1. Delphine Sculier, MD,MPH Stop TB Department World Health Organisation Geneva, Switzerland Update on the revision of ART guidelines for TB patients

2. Outline of presentation Critical ART issues that were reviewed Process of drafting recommendations Main changes from 2006 to 2010 Recommendations for HIV-infected TB patients Conclusions

3. WHO ART treatment guidelines –the critical issues being reviewed How to diagnose earlier? How to monitor? When to Start? What to Use 1 st Line? What to use- 2 nd Line? Critical patient & public health important outcomes: Mortality Disease progression (morbidity) Severe or regimen limiting adverse events Adherence & retention on ART Durability of regimen effect Reduction of HIV transmission Cost Third line ?

4. Drafting Recommendations and Risk Benefit Analysis Systematic reviews and GRADE profiles Impact assessment reports PLWH consultation reports Costing and feasibility analysis DRAFT RECOMMENDATIONS VALIDATION BY REVIEW GROUPS FINAL RECOMMENDATIONS

5. ART guidelines Changes from 2006 to 2010

6. WHO 2006Proposed WHO 2010 Criteria for ART initiation All stages 4, irrespective of CD4 count Stages 3 and CD4<350 Stages 1 & 2 and CD4<200 All stages 3 & 4, irrespective of CD4 count Stages 1 & 2 and CD4 <350 Preferred first line regimens AZT or D4T + 3TC + NVP or EFV or TDF or ABC + 3TC/FTC + NVP or EFV Triple NRTI regimen Adults: AZT+3TC+NVP or TDF+3TC/FTC+EFV Adolescents: AZT+3TC+NVP or AZT+3TC+EFV Pregnant women: AZT+3TC+NVP or AZT+3TC+EFV (2 nd trim. onwards) 1st line.ppt Preferred second line regimens ddI or TDF + ABC or 3TC (+/-AZT) + boosted PI (+NVP or EFV if NNRTI sparing regimen) Depending on first line regimen 2nd line.ppt Preferred boosted PI : LPV/r and ATV/r

7. Laboratory monitoring Phase of HIV management RecommendedDesirable At HIV diagnosisCD4 HBsAg, ?HCV test Pre ART CD4 (6 monthly) Viral Load At start of ARTCD4 - Hb for AZT - Renal screen for TDF On ARTCD4Viral load At clinical failureCD4Viral load At immunological failure Viral load WHO 2006Proposed WHO 2010

8. Recommendations for HIV infected TB patients When to start? What to start?

9. Grade review: When to start ART in HIV-infected TB patients? SAPiT: Optimal Time to Initiate ART in HIV/TB- Coinfected Patients HIV-infected patients diagnosed with TB and CD4+ cell count < 500 cells/mm 3 (N = 642) Early ART ART initiated during intensive or continuation phase of TB therapy (n = 429) Sequential ART ART initiated after TB therapy completed (n = 213) Primary endpoint: all-cause mortality From Larry William Chang, MD, MPH, Johns Hopkins School of Medicine, Cochrane Collaborative Group on HIV/AIDS at UCSF

10. Abdool Karim SS, et al. CROI 2009. Abstract 36a. 0.70 0.75 0.80 0.85 0.90 0.95 1.00 Survival Months Post-randomization 0123456789101112131415161718192021222324 Intensive phase of TB treatment Post-TB treatment Continuation phase of TB treatment Early ART Sequential ART SAPiT: Increased survival with concurrent HIV and TB treatment

11. GRADE Table From Larry William Chang, MD, MPH, Johns Hopkins School of Medicine, Cochrane Collaborative Group on HIV/AIDS at UCSF

12. Grade review: What to start in HIV-infected TB patients? EFV vs. NVP in patients taking rifampicin Randomised controlled trials –N2R (Manosuthi 2009) (Thailand, N=142) Observational studies –Boulle 2008 (South Africa, N=1 283) –Manosuthi 2008 (Thailand, N=188) –Sathia 2008 (UK, N=103) –Shipton 2009 (Botswana, N=155) –Sungkanuparph 2006 (Thailand, N=29) –Varma 2009 (Thailand, N=667) From George W. Rutherford, M.D. University of California, San Francisco Global Health Sciences

