Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis.

Rifamycins exhibit concentration-dependent killing of Mycobacterium tuberculosis; higher exposures potentially induce better outcomes. We randomized 180 tuberculosis patients in Peru to receive rifampin at 10, 15, or 20 mg/kg/day. A total of 168 had noncompartmental pharmacokinetic analyses; 67% were sampled twice, and 33% were sampled six times. The doses administered were well tolerated. The median area under the concentration-time curve from 0 to 6 h (interquartile range) was 24.9 (17.6 to 32.1), 43.1 (30.3 to 57.5), or 55.5 (35.7 to 73.2) h · µg/ml. The median maximum drug concentration in serum in the experimental arms reached the target of 8 µg/ml. Continued investigation of higher rifampin doses is warranted. (This study has been registered at ClinicalTrials.gov under registration no. NCT01408914.).

Concordance of three approaches for operationalizing outcome definitions for multidrug-resistant TB.

BACKGROUND: The WHO provides standardized outcome definitions for rifampicin-resistant (RR) and multidrug-resistant (MDR) TB. However, operationalizing these definitions can be challenging in some clinical settings, and incorrect classification may generate bias in reporting and research. Outcomes calculated by algorithms can increase standardization and be adapted to suit the research question. We evaluated concordance between clinician-assigned treatment outcomes and outcomes calculated based on one of two standardized algorithms, one which identified failure at its earliest possible recurrence (i.e., failure-dominant algorithm), and one which calculated the outcome based on culture results at the end of treatment, regardless of early occurrence of failure (i.e., success-dominant algorithm).METHODS: Among 2,525 patients enrolled in the multi-country endTB observational study, we calculated the frequencies of concordance using cross-tabulations of clinician-assigned and algorithm-assigned outcomes. We summarized the common discrepancies.RESULTS: Treatment success calculated by algorithms had high concordance with treatment success assigned by clinicians (95.8 and 97.7% for failure-dominant and success-dominant algorithms, respectively). The frequency and pattern of the most common discrepancies varied by country.CONCLUSION: High concordance was found between clinician-assigned and algorithm-assigned outcomes. Heterogeneity in discrepancies across settings suggests that using algorithms to calculate outcomes may minimize bias.

Outcomes of WHO-conforming, longer, all-oral multidrug-resistant TB regimens and analysis implications.

BACKGROUND: Evidence of the effectiveness of the WHO-recommended design of longer individualized regimens for multidrug- or rifampicin-resistant TB (MDR/RR-TB) is limited.OBJECTIVES: To report end-of-treatment outcomes for MDR/RR-TB patients from a 2015-2018 multi-country cohort that received a regimen consistent with current 2022 WHO updated recommendations and describe the complexities of comparing regimens.METHODS: We analyzed a subset of participants from the endTB Observational Study who initiated a longer MDR/RR-TB regimen that was consistent with subsequent 2022 WHO guidance on regimen design for longer treatments. We excluded individuals who received an injectable agent or who received fewer than four likely effective drugs.RESULTS: Of the 759 participants analyzed, 607 (80.0%, 95% CI 77.0-82.7) experienced successful end-of-treatment outcomes. The frequency of success was high across groups, whether stratified on number of Group A drugs or fluoroquinolone resistance, and ranged from 72.1% to 90.0%. Regimens were highly variable regarding composition and the duration of individual drugs.CONCLUSIONS: Longer, all-oral, individualized regimens that were consistent with 2022 WHO guidance on regimen design had high frequencies of treatment success. Heterogeneous regimen compositions and drug durations precluded meaningful comparisons. Future research should examine which combinations of drugs maximize safety/tolerability and effectiveness.

Factors associated with screening failure and study withdrawal in multidrug-resistant TB.

