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Background Outcomes of treatment of tuberculosis patients with regimens including pretomanid have not yet been systematically reviewed. Objectives To appraise existing evidence on efficacy and safety of pretomanid in tuberculosis. Data Sources Pubmed, clinicaltrials.gov. and Cochrane library. Study eligibility criteria Quantitative studies presenting original data on clinical efficacy or safety of pretomanid. Participants Patients with tuberculosis. Interventions Treatment with pretomanid or pretomanid-containing regimens in minimum one study group. Methods Two authors independently extracted data and assessed risk of bias. Data on efficacy (early bactericidal activity, bactericidal activity, end-of-treatment outcomes and acquired resistance) and safety were summarized in tables. Mean differences in efficacy outcomes between regimens across studies were calculated. Results Eight studies were included; four randomized controlled trials on 2-week early bactericidal activity in rifampicin-susceptible tuberculosis, three trials with randomized rifampicin-susceptible tuberculosis arms and a single rifampicin-resistant tuberculosis arm (two on 8-week bactericidal activity, one on end-of-treatment outcomes), one single-arm trial with end-of-treatment outcomes in highly resistant tuberculosis. Activity of pretomanid–moxifloxacin–pyrazinamide was superior to standard treatment on daily change in colony-forming units at days 0–2, 0–56 and 7–56 and time to culture conversion in rifampicin-susceptible tuberculosis (hazard ratio: 1.7; 95% CI 1.1–2.7), but not at end of treatment in one study. This study was stopped due to serious hepatotoxic adverse events, including three deaths, in 4% (95% CI 2–8) patients on pretomanid–moxifloxacin–pyrazinamide and none in controls. In patients with uncomplicated rifampicin-resistant tuberculosis on pretomanid-moxifloxacin-pyrazinamide treatment, 91% (95% CI 59–100) had favourable end-of-treatment outcomes. In patients with highly resistant tuberculosis, 90% (95% CI 83–95) on pretomanid–bedaquiline–linezolid had favourable outcomes six months after treatment, but linezolid-related toxicity was frequent. No acquired resistance to pretomanid was reported. Conclusions Evidence suggests an important role for pretomanid in rifampicin-resistant and highly resistant tuberculosis. Trials comparing pretomanid to existing core and companion drugs are needed to further define that role.

Introduction Ukraine has a high burden of drug-resistant tuberculosis (DR-TB). Mental health problems, including alcohol use disorder (AUD), are common comorbidities. As part of health reform, the country is moving from inpatient-care to ambulatory primary care for tuberculosis (TB). This study describes the preparedness of ambulatory care facilities in Zhytomyr oblast, Ukraine. Methods This is a cross-sectional study in which routine program data was collected during June 2018 and February 2020. Before discharge of every patient from the hospital, MSF teams assess outpatient facilities available using a standardized checklist. The assessment evaluates access, human-resources, availability of medicines, infection control, laboratory and diagnostic services, and psychosocial support. Results We visited 90 outpatient facilities in 23 districts and 1 city between June 2018 and February 2020. Forty health posts, 27 TB-units, 23 ambulatories including two family doctors and one polyclinic were included. All facilities provided DOT, but only nine (10%) provided weekend-services. All facilities had at least one medical staff member, but TB-training was insufficient and limited to TB-doctors. TB-medicines and storage space were available in all facilities, but only twenty two (24%) stored ancillary medicines. HIV-patients had to visit a separate facility to access HIV-care. Personal protective equipment for infection control was unavailable in 41 (46%) facilities. Basic laboratory services were available in TB-units, but only 3 (11%) performed audiometry. Only twenty (22%) TB-units had psychosocial support available, and 1 (4%) psychiatric support. Conclusions Outpatient facilities in Zhytomyr oblast are not yet fully prepared to provide comprehensive care for DR-TB patients. Integration of psychosocial services, treatment of co-morbidities and adverse events at the same facility are essential to establish high quality, patient-centered care.

