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I would like to know MDR-TB Treatment Community opinion on the following subject. Whether new patients should be treated with 6-month standard regimen only or treatment duration can be prolonged in some situation like extensive cavitation, slow resolution and so on?
What existing guidelines tell about this?

 
Masoud Dara, MD
Replied at 3:11 PM, 29 Oct 2010

Dear Alexander,

WHO has recently commissioned a meta-analysis of available evidence before revising treatment guidelines http://whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf . After reviewing all available publications, the group of experts rated different recommendations and bottom line: New patients with pulmonary TB should receive a regimen containing 6 months of rifampicin: 2HRZE/4HR
(Strong/High grade of evidence)
Remark a: Recommendation 1.1 also applies to extrapulmonary TB except TB of the central nervous system, bone or joint for which some expert groups suggest longer therapy.

I assume you are referring to new pulmonary TB patients, strong body of evidence suggests six months treatment regimen. Existence of extensive cavity and/or delay in radiologic improvement are not indication to prolong treatment. One would expect six months of quality Rifampicin as a pretty strong bactericidal medicine along with other first line medicines would be enough to cure the drug susceptible patient and avoid relapse. In your setting with high Isoniazid mono-resistance, and in case isoniazid susceptibility testing is not done (or results are not available) before the continuation phase begins, one could consider HRE in the continuation phase and in any case, prolongation of treatment would not have an added value. It is extremely important to identify drug resistance as early as possible and treat patients accordingly.

Best regards,
Masoud

Alexander Pasechnikov
Replied at 9:33 AM, 1 Nov 2010

Dear Masoud,
thank you so much for your replay. It is clear.

You mentioned meta-analysis. I assume it is works of D.Menzies and
colleagues. Effect of duration and intermittency of rifampin on
tuberculosis treatment outcomes: a systematic review and
meta-analysis. PLoS Med. 2009 Sep;6(9):e1000146. Epub 2009 Sep 15.

But could you comment on some statements of these analysis?
For example:
• Head-to-Head Comparisons: “Rates of relapse (Table 3) were
progressively lower with longer duration of rifampin up to 8 mo or
more”
• Pooled Results across Trials: “Relapse rates were progressively
lower with longer rifampin duration, up to 8 mo or more of rifampin
(see Figure S1)”
• Meta-Regression: «Interestingly, adjusted relapse rates were lower
with regimens using rifampin for at least 8 mo than with the 6-mo
rifampin reference group”.
• Table 6. Stratified estimates of treatment failures in RCT in new
cases: the failure rate is lowest for regimens containing Rifampin
more then 8 month in comparison with shorter durations.

In discussion part of article: “The lower risk of relapse with
regimens using rifampin for at least 8 mo is consistent with subgroup
analyses of other trials [98] and a recent cohort report from Hong
Kong [99]. These have shown that patients with extensive cavitary
pulmonary disease have increased risk of relapse with 6-mo regimens.
Taken together these findings support recommendations to extend
therapy for patients at high risk of relapse".



A.Pasechnikov,
TB Advisor
Primary Health Strengthening Project, Azerbaijan
Abt Associates Inc.
14/16 Khagani str., apt. 41, 1005 Baku
Tel +994 12 498 10 08
Fax +994 12 493 83 65
Mob +99450 235 75 23

Masoud Dara, MD
Replied at 12:48 PM, 3 Nov 2010

Dear Sacha,
I contacted Dr Menzies and asked him kindly shed light on the mentioned article
through the community. We shall hear from him soon.
All the best,
Masoud

Gabit Ismailov
Replied at 4:37 PM, 4 Nov 2010

Dear Masoud,

Thank you for this kind intervention. The published reviews of Dr Menzies were indeed often quoted and referenced in our intense discussions this week when revising draft treatment protocol in Azerbaijan.

One particular point (of disagreement) was related to the choice of treatment regimen for new PTB patients with lab confirmed susceptibility to all first-line drugs. WHO recommends standard Cat 1 regimen [2HREZ/4HR(E)] with strong degree of evidence. However, the national protocol working group in Azerbaijan interpreted Dr Menzies' publications supporting Cat 2 regimen [2HREZS/HREZ/5HR(E)] for fully susceptible new cases.

It will indeed be helpful if the author could comment if such conclusion can indeed be drawn from his reviews.

