Treatment of Drug-Resistant Tuberculosis: Current Status

Treatment of Multidrug-Resistant/Rifampicin-Resistant-Tuberculosis

For treatment of MDR/RR-TB, standardized, empirical, and individualized approaches have been laid down.^5,6 Individualized treatment based on individual DST and prior treatment history is costly and needs skilled professionals and quality assured bacteriological and molecular diagnostic laboratories whereas, standardized treatment is simple, less costly and same treatment is given to all patients. There are two types of treatment regimen MDR/RR-TB shorter and longer regimen according to recent update from World Health Organization (WHO) in which they have also reclassified anti-TB drugs (ATD) for MDR/RR-TB⁷ (►Table 1).

Shorter Regimen for Multidrug-Resistant/Rifampicin-Resistant Tuberculosis

In 2016, WHO approved the use of a shorter regimen for treatment for subset of MDR/RR-TB patients who have not been previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents has been excluded or is considered highly unlikely, a shorter MDR/RR-TB regimen of 9 to 11 months may be used instead of a longer regimen of 20 to 24 months. The intensive phase of 4 months which may be extended to 6 months in case of lack of sputum smear conversion consists of kanamycin, High dose moxifloxacin, ethionamide, clofazimine, pyrazinamide, High-dose isoniazid, ethambutol, followed by continuation phase of 5 months which consist of high-dose moxifloxacin, clofazimine, pyrazinamide, and ethambutol.^7,8,9 Recommendation for use of shorter regimen was conditional and it can be used in selected patients with MDR/RR-TB with the exception of confirmed resistance or suspected ineffectiveness to any medicine in the shorter regimen (except isoniazid), exposure to one or more second-line medicines in the shorter regimen for 1 or more months unless susceptibility to these second-line medicines is confirmed, intolerance to one or more medicines in the shorter regimen or at increased risk of toxicity from such medication (e.g., drug-drug interactions, preexisting QT-interval prolongation), pregnancy, extra pulmonary disease in people living with human immunodeficiency virus and disseminated, meningeal or central nervous system TB. WHO updated guidelines for MDR/RR-TB in 2018 and 2019^10,11 continued to include the shorter regimen as an option for patients who have not been previously treated for more than 1 month with second-line medicines used in the shorter MDR-TB regimen or in whom resistance to fluoroquinolones and second-line injectable agents has been excluded and now the shorter MDR-TB regimen may be offered under certain criteria which were similar to the previous guidelines except that shared decision making between the clinician and patient is important when choosing between a shorter and longer regimen and kanamycin should be replaced by amikacin. Doses of drugs used in shorter regimen has been revised in recently for patients older than 14 years (►Table 2).

Abidi et al reported results of individual patient data meta-analysis comparing the standardized shorter regimen with individualized longer regimen. They reported that treatment success rate was higher with the shorter regimen than with individualized longer regimen due to less loss to follow-up. The failure and relapse was slightly higher with shorter regimen and was greater in magnitude with baseline resistance to pyrazinamide, ethionamide/prothionamide or ethambutol. These finding also support the need to improve access to reliable drug susceptibility test.¹² STREAM has recently expanded (stage 2) to test two additional shorter treatment regimens using bedaquiline.¹³ This expanded arm will evaluate a 9-month all-oral regimen without injections and an even shorter simplified 6-month regimen. It will finish enrollment of patients in 2018 and initial results are expected by 2021.

Longer Regimen for Multidrug-Resistant/Rifampicin-Resistant Tuberculosis

In patients with MDR/RR-TB, a longer regimen of least five effective ATDs during the intensive phase is recommended, including pyrazinamide and four core second-line ATDs, one chosen from group A (fluoroquinolones: levofloxacin, moxifloxacin, and gatifloxacin), one from group B (second-line injectable drugs: kanamycin, amikacin, and capreomycin), and at least two from group C (other core second-line drugs: ethionamide/prothionamide, cycloserine/terizidone, linezolid, and clofazimine). If the minimum of effective ATDs cannot be composed as above, one drug from group D2 (bedaquiline and delamanid) and other drugs from D3 (para-aminosalicylic acid, imipenem-cilastatin, meropenem, amoxicillin-clavulanate, and thioacetazone) may be added to bring the total number of drugs to five. The regimen may be further strengthened with rest of group D1 (high-dose isoniazid and/or ethambutol). While streptomycin is not usually included with the second-line drugs, it can be used as the injectable drug of the core MDR/RR-TB regimen if none of the three other injectable drugs can be used and if the strain can be reliably shown not to be resistant. Thioacetazone should not be used if the patient is HIV seropositive. Intensive phase including injectables should be given for at least 8 months for most patients which can be modified depending on the response of the patient. The total duration of treatment is at least 20 months which can be prolonged up to 24 months depending upon the response of the patient. Pyrazinamide is usually continued for the entire treatment, especially if there is extensive disease. If the patient has minimal disease, pyrazinamide can be stopped with injectables at end of intensive phase. Bedaquiline or delamanid are used for 6 months in intensive phase and are presently not recommended for whole treatment duration.^7,14,15 It is important that a single drug should never be added to a failing regimen and it is ineffective to combine two drugs of the same group or to add a drug potentially ineffective because of cross resistance. No drug should be kept in reserve and the most powerful drugs should be used initially and in maximum combination so as to ensure that first battle is won and won permanently. All patients initiated on treatment and their family members should be intensively counseled prior to treatment initiation and during all follow-up visits. To reduce the risk of development of resistance to second-line ATDs and promote optimal treatment outcomes, all efforts should be made to administer treatment under direct observation (DOT) over the entire course of treatment. If DOT is not possible, attempts to ensure treatment adherence should be made by checking empty blister packs during follow-up visits every month.¹⁶ All measures should be taken to persuade and encourage patients not to stop treatment despite all its discomforts, as it is the last resort that stands between life and death. Proposed regimen for MDR/RR TB is given in ►Table 3.

WHO has recently revised the grouping of ATDs for use in MDR/RR-TB patients in 2018 into three groups (►Table 4), based on individual patient data meta-analysis of more than 13,000 patients, depending on their individual efficacy, risk of relapse, treatment failure, and death,¹⁷ and advised for preferably all oral regimens for treatment of MDR/RR-TB.^11,18,19 Drugs and their doses according to recent classification and weight bands are given in ►Table 5. Recent 2019 WHO consolidated guideline¹¹ suggested that MDR/RR-TB patients on longer regimens should have all three group-A agents and at least one group-B agent included to ensure that treatment starts with at least four ATDs likely to be effective and that at least three agents are included for the rest of 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 the regimen. Kanamycin and capreomycin are not to be included in the treatment of MDR/RR-TB patients on longer regimens. Government of India is in the process of adopting the changes based on this recent WHO guidelines and it has been proposed to use at least five drugs comprising bedaquiline (only for 6 months), levofloxacin, linezolid, clofazimine, and cycloserine in the intensive phase of treatment for 6 to 8 months and four drugs consisting of linezolid, levofloxacin, clofazamine, and cycloserine in the continuation phase of treatment for 12 months.

Authors' Contributions

R.P.: chief author and editor; H.S.: compilation of data; N.G.: data collection and editing; M.T.: data collection and tabulation; R.N.: primary framework of data.