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MSF Commitments for “1/4/6 x 24” Campaign Launch in October

After half a century of stagnant progress, tuberculosis (TB) treatment has made significant advancements in the last 10 years. Research and development have resulted in new internationally recognised drugs and shorter, safer, and more effective regimens for the treatment of latent, drug-susceptible (DS-TB) and drug-resistant TB (DR-TB).

However, progress on implementation has lagged behind the evidence for shorter TB regimens. The ‘1/4/6 x 24’ campaign, launched by the Treatment Action Group and its allies, calls for the “staff, stuff, space, systems, and support” needed by 2024 to allow every eligible person to access today’s short-course TB regimens.

Médecins Sans Frontières/Doctors Without Borders (MSF) supports the objectives of the ‘1/4/6 x 24’ campaign and wishes to support the campaign’s call to action. As one of the largest non-governmental providers of TB treatment, MSF has an important role to play in terms of implementation, advocacy, access, and scale up.

In 2021, MSF treated approximately 17,000 patients for TB and 2000 for DR-TB. MSF has also engaged actively in operational research. For example, MSF completed the TB-PRACTECAL trial in August 2022 and continues to conduct the endTB trial – critical clinical trials to identify workable short-course regimens for people with DR-TB.

MSF commits to the following actions to support the objectives of the ‘1/4/6 x 24’ campaign:

  1. Increase access to shorter treatments for the prevention of TB

The identification of people eligible for TB preventive treatment (TPT) is one of the three TB priorities for MSF between 2021 and 2023.

As part of this priority objective, MSF has developed a strategy including the following essential elements:

  1. Generating and disseminating evidence for advocacy on the management of latent TB infection and the provision of TPT in HIV positive and HIV negative individuals.
  2. Piloting implementation of shorter TPT regimens (3HP, 1HP or 3RH[1]) for eligible populations in three projects, including supporting drug supply where necessary, training, implementing models of care, and data collection.
  3. Implementation of active case finding as part of an overall strategy of “Zero TB”, including a community model of care for household contact tracing, provision of TPT and operational research using computer-aided diagnosis systems for radiological interpretation.
  1. Increase access to shorter treatments for drug-susceptible TB (DS-TB)

Implementation of shorter regimens for TB is the second of the three TB priorities for MSF between 2021 and 2023.

As part of this objective, MSF will prioritise the diagnosis of TB in children and the implementation of the shorter four-month regimen for children with non-severe TB as part of a comprehensive multi-county project. The project will include:

  1. Implementation of the WHO-recommended treatment decision algorithm to increase case finding and to assess the severity of TB amongst children across MSF projects.
  2. Implementation of tests for TB, including the use of stool as a diagnostic specimen for GeneXpert in three projects.
  3. Implementation of the shorter treatment for non-severe DS-TB for children in at least three projects.
  4. Generating evidence on the treatment decision algorithms, including impact of implementation, health worker and patient perspectives and participation in multicentric validation studies with other actors (led by WHO).
  5. Generating evidence on the feasibility and impact of the implementation of the introduction of short regimen for non-severe DS-TB in children.
  6. Assessment of the feasibility of the implementation of new recommendations for diagnosis, treatment, and prevention of TB in children in all MSF vertical TB projects and relevant integrated projects.
  7. Advocating for the tools needed at national and local level for the introduction of new recommendations for diagnosis, treatment, and prevention of TB in children in places where MSF is not the main provider of DS-TB treatment.
  1. Increase access to shorter treatments for DR-TB

Shorter regimens for DR-TB have been a priority in MSF for more than 10 years. MSF has been a major contributor of the evidence that has led to the recommendations for shorter regimens from both operational research and clinical trials. Now, the priority for MSF is the implementation of these regimens, advocacy for their roll out, whilst generating further operational research on how these regimens will be used in different contexts and in neglected populations. Concretely, MSF will:

  1. Continue to generate evidence in support of shorter regimens for DR-TB and their implementation in different contexts and populations (including children and pregnant women).
    • Publish the full results of TB-PRACTECAL clinical trial[a]
    • Complete the follow-up and analysis of endTB trial[b]
    • Complete enrolment, follow-up and analysis for endTB–Q[c]
    • Complete the substudies of TB-PRACTECAL[d]
    • Complete the substudies of endTB[e]
    • Continue ongoing analyses of the endTB observational cohort including the safety of bedaquiline in children
    • Publish results of operational research on modified shorter regimens conducted in different contexts (e.g. Afghanistan, Ukraine)
    • Develop a framework for an intersectional and interorganisational prospective cohort to document the outcomes of multidrug-resistant /rifampicin-resistant (MDR/RR)-TB treatment in pregnant women and their babies
    • Develop a framework for an intersectional and interorganisational prospective cohort to document the treatment of patients with bedaquiline resistance
    • Monitor bedaquiline resistance through partnerships with other actors including the Institute of Tropical Medicine in Antwerp, Belgium
  2. Work with national treatment programmes to implement 6BPaLM in at least five countries, with the goal to treat 1,000 patients by the end of 2023.
  3. Implement and generate evidence on the use of other shorter DR-TB regimens under operational research in other settings according to local NTP requirements and new WHO recommendations.
    • Shorter regimens for fluoroquinolone-resistant patients e.g. endTB-Q, BPaLC[2]
    • Shorter regimens for children
  1. Advocacy to support implementation

