Safety and effectiveness of three novel all-oral shortened regimens for rifampicin- or multidrug-resistant tuberculosis in Kazakhstan.

BACKGROUND: In 2019, WHO called for operational research on all-oral shortened regimens for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). We report safety and effectiveness of three nine-month all-oral regimens containing bedaquiline (Bdq), linezolid (Lzd), and levofloxacin (Lfx) and reinforced with cycloserine (Cs) and clofazimine (Cfz), delamanid (Dlm) and pyrazinamide (Z), or Dlm and Cfz. METHODS: We conducted a prospective cohort study of patients initiating treatment for pulmonary MDR/RR-TB under operational research conditions at public health facilities in Kazakhstan. Participants were screened monthly for adverse events. Participants with baseline resistance were excluded from the study and treated with a longer regimen. We analyzed clinically relevant adverse events of special interest in all participants and sputum culture conversion and end-of-treatment outcomes among individuals who were not excluded. RESULTS: Of 510 participants, 41% were women, median age was 37 years (interquartile range: 28-49), 18% had a body mass index <18·5 kg/m2, and 51% had cavitary disease. Three hundred and ninety-nine (78%) initiated Bdq-Lzd-Lfx-Cs-Cfz, 83 (16%) started Bdq-Lzd-Lfx-Dlm-Z, and 28 (5%) initiated Bdq-Lzd-Lfx-Dlm-Cfz. Fifty-eight individuals (11%) were excluded from the study, most commonly due to identification of baseline drug resistance (n = 52; 90%). Among the remaining 452 participants, treatment success frequencies were 92% (95% confidence interval [CI]: 89 to 95), 89% (95%CI: 80 to 94), and 100% (95%CI: 86 to 100) for regimens with Cs/Cfz, Dlm/Z, and Dlm/Cfz respectively. Clinically-relevant adverse events of special interest were uncommon. CONCLUSION: All regimens demonstrated excellent safety and effectiveness, expanding the potential treatment options for patients, providers, and programs.

Respiratory, Cardiac, and Neuropsychiatric Manifestations of Postacute Sequelae of Coronavirus Disease 2019 in Lima, Peru.

Background: Few studies have examined the burden of postacute sequelae of coronavirus disease 2019 (COVID-19) (PASC) in low- and middle-income countries. We sought to characterize PASC with self-reported questionnaires and clinical examinations of end-organ function in Lima, Peru. Methods: From January to July 2021, we recruited participants at least 8 weeks after COVID-19 diagnosis from a case registry in Lima, Peru. We evaluated participants for PASC with questionnaires, neuropsychiatric evaluations, chest X-ray, spirometry, electrocardiogram, and echocardiogram. We used multivariable models to identify risk factors for PASC. Results: We assessed 989 participants for PASC at a median 4.7 months after diagnosis. Clinically significant respiratory symptoms were reported by 68.3% of participants, particularly those who had been severely ill during acute COVID-19, and were associated with cardiac findings of ventricular hypertrophy or dilation on echocardiogram. Neuropsychiatric questionnaires were consistent with depression in 20.7% and cognitive impairment in 8.0%. Female sex and older age were associated with increased risk of respiratory (adjusted odds ratio [aOR], 2.36 [95% confidence interval {CI}, 1.69-3.31] and aOR, 1.01 [95% CI, 1.00-1.03], respectively) and neuropsychiatric sequelae (aOR, 2.99 [95% CI, 2.16-4.18] and aOR, 1.02 [95% CI, 1.01-1.03], respectively). Conclusions: COVID-19 survivors in Lima, Peru, experienced frequent postacute respiratory symptoms and depression, particularly among older and female participants. Clinical examinations highlighted the need for cardiopulmonary rehabilitation among persons with severe COVID-19; psychosocial support may be required among all COVID-19 survivors.

Comparing timelines and evidence available to support new TB, HIV, and HCV drug approvals: The same, only different.

