Introduction of Shorter MDR-TB treatment regimen

Clinical description

WHO issued new recommendations designed to speed up the detection and improve treatment of DR-TB.

Malawi adopted the new WHO recommended shorter DR-TB treatment regimen and the implementation is expected to start from early 2018.

Patients eligible for the shorter DR-TB Treatment Regimen

• Patients with DR-TB who have not been previously treated with SLD and with low risk

or with DST results excluding resistance to FQ and/or SLI.

• Children, HIV infected patients, patients with EPTB with clinically diagnosed TB who

have not been previously treated with SLD and with low risk of resistance to FQ and/ or SLI who have been in close contact with patients with DR- TB.

Figure 10.4-1 Algorithm for testing second line drug resistance among rifampicin –resistant TB or MDR TB patients Patients may be initiated on the shorter MDR-TB regiment if the patient is assessed as being at low risk of having resistance to FQs and to SLIDs and meets the eligibly requirement. In patients at high risk of resistance or in setting with high underlying prevalence of resistance to FQs OR SLIDs, selection or design of the treatment regimen in initiation may be guided by SL-LPA if the results can be obtained rapidly. See WHO guideline for the programmatic management of drug-resistant tuberculosis. 2016 publication.

National Tuberculosis Control Programme 81 Diagnostic accuracy is similar when SL-LPA is performed directly on sputum or from cultured isolates. SL-LPA can be used on smear positive or smear negative specimens although a higher indeterminate rate will occur when testing smear negative specimens.

Patients not eligible for the shorter DR-TB treatment regimen

• Patients with confirmed resistance to FQ or SLI by either SL-LPA or phenotypic

DST

• Patients with suspected resistance to FQ or SLI based on contact with patient with

this resistance pattern or other risk factor

• Patients with exposure to SLD for >1 months (E.g. Patients already on treatment

with a conventional DR-TB treatment regimen for more than a month or patients with history of previous DR-TB treatment)

• Patients with intolerance to any of the medicines in the shorter treatment regimen
• Pregnant women
• Patients with extra-pulmonary TB, however, patients with TB pleural effusion

and children with TB lymphadenitis may be considered for the shorter treatment regimen

• Patients with high risk of treatment failure, such as severe TB disease (e.g. multiple

cavities, extensive parenchymal damage)

NB: Presence of any of the above, disqualifies a DR-TB patient from shorter treatment regimen.

Regimen design for the shorter DR-TB treatment regimen The Shorter treatment regimen is given as a standardised regimen with little or no room for customisation with substitutions or switches during treatment.

• The intensive phase consists of Cm19, high dose Mfx20, Cfz, Eto21, Z, E and HHD daily

for four months.

• If the smear conversion is not achieved at month 4, the intensive phase shall be

extended for two more months to a maximum total duration of six months, until smear conversion (and ideally one culture negative result). Then Km (Am or Cm) will be given thrice-weekly (on alternate days), from the fourth month onwards (5th and 6th months).

• If the patient remains smear and /or culture positive at 6 months, will be declared

as a treatment failure and switched to an individualized regimen.

• The criteria to shift to continuation phase is based on smear conversion. Ideally it

would be important to have at least one culture result negative. All attempts should be made to send monthly samples for culture and trace results. It is also important to have SL LPA, culture and SL phenotypic DST results available to exclude resistance to FQ and SLI (though SL LPA test when performed in smear negative samples can have uninterpretable results).

19 Am and Cm are acceptable alternatives 20 . In children <14 Kg Levofloxacin is an acceptable alternative (due to bad palatability of Moxifloxacin)

21 Pto is an acceptable alternative 82 National Tuberculosis Control Programme

• The continuation phase consists of high dose Mfx, Cfz, E and Z for a fixed duration

of five months.