Advocacy for better TB care has been an important element of MSF’s response to the barriers faced by TB treatment providers across the world, led by the MSF Access Campaign[f]. Continuing this legacy in 2023, MSF will:

        1. Pricing advocacy
          • Contribute to a transparent price, patent and license landscape for priority TB formulations for adults and children and to highlight access challenges
          • Advocate for price reductions of rifapentine-based TPT short regimens to reduce the financial burden and to increase uptake
          • Advocate for the price of the new DS-TB regimens (HPMZ) to remain competitive with the current RHZE/RH prices as a benchmark[3]
          • Advocate for the US$500 ceiling price for new oral DR-TB regimens for adults
        2. Advocacy to support upstream prices and access issues
          • Produce analyses of the expected availability, affordability, and suitability of outcomes of TB R&D initiatives
          • Advocate for integration of affordability, suitability, and availability across the TB R&D Landscape
          • Continue calls for the development of paediatric formulations of DR-TB drugs (including clinical assessment in children of pretomanid, generic versions of bedaquiline and delamanid)
        3. Advocacy to support access to TB diagnostics
        • Advocate for a price drop of all Cepheid GeneXpert TB cartridges to $5 based on publicly available cost of goods data (Time for $5 Campaign)
        • Advocate for field-adapted and affordable non-sputum tests for active TB
        • Advocate for field-adapted and affordable non-sputum tests for TB infection
        • Advocate for countries to scale up the use of the currently available Determine B LAM test to diagnose TB in PLHIV at all health care levels as recommended by WHO
        • Advocate for more sensitive next generation TB LAM tests at affordable prices

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    [1] 3HP: three months of weekly doses of isoniazid and rifapentine, 3RH: three months of daily doses of rifampicin and isoniazid, 1HP: one month of daily doses of rifapentine and isoniazid

    [2] endTB-Q : six-nine months of bedaquiline-delamanid-linezolid and clofazimine, BPaLC: six months of bedaquiline-pretomanid-linezolid and clofazimine

    [3] HPMZ: Rifapentine-isoniazid-pyrazinamide-moxifloxacin, RHZE/RH: rifampicin, isoniazid, pyrazinamide, ethambutol

    [a] TB-PRACTECAL: Launched in 2017, TB-PRACTECAL is the first-ever multi-country, randomised, controlled clinical trial to report on the efficacy and safety of a six-month, all-oral regimen for MDR-TB. The trial enrolled 552 patients overall in seven sites across Belarus, South Africa and Uzbekistan. The trial’s primary outcome results found that the new shorter BPaLM treatment regimen was very effective against rifampicin-resistant TB and have already contributed to the new 2022 WHO guidance on the treatment of DR-TB. Additionally, MSF aims to publish a cost breakdown of TB-PRACTECAL to contribute to the publicly available information on clinical trial costs in DR-TB and help funders and implementers in making evidence-based commitments to generating further clinical research.

    [b] endTB trial: The goal of the endTB clinical trials is to find radically shorter (six or nine months), more tolerable, injection-free treatments for MDR-TB. endTB is a randomised, controlled, Phase III clinical trial testing five new, all oral, nine-month regimens compared to the current standard of care. Randomisation was outcome-adapted, rather than fixed. This means that the probability of being randomised to regimens changed as the outcomes were reported: more patients were assigned to regimens that were producing better outcomes.

    Each experimental regimen contains at least one new drug (bedaquiline and delamanid), in combination with up to four companion drugs. The control regimen is the local standard of care consistent with latest WHO recommendations, including bedaquiline and/or delamanid if indicated.

    Recruitment is complete: 754 participants included across seven countries and 12 sites (Georgia (MSF), India (MSF), Kazakhstan (PIH), Lesotho (PIH), Pakistan (IRD), Peru (PIH) and South Africa (MSF).

    Outcomes are expected to be available by Q4 2023.

    [c] endTB-Q clinical trial: This is a randomised, controlled, Phase III clinical trial testing a new, all-oral regimen compared to the current standard of care.

    Six to nine months regimens for FQ-resistant MDR-TB patients including Bdq and Dlm;

    The experimental regimen contains bedaquiline, delamanid, clofazimine, and linezolid, and is delivered for 24 or 39 weeks. endTB-Q adopts a personalised medicine approach, by individualising the treatment duration based on baseline characteristics and treatment response of each participant.

    The control arm regimen is designed and delivered according to local standard of care and consistent with latest WHO guidelines, and may include bedaquiline and/or delamanid in addition to other drugs.

    Enrolments are ongoing 2021-2023 (76% of patients randomised as of September 2022).

    [d] Substudies of TB PRACTECAL: PRACTECAL-PKPD: Pharmacokinetics and Pharmacodynamics; PRACTECAL-PRO: Patient-reported Outcomes; PRACTECAL-EE: Economic Evaluation – all three in Uzbekistan, Belarus, South Africa, results in 2022.

    [e] Substudies of endTB: PandrTB substudy PK/PD substudy on new and repurposed drugs – ongoing 2021-2023, recruiting.

    [f] https://msfaccess.org/

     

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