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Background Tuberculosis (TB) is a major health concern in South Africa, where prior to COVID-19 it was associated with more deaths than any other infectious disease. The COVID-19 pandemic disrupted gains made in the global response to TB, having a serious impact on the most vulnerable. COVID-19 and TB are both severe respiratory infections, where infection with one places individuals at increased risk for negative health outcomes for the other. Even after completing TB treatment, TB survivors remain economically vulnerable and continue to be negatively affected by TB. Methods This cross-sectional qualitative study, which was part of a larger longitudinal study in South Africa, explored how TB survivors’ experienced the COVID-19 pandemic and government restrictions. Participants were identified through purposive sampling and were recruited and interviewed at a large public hospital in Gauteng. Data were analyzed thematically, using a constructivist research paradigm and both inductive and deductive codebook development. Results Participants ( n  = 11) were adults (24–74 years of age; more than half male or foreign nationals) who had successfully completed treatment for pulmonary TB in the past two years. Participants were generally found to be physically, socioeconomically, and emotionally vulnerable, with the COVID-19 pandemic exacerbating or causing a recurrence of many of the same stressors they had faced with TB. Coping strategies during COVID similarly mirrored those used during TB diagnosis and treatment, including social support, financial resources, distraction, spirituality, and inner strength. Conclusions Implications and suggestions for future directions include fostering and maintaining a strong network of social support for TB survivors.

Background People with tuberculosis (TB) may face long-term physical and psycho-social-economic disability related to TB treatment. The Corona Virus Disease 2019 (COVID-19) pandemic and government restrictions disrupted health care services. We describe health-seeking behaviour, perceived financial impact, and the mental health of TB survivors one year after the COVID-19 pandemic. We further explore factors associated with the perceived impact of COVID-19 and government restrictions on health-seeking behaviour. Methods This is a cross-sectional study nested in an ongoing observational TB Sequel cohort study. Adults (≥ 18yrs) who had completed treatment for drug-susceptible pulmonary TB in South Africa, the Gambia, and Mozambique before the start of the COVID-19 pandemic, completed a COVID-19 questionnaire which included the WHO tool for Behavioural Insights on COVID-19, the Kessler Psychological Distress Scale (K10) and Medical Outcomes Short Form Survey (SF-36) for health-related quality of life. Questionnaires were administered during scheduled TB Sequel follow-up study visits between 04/2021 and 10/2021. We used publicly available data on the number of COVID-19 cases and the start and end date of each wave to define country-specific COVID-19 “in-wave” and “out-of-wave” phases. We compared psycho-social and economic measures reported during these phases. In addition, we explored factors associated with poor health-seeking behaviour (comprised of moderate or serious impact) using logistic regression. Results Four hundred eighty seven TB survivors (69% male, median age 33 years IQR 25–42, median time since TB treatment completion 16 months IQR 13–27) completed the COVID-19 questionnaire. About a quarter of TB survivors reported that their financial status ( n  = 117; 24%) or their health-seeking behaviour for any health condition ( n  = 128; 26%) had been seriously impacted by COVID-19 and the governments’ response. A third of patients (30.4%) reported using coping strategies. Logistic regression indicated that males, living with HIV and being on antiretroviral treatment (ART), being impacted financially during COVID-19, and experiencing social changes, were associated with poor health-seeking behaviour. Conclusion Governments’ response to COVID-19 affected TB survivors’ healthcare-seeking behaviour, financial status and mental health. The long-term adverse effects on health-seeking behaviour are important for TB survivors who are at increased risk for recurrent disease and long-term disability in the first two years after treatment completion. Trial registration Clinical trial number: not applicable.