Objectives Frequently used rapid rifampicin drug susceptibility tests (RMP-DST) miss certain rifampicin resistance (RR)-conferring mutations, leaving RR-tuberculosis undetected. Unknown for RR-TB is the therapeutic threshold, the probability of disease at which there is equipoise between treating and not treating. In Mozambique, in a patient not responding to first-line treatment, clinicians decided to start RR-TB treatment without bacteriological proof of RR-TB. We determined the probability of RR-TB in this patient. Methods We converted probabilities and odds ratios of clinical arguments for RR-TB from literature to likelihood ratios. We then combined the associated confirming and excluding power of those arguments to estimate the probability of RR-TB when the patient was started on RR-TB treatment, and simulated its variation. We used a log-odds scale to illustrate the effect of confirming and excluding arguments. Results The starting point was the prevalence of RR-TB in Mozambique. Positive HIV-status, treatment failure after a first treatment and after retreatment were included as confirming arguments, and RMP-DST showing rifampicin susceptibility as excluding argument for RR-TB. In this patient, the probability of RR-TB was 46.6% (95% uncertainty interval: 25.0%-72.0%) when RR-TB treatment was started. Treatment failure and retreatment failure provided strong confirming arguments, and the RMP-DST result a strong excluding argument for RR-TB. Conclusions The therapeutic threshold to start RR-TB-treatment is unknown but probably lower than 47%. The uncertainty in our estimation reflects the clinical uncertainty in low-resource settings. Determining the RR-TB therapeutic threshold is needed to guide clinical decisions.

Background Ukraine has a high burden of drug-resistant tuberculosis (DR-TB). Mental health problems, including alcohol use disorder, are common co-morbidities. One in five DR-TB patients has human immunodeficiency virus (HIV). As part of health reform, the country is moving from inpatient care to ambulatory primary care for tuberculosis (TB). In Zhytomyr oblast, Médecins Sans Frontières (MSF) is supporting care for DR-TB patients on all-oral short DR-TB regimens. This study describes the preparedness of ambulatory care facilities in Zhytomyr oblast, Ukraine, to provide good quality ambulatory care. Methods This is a retrospective analysis of routinely collected programme data. Before discharge of every patient from the hospital, MSF teams assess services available at outpatient facilities using a standardised questionnaire. The assessment evaluates access, human resources, availability of medicines, infection control measures, laboratory and diagnostic services, and psychosocial support. Results We visited 68 outpatient facilities in 22 districts between June 2018 and September 2019. Twenty-seven health posts, 24 TB-units, 13 ambulatories, two family doctors and one polyclinic, serving 30% of DR-TB patients in the oblast by September 2019, were included. All facilities provided directly observed treatment, but only seven (10%) provided weekend-services. All facilities had at least one medical staff member, but TB-training was insufficient and mostly limited to TB-doctors. TB-treatment and adequate storage space were available in all facilities, but only five (8%) had ancillary medicines. HIV-positive patients had to visit a separate facility to access HIV-care. Personal protective equipment was unavailable in 32 (55%) facilities. Basic laboratory services were available in TB-units, but only four (17%) performed audiometry. Only ten (42%) TB-units had psychosocial support available, and nine (38%) offered psychiatric support. Conclusion Outpatient facilities in Zhytomyr oblast are not yet prepared to provide comprehensive care for DR-TB patients. Capacity of all facilities needs strengthening with trainings, infection control measures and infrastructure. Integration of psychosocial services, treatment of co-morbidities and adverse events at the same facility are essential for successful decentralisation. The health reform is an opportunity to establish quality, patient-centred care.

