Bedaquiline resistance probability to guide treatment decision making for rifampicin-resistant tuberculosis: insights from a qualitative study

Background Bedaquiline (BDQ) is a core drug for rifampicin-resistant tuberculosis (RR-TB) treatment. Accurate prediction of a BDQ-resistant phenotype from genomic data is not yet possible. A Bayesian method to predict BDQ resistance probability from next-generation sequencing data has been proposed as an alternative. Methods We performed a qualitative study to investigate the decision-making of physicians when facing different levels of BDQ resistance probability. Fourteen semi-structured interviews were conducted with physicians experienced in treating RR-TB, sampled purposefully from eight countries with varying income levels and burden of RR-TB. Five simulated patient scenarios were used as a trigger for discussion. Factors influencing the decision of physicians to prescribe BDQ at macro-, meso- and micro levels were explored using thematic analysis. Results The perception and interpretation of BDQ resistance probability values varied widely between physicians. The limited availability of other RR-TB drugs and the high cost of BDQ hindered physicians from altering the BDQ-containing regimen and incorporating BDQ resistance probability in their decision-making. The little experience with BDQ susceptibility testing and whole-genome sequencing results, and the discordance between phenotypic susceptibility and resistance probability were other barriers for physicians to interpret the resistance probability estimates. Especially for BDQ resistance probabilities between 25% and 70%, physicians interpreted the resistance probability value dynamically, and other factors such as clinical and bacteriological treatment response, history of exposure to BDQ, and resistance profile were often considered more important than the BDQ probability value for the decision to continue or stop BDQ. In this grey zone, some physicians opted to continue BDQ but added other drugs to strengthen the regimen. Conclusions This study highlights the complexity of physicians' decision-making regarding the use of BDQ in RR-TB regimens for different levels of BDQ resistance probability.. Ensuring sufficient access to BDQ and companion drugs, improving knowledge of the genotype–phenotype association for BDQ resistance, availability of a rapid molecular test, building next-generation sequencing capacity, and developing a clinical decision support system incorporating BDQ resistance probability will all be essential to facilitate the implementation of BDQ resistance probability in personalizing treatment for patients with RR-TB. Supplementary Information The online version contains supplementary material available at 10.1186/s12879-022-07865-7.


Patient scenarios
In each patient scenario, we present a hypothetical but realistic patient. For each patient, we describe important sociodemographic and clinical characteristics including information related to TB and comorbidities. We present the drug resistance profile based on the whole genome sequencing (WGS) results. For BDQ, the WHO has listed pepQ, Rv0678, mmpL5, mmpS5, atpE, and Rv1979c as candidate genes for BDQ resistance but for none of the variants the information available allowed for a classification as associated with resistance. We used a Bayesian approach to estimate the probability of BDQ resistance. Typically, a Bayesian approach combines different sources of data. We combined the opinions of 33 experts on genotype and phenotype association for BDQ with the data on phenotypic and genotypic BDQ resistance from a recent systematic review. The output of the analysis is the probability of BDQ resistance for a specific genomic variant and the 95% credible interval for that probability. The probability can be interpreted as the prediction that an isolate with that variant will be resistant to BDQ Regarding BDQ, a, 337G>A variant was detected in the Rv0678 gene.
• This SNP is a missense mutation. The majority of experts believe that missense mutations in Rv0678 frequently confer BDQ resistance. • Globally, this variant has only been observed in 3 clinical isolates: 1 phenotypically BDQ resistant and 2 phenotypically BDQ sensitive isolates.
Based on this data, the Bayesian analysis predicts a 47% probability of BDQ resistance with a credibility interval of 12% -84% for an Mtb isolate with the 337G>A variant in the Rv0678 gene.
Do you continue BDQ in the treatment regimen for this patient?

PATIENT 2
A 42-year-old male was diagnosed with RR-TB on Xpert. He has no history of TB treatment.
At diagnosis, his BMI was 19 kg/m 2 . CXR showed infiltrations in the right lobe, no large cavities. His smear was positive (1+). He is HIV positive, on ART (TDF-3TC-DTG), recent CD4 count is 370 cells/uL, undetectable viral load. His blood tests and QT interval were normal (430 ms). He is not taking (other) QT-prolongation drugs.
At the follow-up consultation one month into treatment, he reports that he has been adherent to his TB treatment and is doing well, coughing less. He has gained weight. His blood tests are normal, and QT interval is unchanged (430 ms).
His month 1 smear is negative. The result of the month 1 culture is still pending.
After 5 weeks of treatment, the WGS result is available: the isolate is: • Resistant to RIF • Susceptible to INH, PZA, EMB, FQs, ETH and SLIs Regarding BDQ, a single nucleotide insertion (418_419insG) variant in the Rv0678 gene is detected: • This insertion is a frameshift mutation. The majority of experts believe that a frameshift mutation in the Rv0678 gene frequently or very frequently confers BDQ resistance. • Specifically, the 418_419insG variant has been observed in 9 clinical isolates globally. The phenotypic BDQ DST of all 9 isolates was susceptible. Based on this data, the Bayesian analysis predicts a probability of BDQ resistance of 14% with a credibility interval of 1% -39% for an Mtb isolate with a 418_419insG variant in the Rv0678 gene.

