OVERVIEW OF REVISED WHO GUIDELINES

FOR PROGRAMMATIC MANAGEMENT OF

DRUG RESISTANT TUBERCULOSIS

Wilfred Nkhoma, Regional DR-TB Medical Officer

WHO Office for the African Region

Presentation for meeting on Country TA Planning

Harare, 30 November 2011

HAND IN HAND ... COMPLEMENTARY

DOCUMENTS

TAKE HOME MESSAGE

The 2008 Emergency update and the 2011

Revised PMDT Guidelines are complementary.

The 2011 Revision responds or updates some

sections in the 2008 version ..... Thus they are

to be used as complementary documents

THE ROAD TO THE 2011 VERSION OF

THE PMDT GUIDELINES

Early 2009 : Evaluation of old guidelines Mid-2009 : Scoping Late 2009 - Early 2010 : Evidence reviews October 2010 : Guideline Development Group Meeting December 2010 : first draft of Guideline February 2011 : GRC approval June 2011 : release of 2011 update of Guidelines September 2011 : publication in European Respiratory

Journal September 2011 : Evaluation starts

SOME PRIORITY QUESTIONS ADDRESSED

IN THE 2011 UPDATE OF THE PMDT

GUIDELINES

1) Prevalence of MDR-TB in any risk group of TB patients at which level rapid drug susceptibility testing to detect resistance to rifampicin and Isoniazid or rifampicin alone on all patients in the group at the time of TB diagnosis, is warranted in order to prescribe appropriate treatment at the outset

2) Whether or not there is a place for monitoring treatment using sputum smear microscopy alone rather than sputum smear and culture among patients with MDR-TB receiving appropriate treatment in settings with reliable direct microscopy 3) Whether inclusion of specific drugs (with or without documented susceptibility) in designing regimens for patients with MDR-TB is associated with treatment success or any other treatment outcomes

4) Whether inclusion of fewer drugs in the MDR-TB regimen (depending on the drug used, the patient’s history of its use and isolate susceptibility) is more or less likely to lead to treatment success (and other outcomes)

5) Whether shorter M/XDR-TB treatment regimens, than those currently recommended by WHO, are more or less likely to lead to treatment success (or other treatment outcomes)

6) Whether in patients with HIV infection and drug-resistant TB receiving antiretroviral therapy, the use of drugs with overlapping and potentially additive toxicities, compared with their avoidance, are more or less likely to lead to treatment success (or other treatment outcomes) 7) Whether among patients with MDR-TB, ambulatory or inpatient treatment is more or less likely to lead to treatment success (or other treatment outcomes)

Some priority questions addressed in

the 2011 update of the PMDT Guidelines

EVIDENCE REVIEWS

Teams based in leading academic centres assessed existent evidence for the questions using : 1. - Systematic reviews of literature (as per Cochrane Handbook) 1.- Meta-analysis of individual patient data 2.- Simulations using modelling 3.- Cost-effectiveness analysis

Assessing the quality of

evidence

Definition Quality

Further research is very unlikely to change our confidence in the estimate of effect.

High

Further research is likely to have an important impact on our confidence in the effect and may change the estimate.

Moderate

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Low

Any estimate of effect is very uncertain. Very low

Guyatt GH et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008 Apr 26;336(7650):924-6

IMPLICATIONS OF THE STRENGTH OF A

RECOMMENDATION FOR DIFFERENT USERS

Adapted from Guyatt GH et al. GRADE Working Group. Going from evidence to recommendations. BMJ, 2008, 336(7652):1049–1051

RECOMMENDATION 1: RAPID DST

Rapid drug susceptibility testing (DST) of Isoniazid and

Rifampicin or of Rifampicin alone is recommended over

conventional testing or no testing at the time of diagnosis

of TB, subject to available resources (conditional

recommendation / very low quality evidence)

Evidence : simulations from modeling work

•Rapid DST of INH & RIF at the time of diagnosis was the most cost

effective testing strategy for any patient group or setting, even at very low

levels of resistance among TB patients (MDR-TB in >1% and Isoniazid

resistance (other than MDR-TB) in >2%).

•Rifampicin resistance detected by Xpert MTB/RIF in patient groups in

whom MDR is rare has low predictive value and results need to be

confirmed by phenotypic DST or line probe assay.

