school and they are expected to represent the family. Unlike women who are expected to be faithful or monogamous men are expected to have multiple partners (wives or girlfriends) thus signaling their masculinity. As other investigators have observed these gender roles interfere with HIV prevention efforts. Gender roles may also constrain women’s access to health services including those for the prevention of mother-to-child transmission of HIV (PMTCT). Globally all countries are working toward achieving the goal of having 90 percent of people diagnosed with HIV on sustained antiretroviral therapy (ART) by 2020. PMTCT programs in sub-Saharan Africa have had difficulty pursuing this goal owing to countries’ weak health systems and a variety of individual interpersonal and cultural factors. A number of studies have examined barriers to PMTCT participation. Common constraints are fear of HIV stigma fear of divorce or abandonment upon HIV disclosure side effects of ART lack of funds for transport to the clinic negative interactions with health workers and lack of male involvement. Most studies of barriers to PMTCT were conducted prior to the implementation of Option B+ which places HIV-positive pregnant or breastfeeding women on lifelong ART at diagnosis. By examining how gender interacts with individual interpersonal health system and community factors that cause people to discontinue PMTCT this study fills an important gap in knowledge about Option B+ programs. In partnership with the Child Health and Development Centre at Makerere University MEASURE Evaluation—funded by the United States Agency for International Development (USAID) and the United States President’s Emergency Fund for AIDS Relief (PEPFAR)—conducted qualitative research at eight health facilities (four urban and four rural) and their surrounding communities from 2015 to 2016. The purpose of this study was to describe gender-related factors at the individual interpersonal and programmatic or systemic levels that influence women’s participation in the elimination of mother-to-child transmission of HIV (EMTCT) program in Uganda. We used in-depth interviews and focus group discussions (FGDs) to obtain data from women participating in EMTCT (n=32) women who were lost to follow-up (LTFU) (n=16) health workers involved in providing EMTCT services (n=8) stakeholders in organizations supporting EMTCT services (n=8) and men in the community (8 focus group discussions (FGDs) n=73 participants).

Bedaquiline, a diarylquinoline, improved cure rates when added to a multidrug-resistant tuberculosis (MDR-TB) treatment regimen in a previous placebo-controlled, phase 2 trial (TMC207-C208; NCT00449644). The current phase 2, multicenter, open-label, single-arm trial (TMC207-C209; NCT00910871) reported here was conducted to confirm the safety and efficacy of bedaquiline.Newly diagnosed or previously treated patients with MDR-TB (including pre-extensively drug-resistant (pre-XDR)-TB or extensively drug-resistant (XDR)-TB) received bedaquiline for 24 weeks with a background regimen of anti-TB drugs continued according to National TB Programme treatment guidelines. Patients were assessed during and up to 120 weeks after starting bedaquiline.Of 233 enrolled patients, 63.5% had MDR-TB, 18.9% had pre-XDR-TB and 16.3% had XDR-TB, with 87.1% having taken second-line drugs prior to enrolment. 16 patients (6.9%) died. 20 patients (8.6%) discontinued before week 24, most commonly due to adverse events or MDR-TB-related events. Adverse events were generally those commonly associated with MDR-TB treatment. In the efficacy population (n=205), culture conversion (missing outcome classified as failure) was 72.2% at 120 weeks, and 73.1%, 70.5% and 62.2% in MDR-TB, pre-XDR-TB and XDR-TB patients, respectively.Addition of bedaquiline to a background regimen was well tolerated and led to good outcomes in this clinically relevant patient cohort with MDR-TB.