Current tuberculosis treatments leave most patients with bronchiectasis and fibrosis, permanent conditions that impair lung function and increase all-cause post-TB mortality. Host-directed therapies (HDTs) may reduce lung inflammation and hasten eradication of infection. Biomarkers can accelerate tuberculosis regimen development, but no studies have yet examined early biomarkers of TB-HDTs. Biomarkers of inflammation and microbicidal activity were evaluated as a part of a recent phase-2 randomized controlled trial of four HDTs in 200 patients with pulmonary tuberculosis and baseline predictors of poor outcome, including CC-11050 (PDE4i), everolimus (mTORi), auranofin (oral gold salt), and ergocalciferol (vitamin D). Two of the 4 arms (CC-11050 and everolimus) showed superior recovery of lung function at day 180 compared to control; none showed accelerated eradication of MTB infection. Patients underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) on entry and day 56. PET signals were analyzed according to total, maximal, and peak glycolytic activity; CT was analyzed according to total modified Hounsfield units to assess radiodensity. Mycobactericidal activity in ex vivo whole blood culture was measured on days 42, 84, and 140. C-reactive protein (CRP) was measured at multiple time points. All PET/CT parameters showed highly significant reductions from baseline to day 56; however, only maximal or peak glycolytic activity showed further experimental reduction compared to controls, and only in everolimus recipients. CRP dropped precipitously during early treatment, but did so equally in all arms; over the entire period of treatment, the rate of decline of CRP tended to be greater in CC-11050 recipients than in controls but this fell short of statistical significance. Whole blood mycobactericidal activity in ex-vivo culture was enhanced by auranofin compared to controls, but not by other HDTs. None of these early biomarkers correctly predicted HDT effects on inflammation or infection across all four experimental arms. Instead, they each appear to show highly specific responses related to HDT mechanisms of action.

Preamble Nucleoside or nucleotide reverse transcriptase inhibitor class of antiretroviral drugs Integrase strand transfer inhibitor class of antiretroviral drugs Non-nucleoside reverse transcriptase inhibitor class of antiretroviral drugs Protease inhibitor class of antiretroviral drugs Initiation and timing of antiretroviral therapy Baseline investigations Viral load Cluster of differentiation 4 cell (CD4+) count Resistance and genotyping Initial antiretroviral therapy regimens for the previously untreated patient Management of patients currently receiving first-line therapy Management of patients starting or currently receiving second-line therapy Third-line antiretroviral therapy Laboratory monitoring of the efficacy and safety of antiretroviral therapy Patients who return after stopping antiretroviral therapy Drug–drug interactions Tuberculosis Pregnancy and breastfeeding Liver disease Renal disease Psychiatric disease Malaria Antiretroviral drug-induced liver injury Dyslipidaemia Immune reconstitution inflammatory syndrome Opportunistic infection prophylaxis Adherence Acknowledgments Abbreviations References What is new in the 2020 guidelines update? [...]only the treatment and diagnostic options that are available in southern Africa are included. Goals of antiretroviral therapy The goals of ART are to: provide maximal and durable suppression of viral load (VL) restore and/or preserve immune function reduce human immunodeficiency virus (HIV)-related infectious and non-infectious morbidity prolong life expectancy and improve quality of life prevent onward transmission of HIV minimise adverse effects of the treatment These goals are achieved by suppressing viral replication completely for as long as possible, using well-tolerated and sustainable treatment undertaken with good adherence. [...]the drugs are often used in second- and third-line therapies

