Lately I have been thinking a lot about bedaquiline (BDQ). Not the drug exactly, but the ideas around it. With more studies documenting the resistance to bedaquiline, I’ve been thinking about the arc of our expectations for BDQ. My mind dwells on the personalities who yearn for magic bullets and the kinds of people and institutions who shape our expectations of how technology will fix things. People are blaming COVID for the challenges of rolling out of all-oral shorter regimens, and it didn’t help. But that’s not the right place to park our disappointment. I’ve been asking myself whether the loss of BDQ potency was inevitable and what we might learn from it. I am wondering if there might still be a way to right this ship. What do we have to do differently to keep the promise of ambulatory, pain and disability-free, shorter regimens alive?
Hope as the core drug
“Humanitarian devices”, “technology transfer”, and “ frugal innovation” have a complex history (and an uncomfortable relationship with white saviorism). But if I am being honest, I‘ve been known to worship at the church of the magic bullet myself. I can’t help getting excited about the prospect of fewer invasive, painful, stupid obstacles. Yes, Alice Street and Nora Engel’s work lays bare the naivete, grand ambitions, and boom-bust mindset of humanitarian entrepreneurs: but some of us are just hard wired to always think there is a point-of-care gadget or a pill or a shot that can fix it.1,2 We fall hard for every proverbial game changer. Even as the TB space is littered with discarded toys and failed experiments, there is a phenotype in our TB tribe who keep hopeful for the miracle in each prototype, each biomarker, each investigational compound.
That is why it was not surprising that the advent of bedaquiline (BDQ) as core drug filled so many with breathless anticipation. BDQ was heralded as a revolutionary replacement that would shorten and de-institutionalize treatment while reducing toxicity and improving outcomes. The shift to an all-oral regimen was slated to prevent hearing loss in over 50,000 people.3 We were assured BDQ would lessen pain, forced hospitalization, stigma, depression, anxiety, low quality of life, catastrophic costs, and crucially, non-adherence. Robust BDQ-containing regimens were estimated to reduce the overall proportion of MDR-TB infections by 37.6% and blunt the development of XDR by 38.6%.4
And BDQ has done a lot to reset the expectations and meanings of a DR-TB diagnosis and to amplify the voices and choices of the people who need treatment.
But the chatter about baseline and acquired resistance to BDQ is becoming harder to ignore.5 Wherever one builds up the courage to look for it, there it is.5–11 Small proportions for now, but we are not yet looking for BDQ resistance in all the countries that were BDQ early adopters.5
If BDQ flames out, it won’t be a minor setback, like pulling the plug on the GeneXpert Omni or a failed batch of FujiLAM. We’ll have created a monster. Not saved our world, but rather made it worse.
Stakeholders lament that we are losing BDQ potency before we really understand how it works or have grasped all it can do.12 I find myself in the “trough of disillusionment” phase of Gartner’s life sciences Hype Cycle.13
Some say that the unique pharmacokinetics of BDQ made acquired resistance almost inevitable. It’s hard to gauge whether resistance to BDQ was ‘baked in’ to the drug’s long loading phase and half-life, but I keep wondering if the phrenetic roll out had something to do with it. Did we squander the promise of bedaquiline? Or was it always a kind of pharmacokinetic Trojan horse?
The scale-up of shorter all oral regimens was intended to be accompanied by upgrades in antibiotic stewardship capacity: the expansion of post-marketing pharmacovigilance, second line drug susceptibility testing, nimble clinical monitoring, and patient adherence supports. However, the whole host of ancillary investments have not kept pace.14
A pill for changing behavior?
The estimated magnitude of the transformational power of BDQ was not based solely upon greater treatment efficacy from trial data, but rather weighted heavily by assumptions about vastly improved adherence from an all oral, ambulatory regimen.4,15 While trial data showed 10-15% margins in cure, models regularly assumed 20-25% gains in treatment success.44> The expectations for BDQ were not fed by the kind of social science that creates precise estimates. Greater adherence was taken for granted given the devastating side effects of previous regimens.
In models, the boost to treatment completion from BDQ was estimated to be 15%. Yet under routine conditions a more modest 6% reduction in loss to follow-up is a typical all oral dividend.16 It was often unequivocally stated that presence of an injectable played the primary role in the MDR-TB treatment experience. It was frequently assumed to be among the most (if not the most) important challenge for patients and thus the leading driver of non-adherence. However a close read of the qualitative work on DR-TB patient preferences hints that drug formulations and regimen composition were but two aspects of an often complex conceptualization of acceptability that also includes notions about treatment efficacy, treatment duration, drug availability, affordability, length of infectiousness, and isolation.17,18
Indeed, the switch to all oral regimens has not consistently delivered on the promises of freedom and autonomy either. Many countries still needlessly hospitalize DR-TB patients on BDQ-based all oral regimens. Some are even keeping patients longer, as culture conversion can be slower.