Kind regards,
Gabit

Gabit Ismailov
Replied at 5:04 PM, 4 Nov 2010

Dear colleagues,

I would like to add one important point of clarification to the above posting. The issues in question relates to treatment protocol for new fully susceptible patients with radiological findings of extensive PTB (more than 1 lobe affected of PA CXR).

Regards,

Dr Gabit Ismailov
Medical Officer
WHO/Europe

Alexander Pasechnikov
Replied at 5:28 PM, 4 Nov 2010

Dear Gabit,
thank you for joining discussion.

I would like to point out a little detail you have forgotten: indeed
we propose 8 month rifampin regimen [2HREZS/HREZ/5HRE] only for new
full sensitive patients with extensive cavitary disease.

Other my question: what source/s of "strong degree of evidence" do you mean?

Sinceraly

A.Pasechnikov,
TB Advisor
Primary Health Strengthening Project, Azerbaijan
Abt Associates Inc.
14/16 Khagani str., apt. 41, 1005 Baku
Tel +994 12 498 10 08
Fax +994 12 493 83 65
Mob +99450 235 75 23

Irina Gelmanova, MD
Replied at 12:05 AM, 5 Nov 2010

There is another review regarding 6 months regimens. It actually shares D.Menzies view.

Chang KC, Leung CC, Yew WW, Chan SL, Tam CM. Dosing schedules of 6-month regimens and relapse for pulmonary tuberculosis. Am J Respir Crit Care Med. 2006 Nov 15;174(10):1153-8. Epub 2006 Aug 14. It can be accesses for free through Pubmed.

The authors reviewed the existing literature on different 6-months regimens and relapse rates (with daily medications, partly intermittent or fully intermittent)

In the discussion the authors conclude that:
"All 6-mo regimens that we have examined under our study criteria are sufficient for treating noncavitary tuberculosis with negative 2-mo sputum culture. For cavitary tuberculosis with negative 2-mo culture, we recommend 6-mo regimens comprising a daily IP [intensive phase] and thrice weekly CP [continuation phase]. In the presence of both initial cavitation and positive 2-mo culture, even the most efficacious 6-mo daily regimens may be barely adequate. Thus, from the observation that better efficacy is attainable by spreading fewer doses evenly over a longer treatment period (citations 29–31 in the article), we recommend extending the thrice-weekly CP [continuation phase] by 3 mo. This agrees with the recommended treatment for cavitary tuberculosis and strikes the best balance among treatment efficacy, drug costs, and convenience of supervision."

Irina Gelmanova
Partners in Health

Gabit Ismailov
Replied at 12:25 PM, 6 Nov 2010

Dear Alexander,

WHO recommendations are based on the quality of the evidence, values, and costs, as well as judgements about trade-offs between benefits and harm. The quality of the evidence is assessed according to the GRADE methodology (Atkins et al. 2004). For high-quality evidence further research is unlikely to change confidence in the estimate of effect.

A 6-mo R-containing regimen for all (especially fully susceptible) new PTB cases irrespective of severity of disease is a current WHO recommendation with high/strong grade of evidence (recommendation 1.1), as well as the Standard 8 of the International Standards for Tuberculosis Care. The complete evidence base behind these WHO, as well as other agencies/organization recommendations behind ISTC can be found in (World Health Organization. Stop TB Dept. 2010) and (Tuberculosis Coalition for Technical Assistance. and World Health Organization. 2006)

Kind regards,
Gabit

Atkins, D., D. Best, P. A. Briss, M. Eccles, Y. Falck-Ytter, S. Flottorp, G. H. Guyatt, R. T. Harbour, M. C. Haugh, D. Henry, S. Hill, R. Jaeschke, G. Leng, A. Liberati, N. Magrini, J. Mason, P. Middleton, J. Mrukowicz, D. O'Connell, A. D. Oxman, B. Phillips, H. J. Schunemann, T. T. Edejer, H. Varonen, G. E. Vist, J. W. Williams, Jr. & S. Zaza (2004) Grading quality of evidence and strength of recommendations. BMJ, 328, 1490.

Tuberculosis Coalition for Technical Assistance. & World Health Organization. 2006. International standards for tuberculosis care : diagnosis, treatment, public health. [The Hague]: Tuberculosis Coalition for Technical Assistance.

World Health Organization. Stop TB Dept. 2010. Treatment of tuberculosis: guidelines. Geneva: World Health Organization.


--
Dr Gabit Ismailov
Medical Officer
Tuberculosis Control Programme
WHO/Europe

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