Expanded access to combination antiretroviral therapy (ART) in resource-poor settings is dependent on task shifting from doctors to other health-care providers. We compared outcomes of nurse versus doctor management of ART care for HIV-infected patients. This randomised non-inferiority trial was undertaken at two South African primary-care clinics. HIV-positive individuals with a CD4 cell count of less than 350 cells per μL or WHO stage 3 or 4 disease were randomly assigned to nurse-monitored or doctor-monitored ART care. Patients were randomly assigned by stratified permuted block randomisation, and neither the patients nor those analysing the data were masked to assignment. The primary objective was a composite endpoint of treatment-limiting events, incorporating mortality, viral failure, treatment-limiting toxic effects, and adherence to visit schedule. Analysis was by intention to treat. Non-inferiority of the nurse versus doctor group for cumulative treatment failure was prespecified as an upper 95% CI for the hazard ratio that was less than 1·40. This study is registered with ClinicalTrials.gov, number NCT00255840. 408 patients were assigned to doctor-monitored ART care and 404 to nurse-monitored ART care; all participants were analysed. 371 (46%) patients reached an endpoint of treatment failure: 192 (48%) in the nurse group and 179 (44%) in the doctor group. The hazard ratio for composite failure was 1·09 (95% CI 0·89–1·33), which was within the limits for non-inferiority. After a median follow-up of 120 weeks (IQR 60–144), deaths (ten vs 11), virological failures (44 vs 39), toxicity failures (68 vs 66), and programme losses (70 vs 63) were similar in nurse and doctor groups, respectively. Nurse-monitored ART is non-inferior to doctor-monitored therapy. Findings from this study lend support to task shifting to appropriately trained nurses for monitoring of ART. National Institutes of Health; United States Agency for International Development; National Institute of Allergy and Infectious Diseases.

IntroductionIn 2022, tuberculosis (TB) was the second-leading cause of global deaths from a single infectious agent. Delays in initiating TB treatment can lead to increased morbidity and mortality. We describe the total delay in treatment initiation, identify patient-related factors associated with time to treatment initiation and explore health-seeking behaviour prior to treatment initiation among people living with TB (PLTB) in four African countries.MethodsCross-sectional survey nested in a large prospective cohort of adults (≥18 years) with drug-susceptible pulmonary TB. PLTB enrolled in South Africa, Tanzania, Mozambique and The Gambia between September 2017 and January 2020. Structured questionnaires were used to collect data on demographics and map the patient experience prior to treatment initiation. Total delay (weeks) was the time between the onset of the first TB symptom and the initiation of treatment at the health facility. We developed a Cox regression model to study the relationship between explanatory variables and the time-to-event outcome, TB treatment initiation.ResultsWe enrolled 1400 participants (South Africa: 344, Tanzania: 282, Mozambique: 407, The Gambia: 367) (mean age 36 years, 66% male). Overall HIV prevalence was 42% but varied by country (South Africa: 68%, Tanzania: 49%, Mozambique: 45%, The Gambia: 7%). The overall median total delay was 6 weeks (IQR 4–10). People living with HIV (vs HIV negative; adjusted HR (aHR)=1.33 (95% CI 1.2 to 1.5)) and those living with a partner (vs married; aHR=1.35 (95% CI 1.1 to 1.6)) or single (vs married; aHR=1.24 (95% CI 1.1 to 1.4)) had a higher chance of initiating TB treatment. Primary care facilities and pharmacies were the main providers where individuals first sought care after experiencing TB symptoms.ConclusionThere are delays in TB treatment initiation among presumptive TB individuals. Partnerships with pharmacies, active case finding and decentralised TB services may be important to incorporate into the National TB Control Programme.

IntroductionCurrent treatment regimens for multidrug-resistant tuberculosis (MDR-TB) are long, poorly tolerated and have poor outcomes. Furthermore, the costs of treating MDR-TB are much greater than those for treating drug-susceptible TB, both for health service and patient-incurred costs. Urgent action is needed to identify short, effective, tolerable and cheaper treatments for people with both quinolone-susceptible and quinolone-resistant MDR-TB. We present the protocol for an economic evaluation (PRACTECAL-EE substudy) alongside an ongoing clinical trial (TB-PRACTECAL) aiming to assess the costs to patients and providers of new regimens, as well as their cost-effectiveness and impact on participant poverty levels. This substudy is based on data from the three countries participating in the main trial.Methods and analysisPrimary cost data will be collected from the provider and patient perspectives, following economic best practice. We will estimate the probability that new MDR-TB regimens containing bedaquiline, pretomanid and linezolid are cost-effective from a societal perspective as compared with the standard of care for MDR-TB patients in Uzbekistan, South Africa and Belarus. Analysis uses a Markov model populated with primary cost and outcome data collected at each study site. We will also estimate the impact of new regimens on prevalence of catastrophic patient costs due to TB.Ethics and disseminationEthical approval has been obtained from the London School of Hygiene & Tropical Medicine and Médecins Sans Frontières. Local ethical approval will be sought in each study site. The results of the economic evaluation will be shared with the country health authorities and published in a peer-reviewed journal.Trial registration numberClinicalTrials.gov Registry (NCT04207112); Pre-results.

Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initial ART. In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe), 500 antiretroviral-naïve HIV-infected women with CD4<200 cells/mm(3) were enrolled into a two-arm randomized trial to initiate open-label ART with tenofovir (TDF)/emtricitabine (FTC) once/day plus either NVP (n = 249) or LPV/r (n = 251) twice/day, and followed for ≥48 weeks. The primary endpoint was time from randomization to death or confirmed virologic failure ([VF]) (plasma HIV RNA<1 log(10) below baseline 12 weeks after treatment initiation, or ≥400 copies/ml at or after 24 weeks), with comparison between treatments based on hazard ratios (HRs) in intention-to-treat analysis. Equivalence of randomized treatments was defined as finding the 95% CI for HR for virological failure or death in the range 0.5 to 2.0. Baseline characteristics were (median): age = 34 years, CD4 = 121 cells/mm(3), HIV RNA = 5.2 log(10)copies/ml. Median follow-up = 118 weeks; 29 (6%) women were lost to follow-up. 42 women (37 VFs, five deaths; 17%) in the NVP and 50 (43 VFs, seven deaths; 20%) in the LPV/r arm reached the primary endpoint (HR 0.85, 95% CI 0.56-1.29). During initial assigned treatment, 14% and 16% of women receiving NVP and LPV/r experienced grade 3/4 signs/symptoms and 26% and 22% experienced grade 3/4 laboratory abnormalities. However, 35 (14%) women discontinued NVP because of adverse events, most in the first 8 weeks, versus none for LPV/r (p<0.001). VF, death, or permanent treatment discontinuation occurred in 80 (32%) of NVP and 54 (22%) of LPV/r arms (HR = 1.7, 95% CI 1.2-2.4), with the difference primarily due to more treatment discontinuation in the NVP arm. 13 (45%) of 29 women tested in the NVP versus six (15%) of 40 in the LPV/r arm had any drug resistance mutation at time of VF. Initial ART with NVP+TDF/FTC demonstrated equivalent virologic efficacy but higher rates of treatment discontinuation and new drug resistance compared with LPV/r+TDF/FTC in antiretroviral-naïve women with CD4<200 cells/mm(3). ClinicalTrials.gov NCT00089505.

In patients with rifampin-resistant tuberculosis, all-oral treatment regimens that are more effective, shorter, and have a more acceptable side-effect profile than current regimens are needed. We conducted an open-label, phase 2-3, multicenter, randomized, controlled, noninferiority trial to evaluate the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis. Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage 2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen. The primary outcome was an unfavorable status (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks after randomization. The noninferiority margin was 12 percentage points. Recruitment was terminated early. Of 301 patients in stage 2 of the trial, 145, 128, and 90 patients were evaluable in the intention-to-treat, modified intention-to-treat, and per-protocol populations, respectively. In the modified intention-to-treat analysis, 11% of the patients in the BPaLM group and 48% of those in the standard-care group had a primary-outcome event (risk difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22). In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of those in the standard-care group had a primary-outcome event (risk difference, -9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the incidence of adverse events of grade 3 or higher or serious adverse events was lower in the BPaLM group than in the standard-care group (19% vs. 59%). In patients with rifampin-resistant pulmonary tuberculosis, a 24-week, all-oral regimen was noninferior to the accepted standard-care treatment, and it had a better safety profile. (Funded by Médecins sans Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782.).