SETTING: Multidrug-resistant TB (MDR-TB) clinical trial in Lima, Peru and Cape Town, South Africa.OBJECTIVE: To identify baseline factors associated with screening failure and study withdrawal in an MDR-TB clinical trial.DESIGN: We screened patients for a randomized, blinded, Phase II trial which assessed culture conversion over the first 6 months of treatment with varying doses of levofloxacin plus an optimized background regimen (ClinicalTrials.gov: NCT01918397). We identified factors for screening failure and study withdrawal using Poisson regression to calculate prevalence ratios and Cox proportional hazard regression to calculate hazard ratios. We adjusted for factors with P < 0.2.RESULTS: Of the 255 patients screened, 144 (56.5%) failed screening. The most common reason for screening failure was an unsuitable resistance profile on sputum-based molecular susceptibility testing (n = 105, 72.9%). No significant baseline predictors of screening failure were identified in the multivariable model. Of the 111 who were enrolled, 33 (30%) failed to complete treatment, mostly for non-adherence and consent withdrawal. No baseline factors predicted study withdrawal in the multivariable model.CONCLUSION: No baseline factors were independently associated with either screening failure or study withdrawal in this secondary analysis of a MDR-TB clinical trial.

Using digital chatbots to close gaps in healthcare access during the COVID-19 pandemic.

INTRODUCTION: Chatbots have emerged as a first link to care in recent years. The COVID-19 pandemic, and consequent health system disruptions, expanded their use. Socios En Salud (SES) introduced chatbots in Peru, which experienced one of the highest excess COVID mortalities in the world. METHODS: SES and the government identified unmet population health needs, which could be amenable to virtual interventions. Chatbots were developed to screen individuals for these conditions; we describe the period of deployment, number of screenings, and number of people who received services. RESULTS: Between April 2020 and May 2021, SES deployed nine ChatBots: four for mental health, two for maternal and child health, and three for chronic diseases: breast cancer, hypertension, diabetes mellitus, and obesity. Mental health services were provided to 42,932 people, 99.99% of those offered services. The other ChatBots reached fewer people. Overall, more than 50% of eligible people accepted chatbot-based services. DISCUSSION: ChatBot use was highest for mental health. Chatbots may increase connections between a vulnerable population and health services; this is likely dependent on several factors, including condition, population, and penetration of smart phones. Future research will be critical to understand user experience and preferences and to ensure that chatbots link vulnerable populations to appropriate, high-quality care.

INTRODUCTION: Les chatbots se sont imposés comme un premier lien aux soins ces dernières années. La pandémie de COVID-19, et les perturbations du système de santé qui en ont résultées, ont élargi leur champ d'application. Socios En Salud (SES) a introduit les chatbots au Pérou, qui a connu l'une des surmortalités dues au COVID les plus élevées au monde. MÉTHODES: SES et le gouvernement ont identifié des besoins non satisfaits en matière de santé de la population, qui pourraient faire l'objet d'interventions virtuelles. Des chatbots ont été développés pour dépister des individus pour ces conditions ; nous décrivons la période de leur déploiement, le nombre de dépistages et le nombre de personnes qui ont reçu ces services. RÉSULTATS: Entre avril 2020 et mai 2021, SES a déployé neuf ChatBots : quatre pour la santé mentale, deux pour la santé maternelle et infantile et trois pour les maladies chroniques, comme le cancer du sein, l'hypertension, le diabète et l'obésité. Des services de santé mentale ont été fournis à 42 932 personnes, soit 99,99% des personnes proposées. Les autres ChatBots ont touché moins de personnes. Dans l'ensemble, plus de 50% des personnes éligibles ont accepté les services proposés par les chatbots. DISCUSSION: L'utilisation des ChatBots était la plus élevée pour la santé mentale. Les chatbots peuvent augmenter les connexions entre une population vulnérable et les services de santé, mais cela dépende de plusieurs facteurs, dont la condition, la type de population et la pénétration des smartphones. Les recherches futures seront essentielles pour comprendre l'expérience et les préférences des utilisateurs et pour s'assurer que les chatbots relient les populations vulnérables vulnérables aux soins appropriés et de qualité.

WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update.

The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.

Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial.

BACKGROUND: Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings. METHODS: endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations. DISCUSSION: The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.

Time for a change: considering regimen changes in analyses of observational drug-resistant TB treatment cohort data.

Randomized clinical trials represent the gold standard in therapeutic research. Nevertheless, observational cohorts of patients treated for multidrug-resistant TB (MDR-TB) or rifampin-resistant TB (RR-TB) also play an important role in generating evidence to guide drug-resistant TB care. Generally, summary exposure classifications (e.g., 'ever vs. never´, 'exposed at baseline´) have been used to characterize drug exposure in the absence of detailed longitudinal data on MDR-TB regimen changes. These summary classifications, along with an absence of data on covariates that change throughout the course of treatment, constrain researchers´ ability to answer the most relevant questions while accounting for known biases. In this paper, we highlight the importance of regimen changes in improving inference from observational studies of longer MDR-TB treatment regimens, and offer an overview of the data and analytic strategies required to do so.

The fourth national anti-tuberculosis drug resistance survey in Peru.

BACKGROUND: Peru has one of the highest burdens of multidrug-resistant tuberculosis (MDR-TB), but universal drug susceptibility testing (DST) has not yet been achieved.OBJECTIVE: To estimate the proportion of drug resistance among smear-positive TB patients in Peru.DESIGN: From September 2014 to March 2015, we performed a national drug resistance survey of patients aged ≥15 years; TB was diagnosed based on sputum smear positivity. We performed DST at the National Reference Laboratory of the Peruvian National Institute of Health, Lima, Peru, using the proportion method in Middlebrook 7H10 agar for four first-line drugs and six second-line drugs, and the Wayne method for pyrazinamide.RESULTS: Of the 1908 new and 272 previously treated patients included in the analysis, 638 (29.3%) patients had resistance to at least one first-line drug. MDR-TB was diagnosed in 7.3% of new and 16.2% of previously treated patients (P < 0.001). There were five (0.2%) patients with extensively drug-resistant TB.CONCLUSION: MDR-TB has increased to 7.3% in new patients from 5.3% in the previous survey, indicating that resistance to anti-tuberculosis drugs is increasing in Peru. Ongoing community transmission of resistant strains highlights an urgent need for early diagnosis, optimised treatment and effective contact tracing of MDR-TB patients.

Introducing new and repurposed TB drugs: the endTB experience.

In 2015, the initiative Expand New Drug Markets for TB (endTB) began, with the objective of reducing barriers to access to the new and repurposed TB drugs. Here we describe the major implementation challenges encountered in 17 endTB countries. We provide insights on how national TB programmes and other stakeholders can scale-up the programmatic use of new and repurposed TB drugs, while building scientific evidence about their safety and efficacy. For any new drug or diagnostic, multiple market barriers can slow the pace of scale-up. During 2015-2019, endTB was successful in increasing the number of patients receiving new and repurposed TB drugs in 17 countries. The endTB experience has many lessons, which are relevant to country level introduction of new TB drugs, as well as non-TB drugs and diagnostics. For example: the importation of TB drugs is possible even in the absence of registration; emphasis on good clinical monitoring is more important than pharmacovigilance reporting; national guidelines and expert committees can both facilitate and hinder innovative practice; clinicians use new and repurposed TB drugs when they are available; data collection to generate scientific evidence requires financial and human resources; pilot projects can drive national scale-up.

Barriers and facilitators to early access of bedaquiline and delamanid for MDR-TB: a mixed-methods study.

