Due to the rather high level of adverse events experienced by patients in the Nix-TB study (as described previously in this section), safety for patients who receive BPaL needs to be actively monitored, following the aDSM framework. Patients need to be tested at baseline and then monitored during treatment using schedules of relevant clinical and laboratory testing. According to the product label of pretomanid, baseline assessments before initiation of the BPaL regimen include assessments for symptoms and signs of liver disease (e.g. fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness and hepatomegaly) and the conduct of laboratory tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase and bilirubin, complete blood count and serum potassium, calcium and magnesium – which should be corrected if abnormal). Treating clinicians should also obtain an ECG before starting a patient on treatment. The baseline monitoring schedule of the Nix-TB study was much more comprehensive than this, and included a thorough baseline clinical assessment, then weekly patient monitoring until week 20, followed by 4–6 weekly monitoring thereafter, partly dependent on whether the patient had treatment for 6 months in total or whether treatment was extended by another 3 months (to 9 months in total).
Detailed schedules of baseline and follow-up monitoring, including after the completion of treatment, should be developed for any BPaL operational research protocol, with standardized measures for recording adverse events. The WHO framework for aDSM needs to be applied to patients on any type of MDR-TB regimen, to ensure appropriate action and an acceptable level of monitoring for and prompt response to adverse events – alongside monitoring for treatment outcomes, including early monitoring for treatment failure. Additional evidence generated on adverse events will be important to build the evidence base on the safety of the BPaL regimen in varied settings.
The monitoring of changes in dosing and duration of linezolid in particular (when needed) will also be important to inform the future evidence base on the wider use of the BPaL regimen and the tolerability of linezolid in this regimen. Based on a pharmacokinetic toxicodynamic model that was developed based on the Nix-TB study data (Savic R., University of California, San Francisco, unpublished data, November 2019), it was concluded that the pharmacokinetics related to linezolid are nonlinear in patients with MDR-TB with fluoroquinolone resistance, and individual linezolid concentration times are the best predictor of toxicity in this model. Higher toxicity rates were observed at higher total daily doses, with comparable toxicity rates for BID and QD²⁰ dosing schedules. Data modelling indicated that anaemia can be managed by closely monitoring changes in haemoglobin over the first 4 weeks of treatment. In particular, decreases in haemoglobin of more than 10% from baseline should trigger a reduction in the dose of linezolid; haemoglobin levels recover well after dose reductions. Peripheral neuropathy and optic neuritis should be closely monitored. Thrombocytopenia was potentially not a major concern at high dose linezolid for MDR-TB in patients with fluoroquinolone resistance (1).
Adverse events related to pretomanid, particularly potential safety signals related to male infertility, were observed in animal (murine and simian) models. The panel highlighted the potential difficulties in monitoring of infertility in a programmatic setting (1). Additional human sperm studies recommended by the United States (US) Food and Drug Administration (FDA) will be carried out by the TB Alliance; however, these data were not available for the GDG to consider at the time of the meeting. The GDG determined that infertility is a serious issue because it affects not only patients but also their families. Judgement about the balance of the desirable and undesirable effects needs additional research evidence to be generated before a decision can be taken on whether to implement the BPaL regimen worldwide under programmatic conditions.
A schedule for monitoring examinations should be established and applied to all patients receiving treatment with the BPaL regimen. Patients should undergo appropriate evaluation at baseline, and during and after treatment (5). This should include necessary clinical evaluations, bacteriological and laboratory tests, radiology and ECG examinations (see the sample schedule in Table 7.3). The baseline visit refers to the beginning of the treatment with the BPaL treatment regimen. The monitoring schedule should take into account the following considerations:
• laboratory and ECG monitoring should be continued at monthly intervals (where indicated) for the duration of treatment (i.e. 9 months in the case of treatment prolongation);
• more frequent monitoring may be advisable in specific situations, including elderly people, patients infected with HIV, those affected by hepatitis (caused by hepatitis B virus [HBV] or hepatitis C virus [HCV]) or diabetes mellitus, or with moderate to severe hepatic or renal impairment; and
• in the case of electrolyte disturbances or ECG abnormalities, more frequent monitoring should be performed.
Active pharmacovigilance should be performed, as well as proper management of adverse events and prevention of complications from drug–drug interactions. The NTP should thus actively monitor drug safety to ensure proper patient care, to report any adverse events to the responsible drug safety authority in the country, and to inform national and global policy.
²⁰ Where BID is twice daily and QD once daily.