5.1. Summary of evidence to recommendation

Based on the GRADE process, the EG had a low level of confidence in using the available data for global decision-making, given that the available evidence was limited. There were concerns about imprecision and indirectness due to the small sample size, the use of mITT (i.e. not ITT) analysis, and the low quality of evidence for the background MDR-TB treatment regimens used in the trial. In particular, the EG was concerned about the low cure rate at 120 weeks observed in the placebo group when compared to those reported from recent published reviews.¹⁸,¹⁹,²⁰ This could indicate that the patients included in the trial were not representative of the MDR-TB population at large and that the effects observed in the bedaquiline arm may not be reproducible under programme conditions.

The EG also discussed the potential to draw conclusions for different sub-categories of MDR-TB patients, such as patients with strains resistant to either fluoroquinolones or injectable drugs. No evidence for use of the drug in XDR-TB patients was available, since these patients were excluded from the mITT analysis. No information, aside from MDR-TB status, was available on drug susceptibility testing at diagnosis. Members of the EG did, however, feel that the use of bedaquiline in XDR-TB patients or those with resistance or contraindication to fluoroquinolones or injectables may have added benefit, given that treatment options for these patients are severely curtailed.

The EG also concluded that recommendations could only be made on the use of bedaquiline in addition to current WHO-recommended regimens. Bedaquiline should not replace drugs generally recommended for MDR-TB treatment unless these are considered ineffective.²¹

There was modest agreement that the quality of evidence for benefits was “low” due to imprecision and indirectness, and high agreement that the quality of evidence for harms was “low” or “very low” due to imprecision, indirectness and risk of bias. The EG expressed particular concern about mortality risk, with a high degree of uncertainty about the evidence.

The need for caution in prescribing bedaquiline was stressed, as well as the importance of clear and understandable communication with patients prior to drug prescription. Mention was made of the need to support this by informed consent, ideally in writing.

The EG could not reach consensus on the overall balance of harms and benefits and proceeded to a vote (observers and technical resources consultants were excluded). The results were as follows: 10 votes that benefits outweighed harms; 4 votes that harms outweighed the benefits; and 2 abstentions (including the chair).

The EG felt that there were potentially large variations in patient values and preferences for each outcome. Most members felt that patients would place high value on survival but that it was less clear that patients would value microbiological culture conversion in the same way. EG members expressed the view that patient acceptance of bedaquiline would depend on the severity of their disease and the likelihood of designing an effective background regimen – e.g. XDR-TB patient groups might be more likely to accept the risk of taking a new drug with apparent increased risk of death than patients with uncomplicated MDR-TB without additional drug resistance.

The EG had difficulty reaching consensus on the resource requirements of the proposed recommendation. While the cost-effectiveness modelling showed overall benefit, there were concerns about the simplifying assumptions used (e.g. no accounting for the difference in serious adverse events, no accounting for effect on transmission, uncertainty about application of trial outcomes – including deaths – to routine programmatic conditions, etc.). The EG also felt that cost effectiveness would not necessarily translate into affordability or country readiness to pay given the potentially high cost of bedaquiline. Resource implications related to programme costs, training of health care staff, and establishing active pharmacovigilance systems were not explicitly discussed due to time constraints. The EG nevertheless concluded that the resource implications of introducing bedaquiline would probably involve “small cost relative to net benefits”.

Lastly, the EG felt that effects on equity of bedaquiline addition to WHO-recommended MDR-TB treatment was difficult to assess, due to the uncertainly of affordability and country willingness to pay, as well as the difference in opinion on the balance of benefits and harms discussed above.

5.2. Expert Group recommendations

The EG suggested that, as an interim recommendation, bedaquiline may be added to a WHO-recommended regimen in MDR-TB adult patients under the following conditions (conditional recommendation, very low confidence in estimates of effects):

• when an effective treatment regimen containing four second-line drugs in addition to pyrazinamide, according to WHO recommendations, cannot be designed;
• when there is documented evidence of resistance to any fluoroquinolone in addition to multidrug resistance.

In addition, the EG recommended that:

• a duly informed decision-making process by patients should be followed;
• bedaquiline be used with caution in people living with HIV, as well as in patients with co-morbidities (such as diabetes) or people reporting alcohol or substance use, due to limited or no information;
• bedaquiline be used for a maximum duration of 6 months and at the suggested dosing (400 mg daily for the first 2 weeks, followed by 200 mg three times per week for the remaining 22 weeks);
• bedaquiline must not be added alone to a failing regimen;
• baseline testing and monitoring for QT prolongation and development of arrhythmia is imperative;
• clinical monitoring and management of co-morbidities (especially cardiac and liver disease) should be in place;
• spontaneous reporting of adverse drug reactions is reinforced at country level and active pharmacovigilance is established among patient groups treated with the drug;²²
• in the absence of a specific drug-susceptibility test, resistance to bedaquiline should be monitored through assessment of minimum inhibitory concentrations (MICs);
• resistance to other anti-TB drugs should be monitored following WHO recommendations.

The EG also recommended that these interim recommendations be re-assessed in 2015, or earlier if additional data of significance become available increasing the knowledge on safety, toxicity and efficacy of bedaquiline (e.g. post-marketing studies, ongoing trials and other studies).

5.3. Research implications

The EG strongly supported the need for an acceleration of Phase III trials to expand knowledge on safety and efficacy of bedaquiline, with particular attention to mortality (including causes of death), in the treatment of MDR-TB. The EG identified further research gaps, including:

• development of a reliable drug susceptibility test for bedaquiline;
• pharmacokinetics, safety and efficacy studies in specific populations (infants and children, HIV patients – especially those on antiretroviral therapy (ART), alcohol and substance users, elderly people, pregnant or nursing women, people with extrapulmonary TB, people with diabetes);
• safety studies, including type, frequency and severity of adverse events (short and long term), and mortality (including cause of death);
• drug–drug interactions, including with other existing and newly developed TB drugs and ART;
• acquisition of resistance to bedaquiline and to other TB drugs;
• identification of optimal combination of drugs including bedaquiline and determination of optimal duration and dosing of treatment;
• patient acceptability;
• appropriate cost-effectiveness studies.

Footnotes

18

Ahuja SD, et al. Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients. PLoS Medicine. 2012;9(8):e1001300. [PMC free article: PMC3429397] [PubMed: 22952439]

19

Orenstein EW, et al. Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infectious Diseases. 2009 Mar;9(3):153–61. [PubMed: 19246019]

20

Johnston JC, Shahidi NC, Sadatsafavi M, Fitzgerald JM. Treatment Outcomes of Multidrug-Resistant Tuberculosis: A Systematic Review and Meta-Analysis. PLoS ONE. 2009 Sep 9;4(9):e6914. [PMC free article: PMC2735675] [PubMed: 19742330]

21

WHO. Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 Update. Geneva: World Health Organization; 2011. (WHO/HTM/TB/2011.6) [PubMed: 23844450]

22

For more details see: A practical handbook on the pharmacovigilance of medicines used in the treatment of tuberculosis: enhancing the safety of the TB patient. Geneva: World Health Organization; 2012. Available from: http://www​.who.int/medicines​/publications​/pharmacovigilance_tb/