RECOMMENDATION 2: SPUTUM SMEAR &

CULTURE

The use of sputum smear microscopy and culture rather

than sputum smear microscopy alone is recommended for

the monitoring of patients with MDR-TB during treatment

(conditional recommendation / very low quality evidence)

Evidence : individual patient data and simulations from modeling

•Monthly sputum smear microscopy and culture was the best strategy in

identifying failures earlier. Sputum smear microscopy alone resulted in

delayed detection of failure.

•Sputum smear microscopy results are of use to clinicians in identifying

patients likely to fail their treatment and instituting infection control

measures in a timely manner. Resource implications are important.

3) In the treatment of patients with MDR-TB, a fluoroquinolone should be used (strong recommendation / very low quality evidence).

4) In the treatment of patients with MDR-TB, a later-generation fluoroquinolone rather than an earlier-generation fluoroquinolone should be used (conditional recommendation / very low quality evidence)

5) In the treatment of patients with MDR-TB, ethionamide (or prothionamide) should be used (strong recommendation / very low quality evidence).

RECOMMENDATIONS 3 TO 5:

TREATMENT REGIMENS (1)

6) In the treatment of patients with MDR-TB, four second-line anti-tuberculosis drugs likely to be effective (including a parenteral agent), as well as Pyrazinamide, should be included in the intensive phase (conditional recommendation / very low quality evidence).

7) In the treatment of patients with MDR-TB, regimens should include at least Pyrazinamide, a fluoroquinolone, a parenteral agent, ethionamide (or prothionamide), and either Cycloserine or PAS (para-aminosalicylic acid) if Cycloserine cannot be used (conditional recommendation / very low quality evidence).

RECOMMENDATIONS 6 AND 7: TREATMENT

REGIMENS (2)

TREATMENT REGIMENS (3): GROUPS

OF SECOND-LINE DRUGS

Evidence: meta-analysis of >9000 individual MDR-TB patient data from 32 published observational studies, none being randomised controlled trials (RCTs) Bias may be due to use of certain drugs for sicker patients, incomplete ascertainment of relapse, the under-representation of certain geographical regions, and missing data for some of the variables examined. Adjustments were made to try to counter these limitations but findings from this analysis may not necessarily be generalizeable to all MDR-TB cases. XDR-TB patients were excluded. There was clear benefit of fluoroquinolones, particularly later-generation drugs. Among the oral bacteriostatic drugs, the association with cure was higher with ethionamide than with Cycloserine, which was higher than with PAS. No particular parenteral agent was considered superior. No effect for Group 5 drugs or Ethambutol.

Treatment Regimens (4): Notes on

recommendations 3 to 7

Changes in recommendations on regimen composition

between the 2008 and 2011 updates of the guidelines

8) In the treatment of patients with MDR-TB, an intensive phase of at least 8 months’ duration is recommended (conditional recommendation / very low quality evidence). 9) In the treatment of patients with MDR-TB, a total treatment duration of at least 20 months is recommended in patients without any previous MDR-TB treatment (conditional recommendation / very low quality evidence).

RECOMMENDATIONS 8 AND 9: DURATION

OF TREATMENT (1)

ABOUT RECOMMENDATIONS 8 AND 9:

DURATION OF TREATMENT (2)

Evidence: same individual patient data meta-analysis as was used for treatment regimen composition questions (recommendations 3 to 7) Recommendation is not “pegged” to sputum conversion. Previous recommendations (2008) were to use a parenteral agent for a minimum of 6 months and at least 4 months past culture conversion, and a minimum total length of treatment of 18 months after culture conversion. Most patients may be expected to receive this length of treatment but in some it may have to be modified depending on their bacteriological status and other indicators of treatment progress

Duration of treatment (3):Odds of success by duration of treatment

Antiretroviral therapy is recommended for all patients with HIV and drug-resistant TB requiring second-line anti-tuberculosis drugs, irrespective of CD4 cell-count, as early as possible (within the first 8 weeks) following initiation of anti-tuberculosis treatment (strong recommendation / very low quality evidence).

