10.3 Building a treatment regimen for MDR-TB

Adapted from Drug-resistant tuberculosis: a survival guide for clinicians. San Francisco, Francis J. Curry National Tuberculosis Center and California Department of Health Services, 2004.


Individual regimens are designed based on DST of the infecting strain, history of TB treatment, and contact history. Figure 10.1 describes the steps to build a regimen for MDR-TB treatment.

Figure 10.1 - Building a regimen for MDR-TB


Box 10.1 - Examples of how to initiate and design MDR-TB regimens

Example 1 - patient doing poorly on first-line treatment

A patient receiving first-line treatment for new patients (2 HRZE/4 HR) continues to be smear positive at Month 3 with symptoms including weight loss, fever, shortness of breath and cough. The patient feels the shortness of breath is getting severe and he spends more than 50% of the day in bed. No DST was performed at the start of treatment. Xpert MTB/RIF performed at Month 3 shows MTB+ and rifampicin resistance. What should be done?

Answer: A positive Xpert MTB/RIF at Month 3 in a patient doing poorly on a first-line regimen that shows R resistance is highly likely to be a true positive. This patient should be placed on MDR-TB therapy. A confirmatory DST with conventional methods to at least H and R and if possible to injectable agents and fluoroquinolones should be performed.

If a rapid molecular test was not available, this patient should be placed on an MDR-TB regimen while waiting conventional DST results.
• If there is low second-line drug resistance in patient’s strains with MDR-TB in the area then a common regimen is: Km-Lfx-Eto (or Pto)-Cs-ZE.
• If there is moderate to high second-line drug resistance in MDR-TB strains in the area or if the level of resistance to second-line drugs is not known: Cm-Mfx-Eto (or Pto)-Cs-PASZE. Once DST becomes available the regimen can be adjusted. In this case, the infecting strain was determined to be resistant to H-R-S and susceptible to Km-Cm-Ofx-E; resistance to Z was unknown. Given the DST results, it is recommended to continue with Km-Lfx-Eto (or Pto)-Cs-ZE and drop the PAS if it was used in the initial regimen.


Example 2 - Xpert RIF positive in a patient with low probability of MDR-TB

A HIV-negative smear-negative TB suspect is referred to Xpert MTB/RIF to establish the diagnosis of TB. The result of the Xpert is MTB+ and rifampicin resistance. The patient has never been diagnosed with TB. The MDR-TB prevalence for new patients in the area is 1%. The patient only complains of a mild cough for 3 weeks and X-ray shows minimal lesions. What should be done?

Answer: The RIF resistance positive predictive value (PPV) for the Xpert MTB/RIF in the setting of 1% rifampicin resistance prevalence is 32% (Appendix 3). Because of the relatively low PPV of the Xpert MTB/RIF under these circumstances and the fact that patient is HIV-negative and not seriously ill, he can be placed on a first-line drug regimen while waiting confirmation DST. If possible, DST confirmation should be done through a rapid phenotypic method or using LPA on culture (indirect method). If the patient deteriorates clinically at any time while waiting confirmation DST, an empirical MDR-TB regimen should be started. When the DST returns, the regimen should be adjusted if the resistance to rifampicin is confirmed.


Note:
An alternative shorter 9 month standard regimen (4 Km-Gfx-Pto-Cfz-high dose H-ZE/5 Gfx- Cfz-ZE)1  has shown good effectiveness in a study in Bangladesh23. Adaptations are made in some countries in Western Africa24 with moxifloxacin replacing gatifloxacin and extension of the regimen to 12 months. At present, this regimen is still considered experimental25.
Given the limited evidence supporting this regimen these guidelines recommend the following:
– Obtain country-level and institutional ethical approval before implementation.
– Implement it under operational research conditions following good practices.
– Consider this regimen on a case-by-case basis for programmes with proper follow-up and outcome documentation in unstable settings where a 2 year-treatment is not an option.
– Perform DST to the fluoroquinolones in a liquid medium and do not use in any patient with documented fluoroquinolone resistance (the third-generation fluoroquinolones are the backbone of the regimen and the regimen does not perform well against strains resistant to fluoroquinolones).
– Use only in HIV-negative patients until more information is published on the regimen and its use in HIV-positive patients.
– Do not use in areas with a high prevalence of resistance to second-line anti-TB drugs until more information is published.



Footnotes
Ref Notes
1

The recommended dosing in the 9-month regimen is described in: Aït-Khaled N, Alarcón E, Armengol R, Bissell K, Boillot F, Caminero J A, Chiang C-Y, Clevenbergh P, Dlodlo R, Enarson D A, Enarson P, Fujiwara P I, Harries A D, Heldal E, Hinderaker S G, Lienhardt C, Monedero I, Rieder H L, Rusen I D, Trébucq A, Van Deun A, Wilson N. Management of tuberculosis: a guide to the essentials of good practice. Paris, France: International Union Against Tuberculosis and Lung Disease, 2010.