BackgroundHIV and TB programs have rapidly scaled-up over the past decade in Sub-Saharan Africa and uninterrupted supplies of those medicines are critical to their success. However, estimates of stock-outs are largely unknown. This survey aimed to estimate the extent of stock-outs of antiretroviral and TB medicines in public health facilities across South Africa, which has the world's largest antiretroviral treatment (ART) program and a rising multidrug-resistant TB epidemic.MethodsWe conducted a cross-sectional telephonic survey (October-December 2015) of public health facilities. Facilities were asked about the prevalence of stock-outs on the day of the survey and in the preceding three months, their duration and impact.ResultsNationwide, of 3547 eligible health facilities, 79% (2804) could be reached telephonically. 88% (2463) participated and 4% (93) were excluded as they did not provide ART or TB treatment. Of the 2370 included facilities, 20% (485) reported a stock-out of at least 1 ARV and/or TB-related medicine on the day of contact and 36% (864) during the three months prior to contact, ranging from 74% (163/220) of health facilities in Mpumalanga to 12% (32/261) in the Western Cape province. These 864 facilities reported 1475 individual stock-outs, with one to fourteen different medicines out of stock per facility. Information on impact was provided in 98% (1449/1475) of stock-outs: 25% (366) resulted in a high impact outcome, where patients left the facility without medicine or were provided with an incomplete regimen. Of the 757 stock-outs that were resolved 70% (527) lasted longer than one month.InterpretationThere was a high prevalence of stock-outs nationwide. Large interprovincial differences in stock-out occurrence, duration, and impact suggest differences in provincial ability to prevent, mitigate and cope within the same framework. End-user monitoring of the supply chain by patients and civil society has the potential to increase transparency and complement public sector monitoring systems.

The introduction of the nine-month short-treatment regimen (STR) has drastically improved outcomes of rifampicin-resistant tuberculosis (RR-TB) treatment. Adverse events (AE) commonly occur, including injectable-induced hearing loss. In Burundi we retrospectively assessed the frequency of adverse events and treatment modifications in all patients who initiated the STR between 2013&ndash, 2017. Among 225 included patients, 93% were successfully treated without relapse, 5% died, 1% was lost-to-follow-up, 0.4% had treatment failure and 0.4% relapsed after completion. AE were reported in 53%, with grade 3 or 4 AE in 4% of patients. AE occurred after a median of two months. Hepatotoxicity (31%), gastro-intestinal toxicity (22%) and ototoxicity (10%) were most commonly reported. One patient suffered severe hearing loss. Following AE, 7% of patients had a dose reduction and 1% a drug interruption. Kanamycin-induced ototoxicity led to 94% of modifications. All 18 patients with a modified regimen were cured relapse-free. In this exhaustive national RR-TB cohort, RR-TB was treated successfully with the STR. Adverse events were infrequent. To replace the present STR, all-oral regimens should be at least as effective and also less toxic. During and after transition, monitoring, management, and documentation of AE will remain essential.

Stockouts of HIV commodities increase the risk of treatment interruption, antiretroviral resistance, treatment failure, morbidity and mortality. The study objective was to assess the magnitude and duration of stockouts of HIV medicines and diagnostic tests in public facilities in Kinshasa, Democratic Republic of the Congo. This was a cross-sectional survey involving visits to facilities and warehouses in April and May 2015. All zonal warehouses, all public facilities with more than 200 patients on antiretroviral treatment (ART) (high-burden facilities) and a purposive sample of facilities with 200 or fewer patients (low-burden facilities) in Kinshasa were selected. We focused on three adult ART formulations, cotrimoxazole tablets, and HIV diagnostic tests. Availability of items was determined by physical check, while stockout duration until the day of the survey visit was verified with stock cards. In case of ART stockouts, we asked the pharmacist in charge what the facility coping strategy was for patients needing those medicines. The study included 28 high-burden facilities and 64 low-burden facilities, together serving around 22000 ART patients. During the study period, a national shortage of the newly introduced first-line regimen Tenofovir-Lamivudine-Efavirenz resulted in stockouts of this regimen in 56% of high-burden and 43% of low-burden facilities, lasting a median of 36 (interquartile range 29-90) and 44 days (interquartile range 24-90) until the day of the survey visit, respectively. Each of the other investigated commodities were found out of stock in at least two low-burden and two high-burden facilities. In 30/41 (73%) of stockout cases, the commodity was absent at the facility but present at the upstream warehouse. In 30/57 (54%) of ART stockout cases, patients did not receive any medicines. In some cases, patients were switched to different ART formulations or regimens. Stockouts of HIV commodities were common in the visited facilities. Introduction of new ART regimens needs additional planning.