Per usual, everything is more complicated than it seemed.19
On flying blind with free drugs
Baseline and acquired resistance is documented in a growing number of countries, but the absence of BDQ phenotypic DST capacity in many early adopter countries means we have no idea of how much resistance to bedaquiline exists.5,14
While often portrayed now as the culmination of many years of activism, the pace of the all-oral scale up may also have been set by the need to capitalize upon the large BDQ donation. The all-hands-on-deck push was not exclusively a response to a groundswell of unmet demand. The fire to put the first doses into clinics in LMIC settings had an accelerant.14,20 Have all the lessons from the donation era been learned? Do we need a new approach before rolling out BPAL? Should we sort out BDQ DST given we’re to start trialing BDQ against TB infection, leprosy, cancer and malaria?21,22
Shorter all oral regimens are consistently preferred by patients, but they were readily embraced by policy makers for a broader set of reasons and logics.23 Injection sparing regimens were intended to expedite decentralized, ambulatory care by avoiding daily health worker administered injections. They were seen as reducing the need for isolation wards with nosocomial transmission risks. In trials, ambulatory DR-TB care had been shown to improve satisfaction, reduce patient catastrophic and health system costs, without sacrificing treatment outcomes,.24,25Devolution of all-oral DR-TB care to primary care staff has gone so sideways in some places that new strategic plans talk of “re-centralizing” DR-TB care and reducing numbers of treatment initiation sites. Community-based clinical monitoring of adverse events of short all oral regimens (e.g. ECG for QT prolongation) seems to be implemented about as well as community-based audiometry was implemented, which is to say, inconsistently.26,27
Dignity as the core drug?
And finally, as I worry about the loss of bedaquiline potency, its troublesome pharmacokinetics, and our earnest but imperfect attempts to deliver it swiftly, I return to treatment perseverance basics. I think about all the boatloads of evidence showing us that for any regimen to work DR-TB patients need to be food secure, to be housed, to be supported, to be engaged by a caregiving human (not a text message or VIR), and to receive the drugs on time.28
In country after country, the switch to all-oral BDQ shorter regimens is not being accompanied by the robust packages of social, economic, nutritional, and psychological supports that probably are the real game changers. Delays in cash transfers still leave patients with catastrophic costs…29 Stockouts of companion drugs still trigger long searches for meds…. Clinicians and policy makers are still making up policy and practice as they go along, many unsure how to deal with DST results and others who finally gave up on waiting to receive them.30,31
Even a dyed-in-the-wool trialist can see that enabling structural and social conditions are what allow people to persevere on all regimens. Our inattention to this fact may be how we got in this mess, distracted by the shiny objects and the pretty modelling.
Trialists and experimentalists will tell you they need enabling conditions (e.g. money, tools, and multi-disciplinary collaboration) to make the magic of innovation happen. Why would DR-TB patients need anything less?
It is the way most hard things get done.
So while we thought bedaquiline would save us, it turns out bedaquiline needs saving too. If the pace of acquired resistance to BDQ is to be slowed, the pre-requisites of treatment perseverance need to be put in place. We’ll need to learn a lot more about implementing effective supports for people on ambulatory, all-oral regimens. This isn’t rocket science, but it might be the technological wonder we’ve been waiting for.
Ellen M.H. Mitchell, PhD is a Public Health Fellow in the unit of Mycobacterial and Neglected Tropical Diseases led by Professor Epco Hasker at the Institute of Tropical Medicine (ITM) in Antwerp since October 2019. Prior to that, she worked at KNCV TB Foundation for ten years. Ellen started out squarely in the Social Sciences frame studying ethnography and politics of public health during her training at Oberlin (’91) and Tulane (‘95, ‘01) and as a Fulbright in Ecuador (’98). Over time she has gravitated toward a version of social epidemiology that mixes tools and hybrid strategies for solving TB problems. Ellen is happiest working in multidisciplinary, multi-country teams to tackle questions about TB risk – not only who and where, but why and what are we doing about it. This has led her to dig into TB stigma, active case-finding, TB mortality measurement, gender, and invite some re-thinking of TB orthodoxies. She has a thing for shiny new ideas, tools, and methods.
