Revising the WHO TB Treatment Guidelines Process and new recommendations Malgosia Grzemska Matteo Zignol Stop TB Department World Health Organization DEWG meeting, October

Outline Rationale for revision New WHO methods for guidelines development Overview of the 7 questions New recommendations and supporting evidence Focus on: Previously treated patients Research needs 2

4 Need for revision of Treatment Guidelines to implement Stop TB Strategy Universal access to quality TB care Current treatment categories assign lower priority to smear negative patients, and MDR Programmatic management of MDR (within NTPs) 7 of 22 high TB burden countries have > 1 lab performing culture per 5 million population < 5% of the world’s 500,000 MDR cases notified Green Light Committee covers <5% of world’s MDR Treatment of HIV associated TB

5 WHO guidelines are insufficiently transparent and not evidence based Lack of use of systematic reviews Lack of transparency about judgements Too much dependence on expert opinion Insufficient resources Oxman, Lavis & Fretheim, Lancet. 2007; 369

New WHO requirements Define scope and target audience Formulate precise questions and critical outcomes Retrieve and synthesize all available evidence Summarize evidence using standard template Assess of quality of evidence (GRADE) Consider resource use, patient values and preferences Link evidence to recommendations, explaining reasons for judgements Source: WHO Handbook for guideline development, March

6 Questions for revision Question 1. Duration of rifampicin for treatment of new patients? 2HRZE/6HE vs. 2HRZE/4RH Question 2. Dosing frequency? Daily throughout Daily intensive/3x weekly 3 times weekly throughout Question 3. High levels of isoniazid resistance Adding a drug in continuation phase to "protect rifampicin"

7 Questions for revision (2) Question 4. TB treatment in presence of HIV? Length of treatment and dosing frequency Question 5. Sputum monitoring (at 2 months and later)? Sputum monitoring for predicting relapse, failure and pre-treatment isoniazid resistance? Question 6. TB treatment extension? Extension of the intensive phase or the continuation phase for reducing failure or relapse Question 7. Previously treated cases Which groups of patients should receive a retreatment regimen with first line drugs?

Overview of methods Systematic literature review for each question Evidence synthesized and presented to the Guideline Group GRADE methodology used for evaluating quality of evidence Recommendations based on: –quality of the evidence, –values, and costs, –feasibility of implementation at country level –judgments about trade offs between benefits and harms.

Guideline Group – meeting on recommendations, Paris October 2008

Question 1. Should new pulmonary TB patients be treated with the 6 months or the 2 months rifampicin regimen? Recommendations New patients should receive a regimen containing 6 months of RIF: 2HRZE / 4HR. The treatment regimen with 2 months RIF: 2HRZE/6HE should be phased out. Supporting evidence Shorter RIF significantly associated with higher Relapse 2RIF somewhat associated with higher Failure If Drug resistance – absolute difference between 2RIF and 6RIF even greater

Question 2. When a country selects 2HRZE/4HR, should patients be treated with a daily or 3 times weekly intensive phase? Recommendations Where feasible, the optimal dosing frequency for new patients is TB is daily throughout the course of therapy New patients may receive a daily intensive phase followed by three times weekly continuation phase Three times weekly dosing throughout therapy [2(HRZE)3 / 4(HR)3] is another alternative as long as: –patient is receiving directly observed therapy of every dose, and –patient NOT living with HIV or living in an HIV- prevalent setting. New patients with TB should not receive twice weekly dosing for the full course of treatment

Question 2. When a country selects 2HRZE/4HR, should patients be treated with a daily or 3 times weekly intensive phase? Supporting evidence –No significant increase in failure, relapse, or acquired drug resistance in pan-susceptible patients - when comparing daily dosing throughout therapy with the intermittent regimens –Patients receiving three times weekly dosing throughout therapy had 3.3 times higher rates of acquired drug resistance than patients who received daily treatment –For patients with INH resistance, three times weekly intensive phase - significantly higher risk of failure and acquired drug resistance –Insufficient data to support the use of regimens that are given two times weekly throughout therapy. On operational grounds, missing one dose means the patient receives only half the regimen

Question 3. What should be the continuation phase in countries with high levels of isoniazid resistance Recommendations In populations with known (or suspected) high levels of INH resistance, new TB patients may receive HRE - in the continuation phase Supporting evidence –Inadequate evidence to quantify the ability of ethambutol to “protect rifampicin” –Expert opinion based

