HIV Resistance Testing: Overview of Indications and Cost Issues

1. HIV Resistance Testing: Overview of Indications and Cost Issues Paul E. Sax, MD Division of Infectious Diseases Brigham and Women’s Hospital Harvard Medical School

2. Disclosures • Consultant: Abbott, BMS, Gilead, GSK • Honoraria for teaching: Abbott, BMS, Gilead, GSK, Merck, Tibotec, Virco • Grant Support: BMS, Pfizer, Merck

3. 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

4. When to Use Resistance Testing *Especially if exposure to someone receiving antiretroviral drugs is likely or if prevalence of drug resistance in untreated patients ≥ 5% (European: ≥10%). 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.

5. Genotype Preferred • Acute (primary) HIV infection • Treatment-naïve • Failure of first regimen • Little or no prior resistance documented • Patient no longer on therapy

6. 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)

7. Cost Issues in Resistance Testing

8. 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”?

9. Zidovudine $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 Antiretroviral & Prophylaxis Costs: United States

10. 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

11. 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.

12. $1,000,000 ONGOING IN 1994: ddI, ddC, AZT $900,000 EFAVIRENZ $800,000 DELAVIRDINE $700,000 NELFINAVIR $600,000 $500,000 HOSPITAL COSTS NEVIRAPINE ANTIVIRAL COSTS $400,000 INDINAVIR $300,000 $200,000 RITONAVIR 3TC SAQUINAVIR $100,000 D4T $0 Q 1/96 Q 1/99 Q 1/94 Q 2/94 Q 2/95 Q 3/95 Q 4/95 Q 2/96 Q 3/96 Q 4/96 Q 1/97 Q 2/97 Q 3/97 Q 4/98 Q 3/94 Q 4/94 Q 1/95 Q 4/97 Q 1/98 Q 2/98 Q 3/98 Cost Timeline with Significant Drug Release Dates

13. 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.

14. Cost-benefit Analysis “I’ve received your credit report, and you seem to be a person worth saving.”

15. 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)

16. $/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 The “$50,000” Threshold: Often Cited, Often Ignored YLS = years of life saved

17. Antiretroviral Therapy is Very Cost Effective Freedberg et al. NEJM2001;344:824-31.

18. Test Costs in $ HIV RNA 119 CD4 83 Genotype 355-676 “Virtual” phenotype 550 Phenotype 700-1148 Phenotype + genotype 800-1690 Tropism assay 1960 What Does HIV Lab Testing Cost? • Sources: BWH hospital lab, private vendors

19. Resistance Testing is Cost-effective after Treatment Failure Separate study: 22,510 euros/life-year gained. Weinstein et al. Ann Int Med. 2001;134:440-50. Corzillius et al. Antivir Ther. 2004;9:27-36.

20. Resistance Testing at Diagnosis Improves Outcome at Reasonable Cost Sax et al.Clin Infect Dis.2005; 41:1316-23.

21. 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 ICER = Incremental Cost-Effectiveness Ratio Coakley et al.ICAAC 2005, Abstract #H1054

22. Resistance Issues in Resource-Limited Settings

23. 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)

24. How to Select MDR HIV: Lessons from the Past Highly adherent, aggressively treated patients with non-suppressive regimens led to selection of multidrug-resistant HIV Sequential NRTI monotherapy and dual-NRTI therapy “Hit hard, hit early” No ART Earlier initiation of therapy with better rx ZDV mono-therapy “Sequential monotherapy” with PIs/NNRTIs Deferral of therapy Early 80s Late 80s Early 90s Mid90s Late 90s Early 00s Late 00s

25. 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

26. 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.

27. 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

28. 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