- Street A. Make me a test and I will save the world: towards an anthropology of the possible in global health. J R Anthropol Inst [Internet]. 2023 Apr 7;29(S1):95–113. Available from: https://onlinelibrary.wiley.com/doi/10.1111/1467-9655.13904
- Engel N, Davids M, Blankvoort N, Pai NP, Dheda K, Pai M. Compounding diagnostic delays: a qualitative study of point-of-care testing in South Africa. Trop Med Int Heal [Internet]. 2015 Apr;20(4):493–500. Available from: http://doi.wiley.com/10.1111/tmi.12450
- Dillard LK, Martinez RX, Perez LL, Fullerton AM, Chadha S, McMahon CM. Prevalence of aminoglycoside-induced hearing loss in drug-resistant tuberculosis patients: A systematic review. J Infect [Internet]. 2021;83(1):27–36. Available from: https://doi.org/10.1016/j.jinf.2021.05.010
- Han WM, Mahikul W, Pouplin T, Lawpoolsri S, White LJ, Pan-Ngum W. Assessing the impacts of short-course multidrug-resistant tuberculosis treatment in the Southeast Asia Region using a mathematical modeling approach. PLoS One [Internet]. 2021;16(3 March):1–14. Available from: http://dx.doi.org/10.1371/journal.pone.0248846
- Timm J, Bateson A, Solanki P, Paleckyte A, Witney AA, Rofael SAD, et al. Baseline and acquired resistance to bedaquiline, linezolid and pretomanid, and impact on treatment outcomes in four tuberculosis clinical trials containing pretomanid. PLOS Glob public Heal [Internet]. 2023;3(10):e0002283. Available from: http://www.ncbi.nlm.nih.gov/pubmed/37851685%0Ahttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC10584172
- Köser CU, Maurer FP, Kranzer K. ‘Those who cannot remember the past are condemned to repeat it’: Drug-susceptibility testing for bedaquiline and delamanid. Int J Infect Dis [Internet]. 2019 Mar;80:S32–5. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1201971219300918
- Moe S, Rekart ML, Hernandez D, Sholpan A, Ismailov A, Oluya M, et al. Primary bedaquiline resistance in Karakalpakstan, Uzbekistan. Int J Tuberc Lung Dis. 2023;27(5):381–6.
- Nguyen TVA, Anthony RM, Bañuls AL, Vu DH, Alffenaar JWC. Bedaquiline Resistance: Its Emergence, Mechanism, and Prevention. Clin Infect Dis. 2018;66(10):1625–30.
- Berry C, Decroo T, Hien P, Tu T. Bedaquiline resistance and the BPaLM regimen for RR-TB treatment – knowledge gaps and translation from guideline to practice. In: University of Antwerp Webinar on BDQ. Antwerp; 2022.
- Nimmo C, Millard J, Brien K, Moodley S, Van Dorp L, Lutchminarain K, et al. Bedaquiline resistance in drug-resistant tuberculosis HIV co-infected patients. Eur Respir J. 2020;55(6).
- Mallick JS, Nair P, Abbew ET, Van Deun A, Decroo T. Acquired bedaquiline resistance during the treatment of drug-resistant tuberculosis: a systematic review. JAC-Antimicrobial Resist. 2022;4(2).
- Sonnenkalb L, Carter JJ, Spitaleri A, Iqbal Z, Hunt M, Malone KM, et al. Bedaquiline and clofazimine resistance in Mycobacterium tuberculosis: an in-vitro and in-silico data analysis. The Lancet Microbe [Internet]. 2023;358–68. Available from: http://www.ncbi.nlm.nih.gov/pubmed/37003285
- Dedehayir O, Steinert M. The hype cycle model: A review and future directions. Technol Forecast Soc Change [Internet]. 2016;108:28–41. Available from: http://dx.doi.org/10.1016/j.techfore.2016.04.005
- Rutta E, Kambili C, Mukadi Y. The bedaquiline donation program: Progress and lessons learned after 4 years of implementation. Int J Tuberc Lung Dis. 2020;24(10):1039–45.
- Agnarson AM, Wang XC, Potluri R, Bhandari H, Dhir A, Kambili C, et al. Long-term impact of the adoption of bedaquiline-containing regimens on the burden of drug-resistant tuberculosis in China. BMC Infect Dis. 2020;20(1):1–9.
- Pai H, Ndjeka N, Mbuagbaw L, Kaniga K, Birmingham E, Mao G, et al. Bedaquiline safety, efficacy, utilization and emergence of resistance following treatment of multidrug-resistant tuberculosis patients in South Africa: a retrospective cohort analysis. BMC Infect Dis [Internet]. 2022 Nov 21;22(1):870. Available from: https://doi.org/10.1186/s12879-022-07861-x
- Furin J, Loveday M, Hlangu S, Dickson-Hall L, Le Roux S, Nicol M, et al. “a very humiliating illness”: A qualitative study of patient-centered Care for Rifampicin-Resistant Tuberculosis in South Africa. BMC Public Health. 2020;20(1):1–11.