The current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ. We compared 4 months of BPaMZ to the standard 6 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in DS-TB. 6 months of BPaMZ was assessed in DR-TB. SimpliciTB was a partially randomised, phase 2c, open-label, clinical trial, recruiting participants at 26 sites in eight countries. Participants aged 18 years or older with pulmonary TB who were sputum smear positive for acid-fast bacilli were eligible for enrolment. Participants with DS-TB had Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid. Participants with DR-TB had M tuberculosis with resistance to rifampicin, isoniazid, or both. Participants with DS-TB were randomly allocated in a 1:1 ratio, stratified by HIV status and cavitation on chest radiograph, using balanced block randomisation with a fixed block size of four. The primary efficacy endpoint was time to sputum culture-negative status by 8 weeks; the key secondary endpoint was unfavourable outcome at week 52. A non-inferiority margin of 12% was chosen for the key secondary outcome. Safety and tolerability outcomes are presented as descriptive analyses. 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 (NCT03338621) and is completed. Between July 30, 2018, and March 2, 2020, 455 participants were enrolled and received at least one dose of study treatment. 324 (71%) participants were male and 131 (29%) participants were female. 303 participants with DS-TB were randomly assigned to 4 months of BPaMZ (n=150) or HRZE (n=153). In a modified intention-to-treat (mITT) analysis, by week 8, 122 (84%) of 145 and 70 (47%) of 148 participants were culture-negative on 4 months of BPaMZ and HRZE, respectively, with a hazard ratio for earlier negative status of 2·93 (95% CI 2·17–3·96; p<0·0001). Median time to negative culture (TTN) was 6 weeks (IQR 4–8) on 4 months of BPaMZ and 11 weeks (6–12) on HRZE. 86% of participants with DR-TB receiving 6 months of BPaMZ (n=152) reached culture-negative status by week 8, with a median TTN of 5 weeks (IQR 3–7). At week 52, 120 (83%) of 144, 134 (93%) of 144, and 111 (83%) of 133 on 4 months of BPaMZ, HRZE, and 6 months of BPaMZ had favourable outcomes, respectively. Despite bacteriological efficacy, 4 months of BPaMZ did not meet the non-inferiority margin for the key secondary endpoint in the pre-defined mITT population due to higher withdrawal rates for adverse hepatic events. Non-inferiority was demonstrated in the per-protocol population confirming the effect of withdrawals with 4 months of BPaMZ. At least one liver-related treatment-emergent adverse effect (TEAE) occurred among 45 (30%) participants on 4 months of BPaMZ, 38 (25%) on HRZE, and 33 (22%) on 6 months of BPaMZ. Serious liver-related TEAEs were reported by 20 participants overall; 11 (7%) among those on 4 months of BPaMZ, one (1%) on HRZE, and eight (5%) on 6 months of BPaMZ. The most common reasons for discontinuation of trial treatment were hepatotoxicity (ten participants [2%]), increased hepatic enzymes (nine participants [2%]), QTcF prolongation (three participants [1%]), and hypersensitivity (two participants [<1%]). For DS-TB, BPaMZ successfully met the primary efficacy endpoint of sputum culture conversion. The regimen did not meet the key secondary efficacy endpoint due to adverse events resulting in treatment withdrawal. Our study demonstrated the potential for treatment-shortening efficacy of the BPaMZ regimen for DS-TB and DR-TB, providing clinical validation of a murine model widely used to identify such regimens. It also highlights that novel, treatment-shortening TB treatment regimens require an acceptable toxicity and tolerability profile with minimal monitoring in low-resource and high-burden settings. The increased risk of unpredictable severe hepatic adverse events with 4 months of BPaMZ would be a considerable obstacle to implementation of this regimen in settings with high burdens of TB with limited infrastructure for close surveillance of liver biochemistry. Future research should focus on improving the preclinical and early clinical detection and mitigation of safety issues together and further efforts to optimise shorter treatments. TB Alliance.