SETTING: Phase II trials for bedaquiline (BDQ) and delamanid (DLM) were completed by 2011 and the drugs were approved by stringent regulatory authorities for the treatment of multidrug-resistant tuberculosis (MDR-TB) between 2012 and 2014. Manufacturers established 'early access' mechanisms to provide drugs before local registration. OBJECTIVE: To inform improvements in early access, we explored experiences of providers and advocates in accessing BDQ and DLM before the end of 2015 using a mixed-methods design. DESIGN: We examined barriers and facilitators to early access through an electronic survey. Barriers and facilitators were classified as occurring at the manufacturer- or country-level. We identified themes using inductive content analysis and illustrated themes through case studies. RESULTS: We analysed 41 survey responses from 36 respondents reporting on 22 countries; early access was attempted in 30 (73%) survey responses. Eligibility restrictions (11/30, 37%) and complicated and slow processes (8/30, 27%) were manufacturer-level barriers; access to companion drugs (10, 33%) and importation difficulties (4, 13%) were country-level barriers. Previous experience with manufacturer (3/30, 10%) and country processes (2/30, 7%) facilitated access. Eight case studies show the human impact of barriers and facilitators. CONCLUSION: Manufacturers and countries should develop transparent processes to permit early access, particularly for diseases that largely affect the poor, such as MDR-TB. Developers should plan for this need and rapidly register drugs with proven benefit, prioritizing high-burden settings.

Feasibility and yield of screening for non-communicable diseases among treated tuberculosis patients in Peru.

INTRODUCTION: The increasing prevalence of non-communicable diseases (NCDs) poses a major challenge to low- and middle-income countries. Patients' engagement with health services for anti-tuberculosis treatment provides an opportunity for screening for NCDs and for linkage to care. METHODS: We explored the feasibility and yield of screening for NCDs in patients treated for tuberculosis (TB) in Lima, Peru, as part of a study focused on chronic respiratory sequelae. A representative sample of community controls was recruited from the same geographical area. Screening entailed taking a medical history and performing ambulatory blood pressure measurement and urinalysis. RESULTS: A total of 177 participants with previous TB (33 with multidrug-resistant TB) and 161 community controls were evaluated. There was an almost four-fold increased prevalence of self-reported diabetes mellitus (DM) in the TB group (adjusted prevalence ratio 3.66, 95%CI 1.68-8.01). Among those without self-reported DM, 3.3% had glycosuria, with a number needed to screen (NNS) of 31. The NNS to find one (new) case of hypertension or proteinuria in the TB group was respectively 24 and 5. CONCLUSION: Patient-centred care that includes pragmatic NCD screening is feasible in TB patients, and the treatment period provides a good opportunity to link patients to ongoing care.

Estimating the global burden of multidrug-resistant tuberculosis among prevalent cases of tuberculosis.

BACKGROUND: Estimates of the multidrug-resistant tuberculosis (MDR-TB) burden are based on incomplete, infrequently updated data among a limited pool of notified or incident pulmonary TB cases. METHODS: Using World Health Organization data reported by 217 countries/territories in 2014, we calculated the MDR-TB burden among prevalent TB cases and compared these with estimates among incident and notified TB patients. We also compared treatment coverage across estimates. RESULTS: Among prevalent TB patients worldwide in 2014, we estimate that 555 545 (95% credible bounds 499 340-617 391) MDR-TB cases occurred. This is 85% more than the 300 000 estimated among notified cases, and 16% more than the 480 000 among incident cases. Only 20% of MDR-TB cases among prevalent-compared to 37% of MDR-TB among notified-TB patients had access to MDR-TB treatment. Applying prior estimates, only 10% of MDR-TB cases will have successful outcomes. CONCLUSION: Estimates based on likely-to-be-diagnosed cases of MDR-TB overlook a significant proportion of morbidity, mortality, and transmission that occur in undiagnosed, untreated, prevalent TB patients. Even though it may still likely underestimate the true disease burden, MDR-TB among patients with prevalent TB represents a closer approximation of disease burden than currently reported indicators. Progress toward elimination or control depends on policies guided by a more complete representation of the disease burden.

