COST-EFFECTIVENESS OF THE WORLD HEALTH ORGANIZATION

TREATMENT GUIDELINES IN AFRICAEran Bendavid

Philip Grant, Annie Talbot, Douglas Owens, Andrew Zolopa

Stanford University

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Motivation (1) – new guidelines When to start: CD4 count of 350

cells/mm3

What to start: one of four regimens containing AZT, TDF, NVP, or EFV

What not to start: regimens containing d4T

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Motivation (2) – resource environment

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2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

HIV

aid

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Next few slides

Framing the question

Approach1. Model structure2. Assumptions

Results1. Comparative effectiveness2. Cost-effectiveness

Implications

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Evaluating the WHO guidelinesWhat is the comparative effectiveness and cost-effectiveness of the 1st line regimens recommended in the new guidelines, as well as the regimen in most common use?1. Tenofovir + lamivudine + efavirenz (TDF/3TC/EFV)2. Tenofovir + lamivudine + nevirapine (TDF/3TC/NVP)3. Zidovudine + lamivudine + efavirenz (AZT/3TC/EFV)4. Zidovudine+ lamivudine+ nevirapine (AZT/3TC/NVP)5. Stavudine + lamivudine + nevirapine (d4T/3TC/NVP)

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Model structure

Badri (Lancet 2006), Lawn (AIDS 2009), Holmes (JAIDS 2006)

Simulation of HIV disease and treatment calibrated to South African data

Simulated individual patient histories

Calculate population average life expectancies, quality-adjusted life expectancies, and costs

A few illustrative patient histories look like this…

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Simulation example

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Simulation example7

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Assumption 1 – virologic failure

Gallant (NEJM 2006, JAMA 2004), Smith (JID 2005 ), Arribas (JAIDS 2008), Nachega (AIDS 2008)

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Regimen Failure (Yr1) Failure(Yr3)

TDF/3TC/EFV 12% (8-16%) 24% (16-32%)

TDF/3TC/NVP 18% (12-24%) 31% (22-40%)

AZT/3TC/EFV 17% (10-24%) 31% (20-42%)

AZT/3TC/NVP 25%(16-34%) 46% (32-60%)

d4T/3TC/NVP 18% (12-24%) 31% (22-40%)

Assumption 2 – toxicities

Haubrich (AIDS 2009), Arribas (JAIDS 2008), Gallant (JAMA 2004, NEJM 2006), Amoroso (CROI 2007)

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Regimen Toxicities Rate (1 year) Substitution

TDF/3TC/EFV LipoatrophyRenal failure

6%1%

No substitutionTDF → AZT

TDF/3TC/NVP LipoatrophyRenal failure

Hepatotoxicity

6%1%

6.3%

No substitutionTDF → AZTNVP → EFV

AZT/3TC/EFV LipoatrophyAnemia

23%6%

AZT → TDFAZT → TDF

AZT/3TC/NVP LipoatrophyAnemia

Hepatotoxicity

23%6%

6.3%

AZT → TDFAZT → TDFNVP → EFV

d4T/3TC/NVP LipoatrophyNeuropathy

Lactic acidosisHepatotoxicity

30%25%0.5%6.3%

d4T → TDFd4T → TDFd4T → TDFNVP → EFV

Assumption 3 - costs

WHO, Global Price Reporting Mechanism

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Annual regimen costs are substantially different TDF/3TC/EFV : $675 TDF/3TC/NVP : $538 AZT/3TC/EFV : $384 AZT/3TC/NVP : $247 d4T/3TC/NVP : $121

Results – comparative effectiveness11

Regimen Quality-adjusted life years (disc.)

Life years

(discounted)

Mean number of opportunistic

diseases

TDF/3TC/EFV 11.27 12.82 2.03

TDF/3TC/NVP 11.08 12.54 2.18

AZT/3TC/EFV 10.69 12.72 2.07

AZT/3TC/NVP 10.47 12.39 2.22

d4T/3TC/NVP 10.31 12.51 2.17

Results – cost-effectiveness12

10.2

10.4

10.6

10.8

11.0

11.2

11.4

7,500 8,000 8,500 9,000 9,500 10,000

Lifetime costs (Discounted 2009 USD)

Dis

coun

ted

QAL

Ys

AZT/3TC/NVP

d4T/3TC/NVP

Results – cost-effectiveness12

10.2

10.4

10.6

10.8

11.0

11.2

11.4

7,500 8,000 8,500 9,000 9,500 10,000

Lifetime costs (Discounted 2009 USD)

