The endTB project

RATIONALE

Treatment outcomes may be compromised among patients with multidrug- or rifampicin-resistant tuberculosis with additional fluoroquinolone resistance. Evidence is needed to inform optimal treatment for these patients.

OBJECTIVES

We compared the effectiveness of longer individualized regimens comprised of bedaquiline for 5 to 8 months, linezolid, and clofazimine to those reinforced with at least 1 third-tier drug and/or longer duration of bedaquiline.

METHODS

We emulated a target trial to compare the effectiveness of initiating and remaining on the core regimen to one of five regimens reinforced with (1) bedaquiline for ≥9 months, (2) bedaquiline for ≥9 months and delamanid, (3) imipenem, (4) a second-line injectable, or (5) delamanid and imipenem. We included patients in whom a fluoroquinolone was unlikely to be effective based on drug susceptibility testing and/or prior exposure. Our analysis consisted of cloning, censoring, and inverse-probability weighting to estimate the probability of successful treatment.

MEASUREMENTS AND MAIN RESULTS

Adjusted probabilities of successful treatment were high across regimens, ranging from 0.75 (95%CI:0.61, 0.89) to 0.84 (95%CI:0.76, 0.91). We found no substantial evidence that any of the reinforced regimens improved effectiveness of the core regimen, with ratios of treatment success ranging from 1.01 for regimens reinforced with bedaquiline ≥9 months (95%CI:0.79, 1.28) and bedaquiline ≥9 months plus delamanid (95%CI:0.81, 1.31) to 1.11 for regimens reinforced by a second-line injectable (95%CI:0.92, 1.39) and delamanid and imipenem (95%CI:0.90, 1.41).

CONCLUSIONS

High treatment success underscores the effectiveness of regimens comprised of bedaquiline, linezolid, and clofazimine, highlighting the need for expanded access to these drugs.

endTB Observational Study had sites in 17 countries. In each country, sites enrolled patients on treatment with bedaquiline and delamanid according to National TB Program guidelines, while collecting clinical and bacteriological data on efficacy and safety. Because many of the endTB Observational Study tools were found to be useful for clinicians and programs that were starting to use the new TB drugs and regimens, we made them freely available at the endTB website. This Technical Basis document provides the rationale for clinical decision-making, screening tools and data definitions that are used at the endTB Observational Study sites.

BACKGROUND

Conversion of sputum culture from positive to negative for M. tuberculosis is a key indicator of treatment response. An initial positive culture is a pre-requisite to observe conversion. Consequently, patients with a missing or negative initial culture are excluded from analyses of conversion outcomes. To identify the initial, or “baseline” culture, researchers must define a sample collection interval. An interval extending past treatment initiation can increase sample size but may introduce selection bias because patients without a positive pre-treatment culture must survive and remain in care to have a culture in the post-treatment interval.

METHODS

We used simulated data and data from the endTB observational cohort to investigate the potential for bias when extending baseline culture intervals past treatment initiation. We evaluated bias in the proportion with six-month conversion.

RESULTS

In simulation studies, the potential for bias depended on the proportion of patients missing a pre-treatment culture, proportion with conversion, proportion culture positive at treatment initiation, and proportion of patients missing a pre-treatment culture who would have been observed to be culture positive, had they had a culture. In observational data, the maximum potential for bias when reporting the proportion with conversion reached five percentage points in some sites.

CONCLUSION

Extending the allowable baseline interval past treatment initiation may introduce selection bias. If investigators choose to extend the baseline collection interval past treatment initiation, the proportion missing a pre-treatment culture and the number of deaths and losses to follow up during the post-treatment allowable interval should be clearly enumerated.

Tuberculosis (TB) is the world’s deadliest infectious disease, and drug-resistant (DR) TB is a global health emergency. The World Health Organization (WHO) has estimated that only 1 in 3 people with DR-TB is started on treatment, and those treated have faced exceedingly poor cure rates of 56% for multidrug- resistant TB (MDR-TB) and 39% for extensively drug-resistant TB (XDR-TB), as of 2018. Before the innovations in TB over the last few years, the best DR-TB treatment entailed long regimens with painful injections, severe side effects and poor outcomes. Safer and more effective DR-TB drugs are now available for use in all- oral regimens recommended by WHO.