Prevalence of pyrazinamide resistance and Wayne assay performance analysis in a tuberculosis cohort in Lima, Peru.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) regimens often contain pyrazinamide (PZA) even if susceptibility to the drug has not been confirmed. This gap is due to the limited availability and reliability of PZA susceptibility testing. OBJECTIVES: To estimate the prevalence of PZA resistance using the Wayne assay among TB patients in Lima, Peru, to describe characteristics associated with PZA resistance and to compare the performance of Wayne with that of BACTEC™ MGIT™ 960. METHODS: PZA susceptibility using the Wayne assay was tested in patients diagnosed with culture-positive pulmonary TB from September 2009 to August 2012. Factors associated with PZA resistance were evaluated. We compared the performance of the Wayne assay to that of MGIT 960 in a convenience sample. RESULTS: The prevalence of PZA resistance was 6.6% (95%CI 5.8-7.5) among 3277 patients, and 47.7% (95%CI 42.7-52.6) among a subset of 405 MDR-TB patients. In multivariable analysis, MDR-TB (OR 86.0, 95%CI 54.0-136.9) and Latin American-Mediterranean lineage (OR 3.40, 95%CI 2.33-4.96) were associated with PZA resistance. The Wayne assay was in agreement with MGIT 960 in 83.9% of samples (κ 0.66, 95%CI 0.56-0.76). CONCLUSION: PZA resistance was detected using the Wayne assay in nearly half of MDR-TB patients in Lima. This test can inform the selection and composition of regimens, especially those dependent on additional resistance.

Representative drug susceptibility patterns for guiding design of retreatment regimens for MDR-TB.

BACKGROUND: There is no gold standard on how national tuberculosis programs should design retreatment regimens. Often drug susceptibility testing (DST) is not available for all patients, and representative DST patterns in patient populations are used to guide therapy. OBJECTIVES: To examine DST patterns in different patient populations based on previous treatment and to estimate the number of effective anti-tuberculosis agents in several retreatment regimens. METHODS: We reviewed DST results from patients treated with individualized regimens in Peru between January 1998 and July 2004. We stratified patients into four groups based on previous treatment exposure from Group 1 who had failed only one regimen to Group 4 who had failed three regimens. We compared resistance frequencies across the four groups. In Groups 1 and 3, the number of likely effective agents under six possible retreatment regimen scenarios was estimated. RESULTS: Resistance to second-line drugs was significantly higher in groups with more previous courses of treatment. A few retreatment regimens could be identified that would allow at least 80% of patients to receive at least four likely effective drugs. CONCLUSION: Because it is associated with resistance frequencies, previous treatment exposure can serve to guide the design of non-individualized MDR-TB regimens.

(Re)moving the needle: prospects for all-oral treatment for multidrug-resistant tuberculosis.

BACKGROUND: Currently recommended regimens for multidrug-resistant tuberculosis (MDR-TB) contain painful daily injections and are unsuccessful in approximately half of patients. Removal of the injectable agent to fashion all-oral regimens could transform MDR-TB treatment and access to care. OBJECTIVE: To explore evidence for all-oral treatment regimens. DESIGN: We review evidence on drugs that could be included in injection-free MDR-TB regimens. The oral drugs considered have an indication for or are recommended for off-label use for TB or MDR-TB, and have demonstrated bactericidal activity. Drugs with weak bactericidal activity should have limited prior population exposure and evidence of effectiveness in MDR-TB regimens. RESULTS: Bedaquiline, delamanid, and linezolid all display strong bactericidal activity, while clofazimine has weak bactericidal activity. They all have limited prior population exposure and demonstrated effectiveness in MDR-TB regimens. Despite widespread exposure to pyrazinamide and late-generation fluoroquinolones in the population, all are bactericidal and have shown great value when included in treatment regimens for MDR-TB. CONCLUSION: The evidence supports the use of all-oral regimens comprising new and existing drugs for MDR-TB treatment. Existing evidence of bactericidal activity and efficacy for these drugs provides a convincing argument for transitioning MDR-TB treatment towards all-oral regimens. These new regimens could mitigate the delivery, cost, and adherence challenges inherent to the current standard.