PATIENT 3
A 23-year-old HIV-negative woman was diagnosed with MDR-pulmonary TB in 2019. She was treated with BDQ + MFX + CFZ + ETH + PZA + INH for 2 months, after which she was lost to follow-up.
In June 2021, she was diagnosed with RR-TB on Xpert. Her BMI is 20kg/m 2 , her CXR shows small cavities. Sputum smear is positive (2+). Her liver and kidney function are normal. QT interval is also normal (430 ms). She is not taking any (other) QT-prolongation drugs.
On consultation after 1 month of MDR-TB treatment, the patient says she is adherent to her treatment but is still coughing and has bouts of nausea. She has not gained weight. Her blood tests are normal, and QT interval is unchanged (430 ms).
Her month 1 smear was 1+, and her month 1 culture result is pending.
Two months after the start of treatment, the WGS results are ready. The isolate is: • Resistant to RIF and INH.
• No variants in genes that may confer resistance to LZD are reported.
Regarding BDQ, a 187A>G variant in the Rv0678 gene is detected.
• This single nucleotide polymorphism (SNP) is a missense mutation (causing an amino acid change in the encoded protein). The majority of experts believe that missense mutations in Rv0678 frequently confer BDQ resistance. • Globally, this variant has only been observed in 2 clinical isolates. The BDQ phenotypic DST of both these isolates was susceptible.
Based on this data, the Bayesian analysis predicts a 35% probability of BDQ resistance with a credibility interval of 4% -78% for an Mtb isolate with a 187A>G variant in the Rv0678 gene.

PATIENT 4
A 70-year-old man was diagnosed with RR-TB by Xpert on 05/02/2021. He has never been diagnosed with TB before. His sister (who lives in the same town) was diagnosed with TB resistant to INH, RIF and AMK in 2017 and was treated with an all-oral short BDQ containing RR-TB regimen. She was not very adherent but did complete her treatment.
At the 70-year-old patient's RR-TB diagnosis, he was HIV negative, BMI was normal (21 kg/m 2 ) and his CXR showed infiltrations but no cavities. His sputum smear was positive (2+). He is known to suffer from alcohol abuse, but his liver tests are normal.
The man has not yet come back to the clinic to start his treatment and does not answer his phone.
Three weeks after his diagnosis of RR-TB on Xpert, the WGS result is ready. The isolate is • Resistant to RIF and INH.
• No variants in genes that may confer resistance to LZD or DLM are reported.
Because of the exposure to pre-XDR TB, the recommended regimen for this patient is an all-oral long regimen containing BDQ + LZD + LVX + CFZ + TRD.
Regarding BDQ, a 254T>C variant in the pepQ gene is detected.
• This SNP is a missense mutation. About half of experts are uncertain whether a mutation in pepQ can confer BDQ resistance, 36% believed that a missense mutation in pepQ can confer resistance to BDQ and 12% believed that variants in pepQ never confer BDQ resistance. • Globally, the T254C pepQ variant has been observed in 2 clinical isolates. Both these samples were susceptible to BDQ on phenotypic DST.
Based on this data, the Bayesian analysis predicts a 25% probability of BDQ resistance with credibility interval of 1% -67% for an Mtb isolate that contains this 254T>C variant in the pepQ gene.
One week after the WGS results became available, the man shows up at the clinic and is ready to start his treatment.
Do you start a BDQ-containing regimen for this patient? When he comes back to the clinic, the WGS results are also ready. On WGS, the isolate is: • Resistant to RIF, INH (katG mutation), PZA and FQs.
• Susceptible to EMB, ETH and SLIs.
• No variants in genes that may confer resistance to LZD or DLM are reported.
Regarding BDQ, a single nucleotide deletion (193delG) variant in the Rv0678 gene is detected.
• This variant is a frameshift mutation. The majority of experts believe that a frameshift in Rv0678 very frequently confers BDQ resistance. • Globally, this variant has been observed in 5 clinical isolates and in 2 laboratory experiments. The phenotypic DST of all 5 isolates showed susceptibility to BDQ. The 2 laboratory strains were resistant to BDQ.
Based on this data, the Bayesian analysis predicts a 39% probability of BDQ resistance with credibility interval 12% -71% for an Mtb isolate with a 193G deletion in the Rv0678 gene.
According to the guidelines, the recommended intensive phase regimen for this patient with FQ resistance is BDQ + LZD + DLM + CFZ + TRD + ETH.