Delphine Sculier, MD,MPH

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

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WHO ART treatment guidelines the critical issues
being reviewed
How to diagnose earlier?

• 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

How to monitor?
When to Start?
What to Use 1st Line?
What to use- 2nd Line?
Third line ?
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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
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ART guidelinesChanges from 2006 to 2010
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WHO 2006 Proposed WHO 2010
Criteria for ART initiation All stages 4, irrespective of CD4 count Stages 3 and CD4lt350 Stages 1 2 and CD4lt200 All stages 3 4, irrespective of CD4 count Stages 1 2 and CD4 lt350
Preferred first line regimens AZT or D4T 3TC NVP or EFV or TDF or ABC 3TC/FTC NVP or EFV Triple NRTI regimen Adults AZT3TCNVP or TDF3TC/FTCEFV Adolescents AZT3TCNVP or AZT3TCEFV Pregnant women AZT3TCNVP or AZT3TCEFV (2nd 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
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Laboratory monitoring
WHO 2006
Proposed WHO 2010
Phase of HIV management Recommended Desirable
At HIV diagnosis CD4 HBsAg, ?HCV test
Pre ART CD4 (6 monthly) Viral Load
At start of ART CD4 - Hb for AZT - Renal screen for TDF
On ART CD4 Viral load
At clinical failure CD4 Viral load
At immunological failure Viral load
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Recommendations for HIV infected TB patients

• When to start?
• What to start?

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Grade review When to start ART in HIV-infected
TB patients?

• SAPiT Optimal Time to Initiate ART in
  HIV/TB-Coinfected Patients

Early ART ART initiated during intensive or
continuation phase of TB therapy (n 429)
HIV-infected patients diagnosed with TB and CD4
cell count lt 500 cells/mm3 (N 642)
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
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SAPiT Increased survival with concurrent HIV and
TB treatment
1.00
Early ART
Sequential ART
0.95
0.90
Survival
0.85
0.80
Intensive phase of TB treatment
Post-TB treatment
Continuationphase of TB treatment
0.75
0.70
0
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Months Post-randomization
Abdool Karim SS, et al. CROI 2009. Abstract 36a.
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GRADE Table
From Larry William Chang, MD, MPH, Johns Hopkins
School of Medicine, Cochrane Collaborative Group
on HIV/AIDS at UCSF
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Grade review What to start in HIV-infected
TB patients? EFV vs. NVP in patients taking
rifampicin

• Observational studies
• Boulle 2008 (South Africa, N1 283)
• Manosuthi 2008 (Thailand, N188)
• Sathia 2008 (UK, N103)
• Shipton 2009 (Botswana, N155)
• Sungkanuparph 2006 (Thailand, N29)
• Varma 2009 (Thailand, N667)

• Randomised controlled trials
• N2R (Manosuthi 2009) (Thailand, N142)

From George W. Rutherford, M.D. University of
California, San Francisco Global Health Sciences
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EFV vs. NVP in TB patients Manosuthi 2009 (N2R)
Outcome Studies N Statistical method Effect estimate
Mortality 1 142 Single study 0.42 (0.08-2.08)
Clinical response 0 0 - -
SAE 1 142 Single study 0.75 (0.17-1.03)
Virologic response 1 142 Single study 0.99 (0.81-1.21)
Adherence/ retention/ tolerability 1 142 Single study 0.56 (0.26-1.19)
Quality of evidence low for design (open label), imprecision Quality of evidence low for design (open label), imprecision Quality of evidence low for design (open label), imprecision Quality of evidence low for design (open label), imprecision Quality of evidence low for design (open label), imprecision
MH Mantel-Haenszel, RE random effects RR lt1.0
favours EFV
From George W. Rutherford, M.D. University of
California, San Francisco Global Health Sciences
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EFV vs. NVP in TB patients Observational studies
From George W. Rutherford, M.D. University of
California, San Francisco Global Health Sciences
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WHO 2009 Proposed Recommendations on When to
Start What to Use in TB/HIV
Recommendations Quality of evidence Strength of recommendations
ART should be commenced in all HIV-infected individuals with active tuberculosis irrespective of CD4 cell count Moderate Strong
TB treatment should be commenced first and ART subsequently, as soon as possible within the first 8 weeks of starting TB treatment Moderate Strong
The recommended preferred ART regimen in naive patients on TB treatment is AZT 3TC EFV or TDF 3TC or FTC EFV High Strong
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WHO 2009 Proposed Recommendations on When to
Start What to Use in TB/HIV (ctd)
Recommendations Quality of evidence Strength of recommendations
In case of intolerance or contraindications to EFV, a NVP-based regimen or a triple NRTI regimen (AZT3TCABC or AZT3TCTDF) are recommended. Moderate Conditional
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 Low Conditional
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. Moderate Conditional
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Risk Benefit Analysis
Domain
Benefits Reduced HIV and TB mortality Use of rifabutin permit standard boosted PI dosing regimens
Risks IRIS 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/acceptability 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
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Risk Benefit Analysis (ctd)
Domain
Cost More 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
Feasibility Will 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 CD4gt350 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
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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.

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Acknowledgments

• Haileyesus Getahun, Stop TB Dept
• Marco Vitoria, HIV/AIDS Dept