Delphine Sculier, MD,MPHStop TB Department

World Health OrganisationGeneva, Switzerland

Update on the revision of ART guidelines for TB patients

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

WHO ART treatment guidelines –the critical issues being reviewed

How to diagnose earlier?

How to monitor?

When to Start?

What to Use 1st Line?

What to use- 2nd 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 ?

Drafting Recommendations and Risk Benefit Analysis

Risk-Benefit Analysis: Existing recommendation: Proposed recommendation Quality of Evidence (for outcomes deemed critical ) High Moderate Low Very low

Benefits/desired effects

Risks/undesired effects

Values/Acceptability

Costs (consider actual costs, modeling; incremental cost of new recommendation; cost effectiveness analysis )

Feasibility

Suggested ranking of recommendation: Strong (for or against) Or Weak (for or against)

Gaps, research needs, comments:

•Systematic reviews and GRADE profiles

•Impact assessment reports

•PLWH consultation reports

•Costing and feasibility analysis

DRAFT RECOMMENDATIONS

VALIDATION BY REVIEW GROUPS

FINAL RECOMMENDATIONS

ART guidelinesChanges from 2006 to 2010

WHO 2006 Proposed 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 (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

Laboratory monitoring

Phase of HIV management

Recommended

Desirable

At HIV diagnosis CD4HBsAg,

?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

WHO 2006 Proposed WHO 2010

Recommendations for HIV infected TB patients

When to start?

What to start?

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/mm3

(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

Abdool Karim SS, et al. CROI 2009. Abstract 36a.

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Su

rviv

al

Months Post-randomization

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Intensive

phase of TB

treatment

Post-TB treatmentContinuationphase of TB

treatment

Early ARTSequential ART

SAPiT: Increased survival with concurrent HIV and TB treatment

GRADE Table

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

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

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

MH Mantel-Haenszel, RE random effectsRR <1.0 favours EFV

From George W. Rutherford, M.D. University of California, San Francisco Global Health Sciences

EFV vs. NVP in TB patients Observational studies

From George W. Rutherford, M.D. University of California, San Francisco Global Health Sciences

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

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 (AZT+3TC+ABC or AZT+3TC+TDF) 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

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

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 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

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.

Acknowledgments

• Haileyesus Getahun, Stop TB Dept

• Marco Vitoria, HIV/AIDS Dept