BACKGROUND: Tuberculosis (TB), human immunodeficiency virus (HIV), and hepatitis C virus (HCV) share a global presence and propensity to disproportionately affect marginalized populations. However, over recent decades, many fewer drugs have been brought to market for TB than for the others. Although three new anti-TB drugs have been approved in the US or Europe in the last 10 years, uptake of these drugs has been limited. Using case examples of drugs developed recently for TB, HIV, and HCV, we explore possible reasons. We examine the use and effect of regulatory pathways intended to address weak economic incentives in the face of urgent, unmet needs; evaluate the extent of data underpinning authorizations for these indications; document development timelines and evidence available at the time of each approval; consider explanations for observed differences; and discuss the implications for clinical guidelines and use. METHODS AND FINDINGS: For each indication, we selected two drugs: one recently approved and one approved between 2012 and 2014, when the first new anti-TB drug from a novel class in more than 40 years received marketing authorization. We calculated time from first published peer-reviewed evidence of activity to date of approval; the number of phase 1, 2, and 3 trials; the number of trial participants randomized to treatment arms containing the drug; and the total number of participants in each trial from the individual drug approval packages. We found that the two TB drugs took longer to gain approval (8.0 and 19.2 years for bedaquiline and pretomanid, respectively) despite availing of special regulatory pathways meant to expedite approval, when compared to the HIV (2.6 years for dolutegravir and 4.7 years for doravirine) and HCV drugs (3.2 and 1.6 years for sofosbuvir and glecaprevir/pibrentasvir, respectively). Moreover, fewer participants were studied prior to TB drug approvals (380 and 879) than prior to approvals for HIV (1598 and 979) and for HCV (2291 and 2448) drugs. CONCLUSIONS: The dramatic disparities observed in TB drug development reaffirm the importance of several actions. Increased investment in TB research and development is necessary to rapidly advance drugs through the pipeline. Development plans and partnerships must provide safety and efficacy evidence on combinations and durations that are relevant to real-world use in heterogeneous populations. Reliable, validated surrogate markers of relapse-free cure are essential to decrease the duration and cost of TB treatment trials and increase the confidence and speed with which new regimens can advance. Lastly, regulators and normative bodies must maintain high evidentiary standards for authorization while ensuring timely and broad approval for TB drugs and regimens.

Clinical Outcomes of Individuals with COVID-19 and Tuberculosis during the Pre-Vaccination Period of the Pandemic: A Systematic Review.

BACKGROUND: Tuberculosis, like COVID-19, is most often a pulmonary disease. The COVID-19 pandemic has severely disrupted tuberculosis services in myriad ways: health facility closures, lockdowns, travel bans, overwhelmed healthcare systems, restricted export of antituberculous drugs, etc. The effects of the shared risk on outcomes of the two diseases is not known, particularly for the first year of the pandemic, during the period before COVID-19 vaccines became widely available. OBJECTIVE: We embarked on a systematic review to elucidate the consequences of tuberculosis on COVID-19 outcomes and of COVID-19 on tuberculosis outcomes during the pre-vaccination period of the pandemic. METHODS: The systematic review protocol is registered in PROSPERO. We conducted an initial search of PubMed, Embase, Web of Science, WHO coronavirus database, medRxiv, bioRxiv, preprints.org, and Google Scholar using terms relating to COVID-19 and tuberculosis. We selected cohort and case-control studies for extraction and assessed quality with the Newcastle-Ottawa scale. RESULTS AND CONCLUSION: We identified 2108 unique abstracts published between December 2019 and January 2021. We extracted data from 18 studies from 8 countries. A total of 650,317 persons had a diagnosis of COVID-19, and 4179 had a diagnosis of current or prior tuberculosis. We explored links between tuberculosis and COVID-19 incidence, mortality, and other adverse outcomes. Nine studies reported on mortality and 13 on other adverse outcomes; results on the association between tuberculosis and COVID-19 mortality/adverse outcomes were heterogenous. Tuberculosis outcomes were not fully available in any studies, due to short follow-up (maximum of 3 months after COVID-19 diagnosis), so the effects of COVID-19 on tuberculosis outcomes could not be assessed. Much of the rapid influx of literature on tuberculosis and COVID-19 during this period was published on preprint servers, and therefore not peer-reviewed. It offered limited examination of the effect of tuberculosis on COVID-19 outcomes and even less on the effect of COVID-19 on tuberculosis treatment outcomes.