Question 4. Should intermittent regimens be used for persons living with HIV? What should be the duration of TB treatment in people living with HIV? Recommendations TB patients living with HIV and TB patients living in HIV prevalent settings should receive daily TB treatment (at least during the intensive phase) For the continuation phase, the optimal dosing frequency is also daily for these patients If a daily continuation phase not possible, three times weekly dosing during the continuation phase acceptable TB patients living with HIV receive the same duration of TB treatment as HIV-negative TB patients

Question 4. Should intermittent regimens be used for persons living with HIV? What should be the duration of TB treatment in people living with HIV? Supporting evidence Double rate of failure and relapse if intermittent regimen administered throughout No change in failure, relapse and death if regimen prolonged to 9 months Use of ARV significantly reduces failure, relapse and death

Question 5. How effective is sputum monitoring for predicting relapse, failure and pre-treatment INH resistance? Recommendations For smear positive pulmonary TB patients, sputum smear microscopy may be performed at completion of the intensive phase (end 2 months) If at end of 2 months smear positive – repeat smear microscopy at the end of 3 months If at end of 3 months smear positive – send for culture and DST

Question 5. How effective is sputum monitoring for predicting relapse, failure and pre-treatment INH resistance? Supporting evidence Sputum smear at month 2 or 3 of treatment has limited utility in predicting relapse Quality of evidence in most studies that assessed failure - very low Main rationale for recommending the addition of a 3 month sputum smear - detect poor response to therapy (due to DR or MDR) earlier than 5 month

Question 6. In new patients, how effective is t reatment extension for preventing failure or relapse? Recommendations In patients treated with the regimen containing Rifampicin for 6 months, if a positive sputum smear is found at completion of the intensive phase, the extension of the intensive phase is not recommended

Question 6. In new patients, how effective is t reatment extension for preventing failure or relapse? Supporting evidence Preliminary results from 1 moderate quality study shows only modest benefit in decreasing risk of relapse Historically, when the new patient regimen included only 2 months of RIF, the extension of the intensive phase meant an extra month of RIF. This extra month is less important now, when the recommended regimen is 6 month of rifampicin.

20 Question 7. Previously treated cases Which (if any) groups of patients should receive a retreatment regimen with first line drugs? –What is the best regimen for previously treated patients, so that if they have MDR, they receive effective treatment?

21 Question 7. Previously treated cases Recommendations All previously treated TB patients should have culture and DST done before or at the start of treatment. In settings where rapid DST is available, the results should guide the choice of regimen

22 Question 7. Previously treated cases Recommendations In settings where rapid DST results are not routinely available, empiric treatment should be started as follows: –TB patients whose treatment has failed or other patient groups with high likelihood of MDR-TB should be started on an empiric MDR regimen. –TB patients returning after defaulting or relapsing from their first treatment may receive the retreatment regimen containing first line drugs 2HRZES / 1HRZE / 5HRE –As soon as DST results known – regimens should be adjusted –NTPs should obtain and use their country-specific drug resistance data of failure, relapse and default patient groups to determine the levels of MDR.

23 Question 7. Previously treated cases Supporting evidence Studies using WHO standard retreatment (2SHRZE/1HRZE/5HRE) –RCT in Retreatment – None –RCT in New cases – None –Cohorts in Retreatment – 12 arms with 1,410 patients D. Menzies, TDG meeting, Paris October 2008

Question 7. Previously treated cases Supporting evidence A few Cohort studies have been reported: –Largest groups were pan-sensitive –In INH resistant – Varying, but poor results –In Mixed (most like programme conditions) Highly variable results, but mostly POOR Perhaps reflecting underlying drug resistance –No data in Strep resistant, or Poly-drug resistance (other than MDR) D. Menzies, TDG meeting, Paris October 2008

* Sub-national coverage in India, China, Russia, Indonesia. The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.  WHO All rights reserved MDR-TB among previously treated TB cases, (IV Global DRS Report)

MDR in retreatment TB cases from drug resistance surveys and surveillance in 10 countries,

“Retreatment” Treatment success (cure + complete) for patients: Who have relapsed 74% (54% - 87%) Returning from default65% (36% - 74%) Smear + after 5 th month (fail) 58% (27% - 69%) Source: WHO, Global TB Control, 2009 Report 28

Research needs (proposed by Guideline Group) In new smear-positive pulmonary TB patients who have failed first line TB treatment, does an empirical MDR-TB regimen compared with the standard WHO retreatment regimen with first line drugs increase treatment success rate and reduce failure at the end of this second course of TB treatment? What is the level of MDR in subgroups of previously treated patients: failed first vs. subsequent course of therapy, returned after defaulting, relapsed?