13. EFV vs. NVP in TB patients Manosuthi 2009 (N 2 R) OutcomeStudiesNStatistical method Effect estimate Mortality1142Single study0.42 (0.08-2.08) Clinical response00-- SAE1142Single study0.75 (0.17-1.03) Virologic response1142Single study0.99 (0.81-1.21) Adherence/ retention/ tolerability 1142Single study0.56 (0.26-1.19) Quality of evidence low for design (open label), imprecision MH Mantel-Haenszel, RE random effects RR <1.0 favours EFV From George W. Rutherford, M.D. University of California, San Francisco Global Health Sciences

14. EFV vs. NVP in TB patients Observational studies From George W. Rutherford, M.D. University of California, San Francisco Global Health Sciences

15. WHO 2009 Proposed Recommendations on When to Start & What to Use in TB/HIV RecommendationsQuality of evidence Strength of recommendations ART should be commenced in all HIV-infected individuals with active tuberculosis irrespective of CD4 cell count ModerateStrong TB treatment should be commenced first and ART subsequently, as soon as possible within the first 8 weeks of starting TB treatment ModerateStrong The recommended preferred ART regimen in naive patients on TB treatment is AZT +3TC + EFV or TDF +3TC or FTC +EFV HighStrong

16. WHO 2009 Proposed Recommendations on When to Start & What to Use in TB/HIV (ctd) RecommendationsQuality of evidence Strength of recommendations In case of intolerance or contraindications to EFV, a NVP- based regimen or a triple NRTI regimen (AZT+3TC+ABC or AZT+3TC+TDF) are recommended. ModerateConditional If ART is changed for the duration of TB treatment, switching back to the original regimen following the completion of TB treatment is a country decision LowConditional In individuals who need a boosted PI-based regimen, rifabutin based TB treatment is recommended. If rifabutin is not available, use of rifampicin and LPV/r or SQV/r containing regimen with additional RTV dosing is recommended with close monitoring. ModerateConditional

17. Risk Benefit Analysis Domain BenefitsReduced HIV and TB mortality Use of rifabutin permit standard boosted PI dosing regimens RisksIRIS Reduced adherence due to high pill burden More laboratory monitoring need (LFTs, Hb) TB diagnosis uncertain in situations where TB diagnosed clinically (or smear negative TB) Increased risk of drug-drug interactions and drug toxicity Different TB regimens (rifampicin and rifabutin) with different ART regimens can increase program management complexity Rifabutin is still not available in FDC and daily dose still not approved Values/accept ability Treatment of all patients will reduce transmission of TB within the community Physician fear of IRIS and toxicity risks on concomitant use of ART and TB regimens HCW and families may value reduced risk of TB transmission

18. Risk Benefit Analysis (ctd) Domain CostMore cost initially Net cost may be favourable given reduced TB transmission Rifabutin costs more than rifampicin, but overall cost may be offset against cost of extra doses of RTV needed with bPI FeasibilityWill require better integration of TB and HIV services The use of rifabutin in patients using bPIs still poses significant operational challenges Gaps, research needs, comments Are HIV infected people with TB and CD4>350 in urgent need of ART? Should it be delayed? If so, until when? Establishment of FDC formulations that permit the use of rifabutin once daily More on use of nevirapine with rifampicin, results awaited from studies

19. Conclusions Trends: –Encourage earlier diagnosis –Treat earlier –Promote less toxic/ more friendly regimens –Monitor more strategically –Will cost more The major operational question is not if these recommendations should be followed or not, but how to do it safely and with equity For TB/HIV, the panel placed high value on the reduction of the current high level of mortality from HIV/TB co-infection and the positive impact on TB transmission and prevalence of initiating ART in all HIV infected individuals with TB in developing these recommendations.

20. Acknowledgments Haileyesus Getahun, Stop TB Dept Marco Vitoria, HIV/AIDS Dept