hiv resistance testing: overview of indications and cost issues paul e. sax, md division of...
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HIV Resistance Testing: Overview of Indications and Cost
Issues
Paul E. Sax, MDDivision of Infectious DiseasesBrigham and Women’s Hospital
Harvard Medical School
Disclosures
• Consultant: Abbott, BMS, Gilead, GSK
• Honoraria for teaching: Abbott, BMS, Gilead, GSK, Merck, Tibotec, Virco
• Grant Support: BMS, Pfizer, Merck
Outline
• Review of available resistance tests
• What tests to order when
• Review of cost analyses
• How cost issues relate to resistance testing– USA and other developed countries
– Resource-limited settings
When to Use Resistance Testing
IAS-USA[1] DHHS[2] European[3]
Primary/acute Recommend Recommend Recommend
Postexposure prophylaxis
— — Recommend
Chronic, Rx naïve Consider* Recommend Strongly consider*
Failure Recommend Recommend Recommend
Pregnancy Recommend — Recommend*
Pediatric — — Recommend†
1. Hirsch et al. Clin Infect Dis. 2003;37:113-28.2. Available at: http://www.aidsinfo.nih.gov. Accessed May 4, 2006.3. Vandamme et al. Antivir Ther. 2004;9:829-48.
*Especially if exposure to someone receiving antiretroviral drugs is likely or if prevalence of drug resistance in untreated patients ≥ 5% (European: ≥10%).
Genotype Preferred
• Acute (primary) HIV infection
• Treatment-naïve
• Failure of first regimen
• Little or no prior resistance documented
• Patient no longer on therapy
Phenotype, Virtual Phenotype, or Combined Pheno/genotype Preferred • High-level resistance to NRTIs or PIs on genotype
• Multiple regimen failure with limited treatment options
• Viral tropism assay needed (phenotype only)
Who Decides if a Test is Indicated? Should be Reimbursed?• Clinician and/or patient?
• Medicaid or ADAP or VA?
• Insurance companies?– Kaiser or BC/BS or Harvard University Health Plan?
• USPHS or IAS or WHO guidelines?
• Resistance testing vendors?
• “Society”?
Antiretroviral & Prophylaxis Costs: United StatesZidovudine $3,300 TMP-SMX $ 105
Tenofovir $5,500 Dapsone $ 60
Lamivudine $4,000 Atovaquone $ 9,560
Indinavir $7,000 Azithromycin $ 1,450
Nelfinavir $9,125 Fluconazole $ 510
Efavirenz $5,900 Ganciclovir $15,600
Lopinavir/r $8,500 Enfuvirtide $20,000
*Wholesale cost per person for one year
Resources are Limited – Even Here (USA)• Coverage in AIDS Drug Assistance Programs varies
widely by state/territory– 35/54: all antiretrovirals covered
– 25/54: HCV treatment covered
– 21/54: Hep A and Hep B vaccines covered
• As of March 2007, four ADAPs had waiting lists for antiretrovirals (571 individuals)
• Eight states initiated other cost-containment measures in the past fiscal year, three more expected in FY 2007
Source: National ADAP Monitoring Project Annual Report http://www.kff.org/hivaids/upload/7619ES.pdf, April 2007
Question: How has effective antiretroviral therapy influenced the cost of HIV care?
Costs are down due to reduced opportunistic infections and hospitalizations.
Costs are up due to the cost of antiretroviral medications and prolonged survival.
Costs are unchanged, as these two forces balance each other.
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D4T3TCSAQUINAVIR
RITONAVIR
INDINAVIR
NEVIRAPINE
NELFINAVIR
DELAVIRDINE
EFAVIRENZ
ONGOING IN 1994:ddI, ddC, AZT
HOSPITAL COSTS
ANTIVIRAL COSTS
Cost Timeline with Significant Drug Release Dates
Cost Analyses: HIV Care is Becoming More Expensive• What does it cost/year to care for an HIV patient in the
USA?– HCSUS,1992: $14,700
– HCSUS, 1998: $20,000
– Johns Hopkins, 1999: $15,660
– CEPAC Collaboration, 2004: $26,800
• What is the lifetime cost?– 1992: $100,000 (survival 6.8 years)
– 2004: $649,000 (survival 24.2 years)
Bozzette et al. NEJM 1998;339:1897-904.Gebo et al. AIDS 1999;13:963-9.Schackman et al. Med Care. 2006;44:990-7.
Cost-effectiveness Analysis
• Two different outcome measures:– Cost in dollars
– Effectiveness: years of life saved (YLS) or quality-adjusted life years (QALY)
• Cost-effectiveness ratio: – Resource use ($)/Health benefit (QALY)
The “$50,000” Threshold: Often Cited, Often Ignored
$/YLS
Propranolol, mild HTN 14,000
TPA vs streptokinase 33,000
Rx hypercholesterolemia 47,000
Dialysis, ESRD 51,000
Screening mammography:Annual 50-69 57,500Annual 40-49 168,400
YLS = years of life saved
Antiretroviral Therapy is Very Cost Effective
Freedberg et al. NEJM 2001;344:824-31.
