9.5 The Standard DR TB Regimen

In patients with confirmed rifampicin-susceptible and isoniazid-resistant tuberculosis, the recommended treatment regimen is a combination of rifampicin, ethambutol, pyrazinamide and levofloxacin for a duration of 6 months

Regimen: 6 (H) R- E- Z- Lfx

• In cases where a diagnosis of Hr-TB is strongly presumed (e.g. close contacts of known Hr-TB cases with active TB but without laboratory confirmation of Hr-TB), (H) REZ–levofloxacin regimen may be initiated and then suitably modified based on subsequent DST results.
• DST results eventually indicate susceptibility to isoniazid
• For new TB cases, levofloxacin is stopped and the patient completes a 2HREZ/4HR regimen.
• For Previously Treated (retreatment) cases, levofloxacin is continued along with 6HREZ regimen.
• For other patients, in whom Hr-TB is detected provide 6 months 6LfxHREZ regimen.

MDR/RR-TB patients who have not been previously treated for more than 1 month with second-line anti TB medicines used in the shorter MDR-TB regimen or in whom resistance to fluoroquinolones has been excluded by SL-DST/LPA, the recommended shorter MDR-TB regimen is largely standardized. This is a daily regimen of 9–11 months with an intensive phase of 4 to 6 months, followed by a continuation phase of a fixed duration of 5 months.

Eligibility for STR:

The following MDR/RR-TB patients, with confirmed resistance to at least rifampicin, are eligible:

• No documented or suspected resistance to any of the medicines in the shorter regimen (except isoniazid resistance)
• No prior exposure to any of the medicines in the shorter regimen for more than 1 month. However, patients with an exposure of more than a month can be considered if there is documented evidence showing effectiveness of the drugs on a DST.
• The patient should not be suffering from extensive TB or severe extra-pulmonary TB
• The patient should not be pregnant.
• Only children aged 6 years and above are eligible.

Regimen and duration of treatment:

The shorter all-oral Bedaquiline containing MDR/RR-TB regimen is given in 2 phases as under:

• Intensive Phase (4 – 6 months): The IP contains 7 drugs, namely, bedaquiline, levofloxacin, clofazimine, ethionamide, ethambutol, high dose isoniazid and pyrazinamide given for 4 months. The IP can be extended up to 6 months if the patient remains sputum smear positive or culture positive at the end of the fourth/fifth month.
• Continuation Phase (5 months): The IP is followed by a CP containing 4 drugs, namely, levofloxacin, clofazimine, ethambutol and pyrazinamide given for a fixed period of 5 months.

Important:

- Bedaquiline is used for a fixed duration of 6 months (24 Weeks). It is taken daily for the first 2 weeks of treatment, followed by three times a week for the remaining 22 weeks (total 24 weeks).

- All other medicines are taken once a day for the entire course of the treatment.

Regimen: (4 - 6) Bdq(6m)-Lfx-Eto-Cfz-Z- H^{high dose}-E / 5 Lfx-Cfz-Z-E
Initial phase: (4 - 6) Bdq(6 m)-Lfx-Cfz-Z-E- H^{high dose}-E
Continuation phase: 5 Lfx-Cfz-Z-E

Considerations for the all oral STR

Any changes to the regimen composition or the duration of the initial or continuation phase (including prolonging these phases in case of lack of response) is not advisable while using the shorter all-oral bedaquiline-containing MDR/RR-TB regimen under programmatic conditions. The only modifications that are allowed are as under:

• If the sputum smear or culture does not become negative by the fourth month, the initial phase is prolonged until the sputum smear or culture converts. However, the initial phase cannot be prolonged beyond 6 months (i.e., the IP can be extended only for a maximum of 2 months). The duration of the Continuation Phase remains fixed at 5 months regardless.
• Bedaquiline is used for 6 months.
• Prothionamide may be used instead of ethionamide.
• Moxifloxacin may be used instead of levofloxacin.
• Any other changes to the regimen (e.g. removing ethionamide or replacing ethionamide or clofazimine by linezolid etc.) are not recommended in programmatic use.

All MDR/RR-TB patients may be treated with longer regimens; however, the longer regimen is preferably given to those MDR/RR-TB patients who are not eligible for shorter all-oral regimens, including those with quinolone resistance.

Eligibility for LTR:

• MDR/RR-TB patients with extensive TB disease and severe EP TB, additional resistance to fluoroquinolones or exposure to treatment with second-line medicines for more than 1 month (without DST results).
• Any patient – child or adult – with MDR/RR-TB is eligible for the longer MDR-TB regimen
• All MDR/RR-TB patients for whom the shorter all-oral bedaquiline-containing MDR-TB regimen cannot be used or continued.
• If required, a patient initiated on the shorter all-oral bedaquiline-containing MDR-TB regimen can later be transferred to the longer MDR-TB regimen. The recommended regimen are:

For Quinolone susceptible: 6(Bdq-Lzd-Lfx-Cfz-Z)/14(Lzd-Lfx-Cfz-Z)
For Quinolone resistant: 6(Bdq-Dlm-Lzd-Cfz-Z-Cs)/14(Lzd-Cfz-Z-Cs)

Grouping of medicines recommended for use in longer MDR-TB regimens:

Principles of Individualized Longer MDR-TB regimen formulation:

In MDR/RR-TB patients on longer regimens, all three Group A agents and at least one Group B agent should be included to ensure that treatment starts with at least four TB agents likely to be effective, and that at least three agents are included for the rest of the treatment after bedaquiline is stopped. If only one or two Group A agents are used, both Group B agents are to be included. If the regimen cannot be composed with agents from Groups A and B alone, Group C agents are added to complete it. Kanamycin and Capreomycin are no longer recommended for use in longer regimens.

Data from the single arm, open-label Nix-TB study assessed the efficacy of a 6-9-month novel treatment regimen consisting of 3 drugs - Bedaquiline, Pretomanid and Linezolid - and demonstrated that this regimen safely improves treatment outcomes in patients with XDR-TB when compared with other regimens conforming to WHO guidelines. This regimen is being considered for treatment of multidrug-resistant tuberculosis (MDR-TB) patients with additional resistance to fluoroquinolones (pre-XDR), XDR-TB, intolerant and non-responsive MDR-TB, who have either had less than 2 weeks previous exposure to Bedaquiline and Linezolid under operational research conditions to acquire adequate evidence on safety and efficacy for use under programmatic conditions.

BPaL regimen should be used under operational research conditions with proper ethical approval, patient-centered care and support, pre-defined eligibility criteria, informed consent from patients and implemented according to the principles of good clinical practice, with active drug safety monitoring and management, treatment monitoring, outcome evaluation, and comprehensive, standardized data collection.

BPaL regimen: 6–9 Bdq- Pa-Lzd