• Moxifloxacin can be replaced with Gatifloxacin however since there is no quality-

assured brand of Gatifloxacin currently available, Moxifloxacin is not to be replaced by levofloxacin

• Ethionamide can be used instead of Prothionamide

Shorter Regimen 4-6 Cm-Mfx-Cfz-Eto-Z-E- Hh / 5 Mfx-Cfz-E-Z Add vitamin B6 100 mg Criteria to change from STR to conventional / individualized regimen

• Lack of response to treatment (e.g. no smear and/or culture conversion by 6 months

or deterioration of clinical condition despite treatment)

• Culture reversion in the continuation phase after conversion to negative
• Evidence of resistance to a FQ or a SLI
• Adverse drug reaction requiring discontinuation of >1 key drug
• Confirmed susceptibility or presumed effectiveness to all medicines in the shorter MDR-TB

regimen (isoniazid resistance excepted)

• No exposure to second-line medicines in the shorter MDR-TB regimen for >1 month
• No intolerance to any medicine in the shorter MDR-TB regimen and no risk of toxicity (e.g.

drug-drug interactions)

• Pregnancy excluded
• Only pulmonary disease
• All medicines of the shorter MDR-TB regimen available to the program

YES NO Individualized Shorter DR-TB /standardized DR-TB FAILING REGIMEN, DRUG INTOLERANCE, regimen regimens RETURN AFTER INTERRUPTION >2 MONTHS, EMERGENCE OF AN EXCLUSION CRITERION National Tuberculosis Control Programme 83 Additional tests and equipment required

• ECG monitoring: Cfz and Mfx that might lead to QTc prolongation.
• Other clinical test: audiometry, CXR, complete blood count, serum creatinine, serum

potassium, blood glucose, thyroid tests, liver function test, pregnancy test and visual acuity tests.

• Medicines are taken once per day, all days of the week. If the intensive phase is

prolonged the injectable agent is only given three times a week after the fourth month.

• All MDR-TB patients are to be tested for resistance to fluoroquinolones and second-

line injectable agents before starting any MDR-TB treatment.

• The shorter MDR-TB regimen can be used for children younger than 14years and in

people living with HIV, including those who are receiving antiretroviral treatment Treatment monitoring and the need for modif ication Criteria to change from shorter regimen to an individualized regimen Switching from the shorter DR-TB regimen to a longer regimen All the care needs to be taken to select the right patients to receive the shorter MDR-TB regimen.

However, fresh information or developments while the patient is on treatment may require that the shorter MDR-TB regimen is stopped and a longer, individualized DR-TB regimen or other treatment is started. This is most likely to happen in the following condition:

 DST results show resistance to medicines in the shorter MDR-TB regimen:

 Lack of response to treatment (e.g. no sputum smear conversion by 6 months or deterioration of clinical condition despite treatment);

 Patient is treated for more than one month, interrupts treatment and returns after an interval >2 months (i.e. fulfils another exclusion criterion);

 Emergence of another exclusion criterion (e.g. extrapulmonary disease, pregnancy, intolerance to a medicine in the regimen).

Monitoring of patient on the shorter MDR-TB regimen  The treatment outcome definitions and reporting framework are the same as those for longer DR-TB regimens.

 Response to treatment is monitored based on monthly sputum smear microscopy, as well as culture ideally at the same frequency.

 Active TB drug safety monitoring and management (aDSM) with scheduled of patient monitoring is thus recommended for the whole duration of treatment.

 The most frequent drug-toxicities reported in patients on the shorter MDR-TB regimen are hearing impairment linked to the injectable agents and gastro-intestinal disturbances related to Prothionamide.

84 National Tuberculosis Control Programme  Concomitant use of clofazimine and moxifloxacin - both of which prolong the QT interval –There is no need to change the Second-line TB treatment register or the Annual treatment outcomes report for RR-TB/MDR-TB when monitoring patients on the shorter MDR-TB regimen.

 The definitions of “Cured” and “Treatment Failed” can be equally applied to shorter MDR TB regimen