Dis

coun

ted

QAL

Ys

AZT/3TC/NVP

d4T/3TC/NVP

TDF/3TC/NVP

$1,045/QALY gained

Results – cost-effectiveness12

10.2

10.4

10.6

10.8

11.0

11.2

11.4

7,500 8,000 8,500 9,000 9,500 10,000

Lifetime costs (Discounted 2009 USD)

Dis

coun

ted

QAL

Ys

AZT/3TC/NVP

d4T/3TC/NVP

TDF/3TC/NVP

$1,045/QALY gained

AZT/3TC/EFV

Results – cost-effectiveness12

10.2

10.4

10.6

10.8

11.0

11.2

11.4

7,500 8,000 8,500 9,000 9,500 10,000

Lifetime costs (Discounted 2009 USD)

Dis

coun

ted

QAL

Ys

AZT/3TC/NVP

d4T/3TC/NVP

TDF/3TC/NVP

$1,045/QALY gained

AZT/3TC/EFV

TDF/3TC/EFV$5,950/QALY gained

Implications13

d4T-containing regimens are more expensive and less effective than AZT-containing regimens, supporting their elimination from the guidelines

While there are no trials directly comparing AZT/3TC/EFV with TDF/3TC/NVP, the latter appears to be more effective and less costly than the former under a broad set of assumptions

Consideration should be given to recommending TDF/3TC/NVP over AZT/3TC/EFV in usual circumstances

Using World Health Organization thresholds for cost-effectiveness TDF/3TC/NVP may be considered cost-effective in most African settings, but AZT/3TC/NVP is the least costly regimen

In Collaboration With

Philip Grant – Stanford Infectious DiseasesAnnie Talbot – Stanford Infectious DiseasesDoug Owens – Stanford Health PolicyAndrew Zolopa – Stanford Infectious Diseases

AcknowledgmentNational Institute of Allergy and Infectious Diseases

Assumption 1 – virologic failure8

Regimen FailureYr1 Failure Yr3 Range

TDF/3TC/NVP 18% 31% 12-24%, 22-40%

AZT/3TC/EFV 17% 31% 10-24%, 21-41%

AZT/3TC/NVP 25% 46% 16-34%, 32-60%

d4T/3TC/NVP 18% 31% 12-24%, 22-40%

TDF/3TC/EFV 12% 24% 8-16% ,16-32%

Results – comparative effectiveness11

Regimen Quality-adjusted life years

(disc.)

Life expectanc

y (discounte

d)

Mean number of

opportunistic diseases

TDF/3TC/EFV 11.27 12.82 2.03

TDF/3TC/NVP 11.08 12.54 2.18

AZT/3TC/EFV 10.69 12.72 2.07

AZT/3TC/NVP 10.47 12.39 2.22

d4T/3TC/NVP 10.31 12.51 2.17

Results – comparative effectiveness11

Assumption 1 – virologic failure8

Risk of virologic failure varies by ART regimen Lowest failure: tenofovir + lamivudine +

efavirenz 2nd lowest: zidovudine + lamivudine +

efavirenz 3rd and 4th lowest: tenofovir + lamivudine +

nevirapine ; stavudine + lamivudine + nevirapine

Highest failure: zidovudine + lamivudine + nevirapine

Assumption 2 of 39

ARV drugs have associated risk of toxicities Stavudine (lipoatrophy, neuropathy, lactic

acidosis) Zidovudine (lipoatrophy, anemia) Tenofovir (lipoatrophy, renal failure) Nevirapine (hepatotoxicity)

Quality of life is decreased with toxicities (least with lipoatrophy, most with lactic acidosis)

TDF/3TC/EFV

10.2

10.4

10.6

10.8

11.0

11.2

11.4

7,500 8,000 8,500 9,000 9,500 10,000

Lifetime costs (Discounted 2009 USD)

Dis

coun

ted

QAL

Ys TDF/3TC/NVP

AZT/3TC/EFV

AZT/3TC/NVP

d4T/3TC/NVP

$1,045/QALY gained

$5,950/QALY gained

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Next few slides

Framing the question (1 slide)

Approach1. Model structure (2 slides)2. Assumptions (3 slides)

Results and implications1. Comparative effectiveness (2 slides)2. Cost-effectiveness (2 slides)

Assumption 1 – virologic failure8

Regimen Failure Yr 1

Failure Yr 3

Range

TDF/3TC/EFV 12% 24% 8-16% , 16-32%

TDF/3TC/NVP

18% 31% 12-24%, 22-40%

AZT/3TC/EFV 17% 31% 10-24%, 21-41%

AZT/3TC/NVP

25% 46% 16-34%, 32-60%

d4T/3TC/NVP 18% 31% 12-24%, 22-40%