C-E Ratio
Strategy Costs ($) QALM ($/QALY)
Dupont 006 (CD4 350)
No ART 59,790 47.52 ---
AZT/3TC/EFV 94,290 79.56 13,000
Johns Hopkins (CD4 217)
No ART 54,150 35.04 ---
AZT/3TC/IDV 80,460 53.16 17,000
What Does HIV Lab Testing Cost?
Test Costs in $
HIV RNA 119
CD4 83
Genotype 355-676
“Virtual” phenotype 550
Phenotype 700-1148
Phenotype + genotype 800-1690
Tropism assay 1960
Sources: BWH hospital lab, private vendors
Trial (Reference)Quality-Adjusted Life Expectancy†
Costs†
Cost-Effectiveness Ratio‡
mo $ $/QALY gained
CPCRA 046 (10)
No genotypicantiretroviral resistance testing§
60.9 90 360 –
Genotypic antiretroviral resistance testing 63.1 93 650 17 900
VIRADAPT (6)
No genotypicantiretroviral resistance testing
62.2 91 980 –
Genotypic antiretroviral resistance testing 66.4 97 790 16 300
Weinstein et al. Ann Int Med. 2001;134:440-50.Corzillius et al. Antivir Ther. 2004;9:27-36.
Resistance Testing is Cost-effective after Treatment Failure
Separate study: 22,510 euros/life-year gained.
Test cost of $400 Cost-effectiveness by test cost, $/QALY
Prevalence of primary resistance in population, %
Incremental cost,$
Life expectancy
gained, QALMs $400 $200 $800
0.25 430 0.03 175,400 97,200 331,500
0.5 480 0.06 97,300 58,200 175,400
1.0 580 0.1 58,300 38,700 97,300
1.5 670 0.2 45,200 32,200 71,300
3.0 950 0.4 32,200 25,700 45,200
5.0 1300 0.6 27,000 23,100 34,800
7.0 1700 0.8 24,800 22,000 30,400
8.3a 2000a 1.0a 23,900a 21,600a 28,600a
9.0 2100 1.1 23,600 21,400 27,900
10.0 2300 1.2 23,100 21,200 27,000
Resistance Testing at Diagnosis Improves Outcome at Reasonable Cost
Sax et al. Clin Infect Dis. 2005; 41:1316-23.
Description GT PTGT
Costs $160,040 $161,299
QALYs 4.54 4.59
Cost per QALY $35,326 $35,175
ICER, PTGT to GT $28,812 per QALY
Genotype versusPhenotype + Genotype
• Results– Costs of GT strategy slightly lower than PTGT– Survival longer with PTGT– Incremental CE ratio = $28,812/QALY
• Limitations: – benefits of PTGT over GT likely to be much smaller in those with limited
resistance– Industry-sponsored
Coakley et al. ICAAC 2005, Abstract #H1054
ICER = Incremental Cost-Effectiveness Ratio
HIV Drug Resistance is Becoming More Important in Resource-Limited Settings• Treatment started with more
advanced disease
• Fewer agents available
• Some older treatments have long-term toxicity that reduces adherence
• Supply chain for medications inconsistent
• Viral load usually not used for monitoring prolonged treatment with virologic failure
• Resistance testing not available
Hospital laboratory, Rwanda
(Photo courtesy W Rodriguez)
Mid90s
Late 00s
Early 00s
Late 90s
Early 90s
Late 80s
Early 80s
No ART
ZDV mono-
therapy
Sequential NRTI monotherapy and dual-NRTI therapy
“Sequential monotherapy”
with PIs/NNRTIs
“Hit hard, hit early”
Deferral of therapy
Earlier initiation of therapy with
better rx
Highly adherent, aggressively treated patients with non-suppressive
regimens led to selection of multidrug-resistant HIV
How to Select MDR HIV: Lessons from the Past
Question:In which of the following countries would resistance testing be offered as part of standard of care to all patients with virologic failure on their first regimen?Argentina
Botswana
Brazil
South Africa
Vietnam
Where is Resistance Testing Being Performed in Resource-Limited Settings?• Brazil
– Available at all sites after panel reviews indication
• Botswana– Limited access; recommended for “second-line”
treatment failure
• All other sites surveyed– Highly-limited access (e.g., private payors only) or no
access at all
Schechter M, Shapiro R, Rodriguez W, Marconi V, Haubrich R, Cahn P, Antunes F, Libman H, Eisenberg M, Cosimi L, Mayer K. Personal communications.
WHO Guidelines: Only Mention of Clinical Use of Resistance Testing
“For highly treatment experienced patients, individual management is necessarily tailored to the availability of alternative ARVs, for which there is very limited provision in the public sector in resource-limited settings, and to additional laboratory investigations, such as individual drug resistance testing.”
Antiretroviral Therapy For HIV Infection In Adults And Adolescents, WHO, 2006 Revision
Question:Which of the following novel technologies do you think is most likely to be available and widely adopted 5 years from now?High sensitivity genotyping for minority variants
Rapid, low-cost screening for CCR5 vs CXCR5 viral tropism
Genotype and/or phenotype testing for resistance to CCR5 antagonists
Genotype and/or phenotype testing for resistance to integrase inhibitors
None will be widely adopted