- Horter S, Achar J, Gray N, Parpieva N, Tigay Z, Singh J, et al. Patient and health-care worker perspectives on the short-course regimen for treatment of drug-resistant tuberculosis in Karakalpakstan, Uzbekistan. PLoS One [Internet]. 2020;15(11 November). Available from: http://dx.doi.org/10.1371/journal.pone.0242359
- Engel N, Krumeich A. Valuing Simplicity: Developing a Good Point of Care Diagnostic. Front Sociol [Internet]. 2020 May 22;5(May):1–11. Available from: https://www.frontiersin.org/article/10.3389/fsoc.2020.00037/full
- Edwards CG, Wares DF, Dravniece G, Gebhard A, Tiemersma E, van der Grinten E, et al. Introducing bedaquiline: experiences from the Challenge TB Project. Int J Tuberc Lung Dis [Internet]. 2020 Oct 1;24(10):1046–53. Available from: https://www.ingentaconnect.com/content/10.5588/ijtld.19.0790
- Agrawal P, Kumari S, Mohmmed A, Malhotra P, Sharma U, Sahal D. Identification of Novel, Potent, and Selective Compounds against Malaria Using Glideosomal-Associated Protein 50 as a Drug Target. ACS Omega [Internet]. 2023 Oct 17;8(41):38506–23. Available from: https://pubs.acs.org/doi/10.1021/acsomega.3c05323
- Najib Ullah SNM, Afzal O, Altamimi ASA, Alossaimi MA, Almalki WH, Alzahrani A, et al. Bedaquiline-Loaded Solid Lipid Nanoparticles Drug Delivery in the Management of Non-Small-Cell Lung Cancer (NSCLC). Pharmaceuticals [Internet]. 2023 Sep 15;16(9):1309. Available from: https://www.mdpi.com/1424-8247/16/9/1309
- Kelly SL, Jaoude GJA, Palmer T, Skordis J, Haghparast-Bidgoli H, Goscé L, et al. Public health benefits of shifting from hospital-focused to ambulatory TB care in Eastern Europe: Optimising TB investments in Belarus, the Republic of Moldova, and Romania. Zwerling A, editor. PLOS Glob Public Heal [Internet]. 2023 Jun 21;3(6):e0001025. Available from: https://dx.plos.org/10.1371/journal.pgph.0001025
- Bada FO, Okpokoro E, Blok N, Meribole E, Dutt S, Dakum P, et al. Cost of three models of care for drug-resistant tuberculosis patients in Nigeria. BMC Infect Dis. 2019;19(1):1–10.
- Oga-Omenka C, Bada F, Agbaje A, Dakum P, Menzies D, Zarowsky C. Ease and equity of access to free DR-TB services in Nigeria- a qualitative analysis of policies, structures and processes. Int J Equity Health. 2020;19(1):1–14.
- Stevenson LJ, Biagio-De Jager L, Graham MA, Swanepoel DW. Community-based ototoxicity monitoring for drug-resistant tuberculosis in south africa: An evaluation study. Int J Environ Res Public Health. 2021;18(21).
- Stevenson LJ. Community-based ototoxicity monitoring with extended high-frequency audiometry and community health workers for drug-resistant tuberculosis By. 2022;(June).
- Mesic A, Ishaq S, Khan WH, Mureed A, Mar HT, Khaing EE, et al. Person‐centred care and short oral treatment for rifampicin‐resistant tuberculosis improve retention in care in Kandahar, Afghanistan. Trop Med Int Heal [Internet]. 2022 Feb 17;27(2):207–15. Available from: https://onlinelibrary.wiley.com/doi/10.1111/tmi.13716
- Timire C, Sandy C, Ferrand RA, Mubau R, Shiri P, Mbiriyawanda O, et al. Coverage and effectiveness of conditional cash transfer for people with drug resistant tuberculosis in Zimbabwe: a mixed methods study. medRxiv [Internet]. 2022;2022.08.19.22278863. Available from: https://www.medrxiv.org/content/10.1101/2022.08.19.22278863v1%0Ahttps://www.medrxiv.org/content/10.1101/2022.08.19.22278863v1.abstract
- Kielmann K, Dickson-Hall L, Jassat W, Le Roux S, Moshabela M, Cox H, et al. “We had to manage what we had on hand, in whatever way we could”: Adaptive responses in policy for decentralized drug-resistant tuberculosis care in South Africa. Health Policy Plan. 2021;36(3):249–59.
31. Tu PHT, Anlay DZ, Dippenaar A, Conceição EC, Loos J, Van Rie A. Bedaquiline resistance probability to guide treatment decision making for rifampicin-resistant tuberculosis: insights from a qualitative study. BMC Infect Dis [Internet]. 2022 Nov 22;22(1):876. Available from: https://doi.org/10.1186/s12879-022-07865-7