RECOMMENDATION 10: TB/HIV

Evidence: from 10 observational studies of treatment outcomes when antiretroviral therapy (ART) and second-line anti-tuberculosis drugs were used together. •Available data did not allow assessment for a number of outcomes of interest, namely avoiding the additional acquisition of drug resistance, preventing TB transmission, sustaining relapse-free cure, establishing the optimal duration of MDR-TB treatment, avoiding unnecessary MDR-TB treatment, and reducing cost and improving population access to appropriate care. •The strength of the recommendation is based in part on indirect evidence from its use in any patient with active TB, which shows large beneficial effects and a very high mortality when ART is not employed, particularly in very immunocompromised patients (CD4 cell-count <50 cells/mm3)

Patients with MDR-TB should be treated using mainly

ambulatory care rather than models of care based principally on

hospitalization (conditional recommendation / very low quality

evidence

RECOMMENDATION 11: MODELS OF CARE

Evidence : cost-effectiveness modelled for all possible countries using a probabilistic

analysis of real data from four countries (Estonia, Peru, Philippines, Russian Fed

[Tomsk]). None were from RCTs.

The benefit of reduced transmission can only be expected if proper infection control

measures are in place in both the home and the clinic. Admission to hospitals for

patients who do not warrant it may also have important social and psychological

consequences which need to be taken into account. There may be important barriers

to accessing clinic-based ambulatory care, including distance to travel and other

costs to individual patients. Shifting costs from the service provider to the patient

has to be avoided, and implementation may need to be accompanied by appropriate

enablers.

GUIDELINE IS A LIVING DOCUMENT:

GAPS IN KNOWLEDGE CALLING FOR FURTHER

RESEARCH

Occasioned by lack of moderate or high quality evidence from randomized controlled trials for optimizing treatment regimens in patients with MDR-TB, including:

i. the best combination of drugs and treatment duration; ii. optimal drug regimens for treating patients with Isoniazid

resistance iii. optimal drug regimens for treating patients with XDR-TB iv. optimal drug regimens for treating patients with non-

MDRTB poly-resistance v. Very limited information about treatment of paediatric

MDR-TB; vi. most effective chemoprophylaxis for contacts of MDR-TB

cases; vii. Therapy for symptomatic relief of adverse reactions linked

to second-line anti-tuberculosis drugs.

IMPORTANT REMINDER ... THE TWO WORK

HAND IN HAND ...

ACKNOWLEDGEMENTS

Denis Falzon, Stop TB Department, WHO Geneva ... For compiling the summary of changes WHO/HQ Léopold Blanc, Chris Duncombe, Dennis Falzon, Christopher Fitzpatrick, Katherine Floyd, Haileyesus Getahun Malgorzata Grzemska, Christian Gunneberg, Ernesto Jaramillo, Christian Lienhardt, Fuad Mirzayev, Paul Nunn, Mario C. Raviglione, Delphine Sculier, Marco Antonio de Avila Vitoria, Fraser Wares, Karin Weyer, Matteo Zignol

Guideline Development Group Jaime Bayona, José A. Caminero, Charles L. Daley, Agnes Gebhard, Myriam Henkens, Timothy H. Holtz, Joël Keravec, Salmaan Keshavjee, Aamir J. Khan, Vaira Leimane, Andrey Mariandyshev, Carole D. Mitnick, Gloria Nwagboniwe, Domingo Palmero, Ma. Imelda Quelapio, Michael L. Rich, Sarah Royce, Sabine Rüsch-Gerdes, Archil Salakaia, Rohit Sarin, Holger Schünemann, Elena Skachkova, Francis Varaine External Review Group Samiha Baghdadi, Mercedes Becerra, Vineet Bhatia, Masoud Dara, Mirtha del Granado, Reuben Granich, Lindiwe Mvusi, Nani Nair, Norbert Ndjeka, Wilfred A.C Nkhoma, Katsunori Osuga, Hendrik Simon Schaaf, Catharina van Weezenbeek, Irina Vasilyeva, Wang Xie Xiu, Richard Zaleskis Evidence review teams Harvard University, US - Chunling Lu, Carole D. Mitnick, Richard A. White McGill University, Canada - Melissa Bauer, Richard (Dick) Menzies, Olivia Oxlade University of California (San Francisco), US - Gail Kennedy, George Rutherford, Karen Steingart University of Washington, US - Matthew Arentz, David Horne, Patricia Pavlinac, Judd L. Walson Consultant Patricia Whyte

IMMEDIATE NEXT STEP: RELEASE OF A

COMPANION MANUAL

It is planned to have a manual to assist in the implementation of the principles contained in the revised Guidelines ... an update of the

WHO / PIH Field Guide below.

THANK YOU

MERCI

OBRIGADO

....COMMENTS, QUESTIONS..???