The Implementation of a Pretomanid-Based Treatment Regimen for Multidrug-Resistant Tuberculosis

A Case Series

Tuberculosis (TB) is the most common deadly infectious disease globally. Multidrug-resistant TB (MDR-TB) constitutes an increasing problem in eastern Europe (1). Armed conflict and instable healthcare provision have in the past resulted in increased TB incidence and mortality (2). In the course oof the war in Ukraine and the resultant refugee movements it is to be expected that the incidence of MDR-TB in western Europe will rise (2, 3, 4).

MDR-TB requires complex treatment that should be managed in centers with relevant expertise. The recommendation of the World Health Organization for treating MDR-TB was updated in 2022; for most patients a combination of bedaquiline, pretomanid, and linezolid plus if required a fluoroquinolone (BPaL or BPaLM scheme) should be used (5). This is an exclusively oral therapeutic regimen, which at six months is notably shorter than any treatment schemes deployed to date. The named combinations achieved a cure rate of >80% under study conditions. By contrast, WHO reports for the therapeutic regimens used to date success rates of up to 59% (5). Pretomanid, a tuberculostatic drug from the class of the nitroimidazoles, which inhibits cell wall synthesis, has, however, to date not been introduced into the pharmaceutical market in Germany.

In the present article we report our initial experiences with pretomanid based therapeutic regimens in the treatment of people with drug resistant TB who fled from Ukraine. We describe the associated opportunities and challenges within the German healthcare system. Furthermore, we present the results of an orientating survey within the Germany MDR-TB network with regard to the estimated need for pretomanid in the treatment of MDR-TB.

Method

From September 2022 through May 2023, seven patients with MDR-TB or pre-XDR-TB (Box) who had fled from Ukraine were treated at the Medizinische Hochschule Hannover (MHH, Hannover Medical School) and the University Hospital Giessen with a pretomanid-based TB regimen. Additionally, between 21 December 2022 and 22 February 2023, an orientating anonymous online survey (SurveyMonkey, San Mateo, Ca, USA) was conducted among the currently 44 members of the German MDR-TB network, which is moderated by the German Central Committee Against Tuberculosis (DZK). Two questions were asked:

• „“Do you think the use of BPaL(M)—such as recommended by WHO for MDR-RB and pre-XDR-TB—makes sense in the setting of Germany?”
• “In your estimate, how much pretomanid is needed at your hospital per year?”

Box

Definitions of drug resistant tuberculosis

Results

The median age of the patients was 37 (range 32–65 years); three persons were female. Four patients had an untreated co-infection with HIV. Five of the seven patients had pre-XDR-TB and the rest MDR-TB. In five persons the treatment has already been completed successfully (Table). The (planned) treatment duration was six months in every case and thus far did not have to be extended. The described TB treatment was well tolerated to date, no interruption/disruption because of adverse effects has taken place so far. Especially polyneuropathy and bone marrow toxicity under linezolid were not observed for the recommended dose of 1×600 mg/day. No liver toxicity occurred either.

Table

Patients’ characteristics

Pretomanid has to date not been introduced into the pharmaceutical market in Germany; the preparation had to be imported. To this end we identified two alternatives:

• Individual import from the USA via an international pharmacy or an importer according to §73(3) of the German Medicines Law with a delivery time of about three weeks and costs of €1000 (plus VAT) for 26 tablets
• Ordering via a “named patient program” with a delivery time of 3–7 days and costs of about €2800 (www.accesspretomanid.com).

To ensure cross-sectoral provision and guarantee the purchase of pretomanid via an established pharmacy, a billing permit from the respective health insurer had to be obtained in each case.

17 of 25 hospitals/clinics that had been contacted (68%) participated in the online survey in the German MDR-TB network. Of these, 14 (82%) with experience in the treatment of MDR-TB rated the preferential use of BPaL or BPaL(M) as recommended by WHO as sensible in Germany too. The resultant future annual requirement of pretomanid was estimated at therapies in about 60 cases.

Discussion

In this case series we described our experiences with pretomanid-based therapeutic regimens according to the recently updated WHO guideline for the treatment of MDR-TB. The patients who were eligible for such a therapeutic regimens at our centers were Ukrainian refugees.

A shorter, entirely oral, and less toxic therapy might improve adherence. Furthermore, in this way onward transmission of TB and the emergence of additional drug resistance could be prevented. A relevant update of the consensus-based (S2k) guideline “Tuberculosis in adulthood” is currently under discussion.

Patients with MDR-TB have to be closely monitored so as to minimize the risk of therapy failure. Who covers the bills for medications to treat MDR-TB—for example, in the context of an allocation process for novel examination and treatment methods —is thus far not clear in Germany. Furthermore, the limited availability of pretomanid sets high barriers to implementing the therapeutic regimen. Still, this small but vulnerable patient group should not be placed at a disadvantage because of this factor.

Acknowledgment

We thank your multiprofessional and interdisciplinary clinical teams and the volunteer interpreters, without whose extraordinary personal commitment the successful treatment of our patients would have been impossible. We also than Brit Häcker and Ralf-Otto Knapp from the German Central Committee Against Tuberculosis (DZK) in Berlin for reviewing our manuscript, for conducting the survey of the German MDR-TB network, and for making the results available.

Conflict of interest statement
GA received fees for sitting on advisory boards from ViiV, GSK, Galapagos, and UCB. He received lecture honoraria from ViiV and Galapagos.

Conference delegate fees and travel expenses for IF were reimbursed by the German Society of Infectious Diseases.

FCR received research funding from Infecto-Pharm, Ismed, DZIF, Mukoviszidose Institute gGmbH, and EFPIA (iABC Consortium). He received lecture honoraria from Interkongress GmbH, AstraZeneca, Insmed, and the University Hospital Frankfurt/Main. The Social Law Court in Cologne financially compensated him for acting as an expert assessor. He was reimbursed for travel expenses and conference delegate fees by AstraZeneca. GP is the spokesperson of the infectious disease section in the German Respiratory Society. Ismed and Zambon paid study funding to him.

The remaining authors declare that no conflict of interest exists.

Manuscript received 19 May 2023, revised version accepted 3 July 2023.

Translated from the original German by Birte Twisselmann, PhD.

Cite this as:
Joean O, Trauth J, Ahrenstorf G, Kuhns M, Friesen I, Picksak G, Welte T, Ringshausen FC: The implementation of a pretomanid-based treatment regimen for multidrug-resistant tuberculosis: a case series. Dtsch Arztebl Int 2023; 120: 641–2. DOI: 10.3238/arztebl.m2023.0172

References

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3. Dahl VN, Tiberi S, Goletti D, Wejse C: Armed conflict and human displacement may lead to an increase in the burden of tuberculosis in Europe. Int J Infect Dis 2022; 124 Suppl 1: S104–S6

4. Hauer B, Kröger S, Haas W, Brodhun B: Tuberkulose bei Patientinnen und Patienten mit Geburtsland Ukraine in Deutschland im Jahr 2022. Epid Bull 2023; 11: 6–19.

5. WHO consolidated guidelines on tuberculosis: Module 4: treatment—drug-resistant tuberculosis treatment, 2022 update. Geneva: World Health Organization; 2022. Licence: CC BY-NC-SA 3.0 IGO.