In the face of poor cure rates and clear need to scale up DR-TB treatment in high-burden places, improvements in DR-TB management are finally at hand. But to achieve these improvements, the barriers to treatment scale-up must be addressed with haste, so that people with TB can benefit from these shorter, less toxic, more potent therapies. Access to testing and key DR-TB medicines, especially bedaquiline and delamanid, and potentially pretomanid, must be accelerated, including through more affordable pricing and by overcoming patent and licensing hurdles.

Also, the global COVID-19 pandemic has complicated and diverted resources from TB care, amongst other health areas. As the pandemic continues, disruption of TB services must be monitored and minimised.

This Issue Brief by Médecins Sans Frontières (MSF)’s Access Campaign examines the current landscape of DR-TB and TB- prevention drug pricing and patents, and what needs to be done to accelerate people’s access to these lifesaving medicines.

Delamanid should be effective against highly resistant strains of Mycobacteriumtuberculosis, but uptake has been slow globally. In the endTB (expand new drug markets for TB) Observational Study, which enrolled a large, heterogeneous cohorts of patients receiving delamanid as part of a multidrug regimen, 80% of participants experienced sputum culture conversion within 6 months.

Drug resistance is a major public health crisis thwarting the effective treatment and care of people living with tuberculosis (TB) – the world’s leading infectious disease killer. Declared a global health emergency by the World Health Organization (WHO) in 2014 and again in 2017, drug-resistant TB (DR-TB) affected an estimated half million people in 2018 yet only 1 in 3 started treatment.

Until recently, the standard DR-TB treatment regimens recommended by WHO – and still in use by many countries – have a high pill burden, long treatment duration (up to two years), painful daily injections, severe side effects and poor treatment outcomes. These regimens cured only 56% of people with multidrug-resistant TB (MDR-TB), and 39% of people with extensively drug- resistant TB (XDR-TB).

In March 2019, WHO released new DR-TB treatment guidelines, recommending more effective and easier-to-take all- oral drug regimens. In July 2019, WHO Director-General Dr Tedros Adhanom Ghebreyesus called for countries to transition to all-oral DR-TB regimens by World TB Day, 24 March 2020. By this time, 100% of people newly enrolled on treatment should be offered these optimal regimens.

This Issue Brief examines the current landscape of DR-TB drug pricing and access policies, and what needs to be done by governments, policymakers and health care providers to get these lifesaving medicines to the people who need them most.

Although tuberculosis (TB) is the number-one infectious disease killer and one of the top ten causes of mortality worldwide, the global response to TB remains off track. 2 The interim 2020 targets set by the World Health Organization (WHO) End TB Strategy – to reduce new TB infections by 20%, reduce TB deaths by 35%, and eliminate catastrophic costs of treatment for families – won’t be reached unless there is a dramatic increase in the pace of the global TB response

Out of Step 2017 includes the results of a 29-country survey on national TB policies and practices. The report was created to identify gaps in implementation and monitor progress towards ending TB. While countries have made progress since the Out of Step 2015 report, much more work needs to be done to make sure that these policies are fully implemented across all communities, so that they will make a real difference to people affected by TB.

Out of Step in EECA is a regional adaptation the Out of Step 2017 report that focuses on TB diagnosis and treatment challenges in Eastern Europe and Central Asia (EECA). An epidemic of drug-resistant TB (DR-TB) is on the rise in EECA, where nearly half of all TB cases are multidrug-resistant and the number of people with DR-TB is increasing by more than 20% each year.

The endTB Medical Committee formulates recommendations for off-label and compassionate use of the new anti-TB drugs for M(X)DR-TB.

It provides advice to any MSF, PIH and IRD projects for individual patient’s management on a case-by-case basis in answer to requests initiated by clinicians from the projects.

This guide is designed to give guidance to the endTB Project site on the use of new TB drugs bedaquiline and delamanid. It is intended to be a resource for physicians and other health care professionals involved in the endTB project. Every effort possible has been made to ensure that the material presented here is accurate, reliable, and in accord with current standards. However, as new research and experience expand our knowledge, recommendations for care and treatment change.

This report – now in its fourth edition – analyses the barriers and factors affecting access to treatment regimens for drug-resistant tuberculosis (DR-TB), including new and repurposed drugs. We provide detailed pricing profiles of key DR-TB drugs, using manufacturer responses to standardised questionnaires and the Global TB Drug Facility website.