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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 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 Consider* Recommend Strongly consider* Failure Recommend Recommend Recommend Pregnancy Recommend — Recommend* — — Recommend† Chronic, Rx naïve Pediatric *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. 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) Cost Issues in Resistance Testing 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 States 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 $ Efavirenz $5,900 Ganciclovir $15,600 Lopinavir/r $8,500 Enfuvirtide $20,000 *Wholesale cost per person for one year 510 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. Cost Timeline with Significant Drug Release Dates $1,000,000 $900,000 ONGOING IN 1994: ddI, ddC, AZT EFAVIRENZ $800,000 DELAVIRDINE $700,000 NELFINAVIR $600,000 HOSPITAL COSTS $500,000 NEVIRAPINE $400,000 INDINAVIR $300,000 $200,000 $100,000 D4T $0 RITONAVIR 3TC SAQUINAVIR ANTIVIRAL COSTS Cost Analyses: HIV Care is Becoming More Expensive • What does it cost/year to care for an HIV patient in the USA? – – – – HCSUS,1992: HCSUS, 1998: Johns Hopkins, 1999: CEPAC Collaboration, 2004: $14,700 $20,000 $15,660 $26,800 • What is the lifetime cost? – 1992: – 2004: $100,000 (survival 6.8 years) $649,000 (survival 24.2 years) Bozzette et al. NEJM 1998;339:1897-904. Gebo et al. AIDS 1999;13:963-9. Schackman et al. Med Care. 2006;44:990-7. Cost-benefit Analysis “I’ve received your credit report, and you seem to be a person worth saving.” Cost-effectiveness Analysis • Two different outcome measures: – Cost in dollars – Effectiveness: years of life saved (YLS) or qualityadjusted life years (QALY) • Cost-effectiveness ratio: – Resource use ($)/Health benefit (QALY) The “$50,000” Threshold: Often Cited, Often Ignored $/YLS Propranolol, mild HTN 14,000 TPA vs streptokinase 33,000 Rx hypercholesterolemia 47,000 Dialysis, ESRD 51,000 Screening mammography: Annual 50-69 Annual 40-49 YLS = years of life saved 57,500 168,400 Antiretroviral Therapy is Very Cost Effective C-E Ratio Strategy Costs ($) QALM ($/QALY) No ART 59,790 47.52 --- AZT/3TC/EFV 94,290 79.56 13,000 No ART 54,150 35.04 --- AZT/3TC/IDV 80,460 53.16 17,000 Dupont 006 (CD4 350) Johns Hopkins (CD4 217) Freedberg et al. NEJM 2001;344:824-31. What Does HIV Lab Testing Cost? Test HIV RNA CD4 Costs in $ 119 83 Genotype “Virtual” phenotype Phenotype Phenotype + genotype Tropism assay 355-676 550 700-1148 800-1690 1960 Sources: BWH hospital lab, private vendors Resistance Testing is Cost-effective after Treatment Failure QualityAdjusted Life Expectancy† Costs† CostEffectiveness Ratio‡ mo $ $/QALY gained No genotypic antiretroviral resistance testing§ 60.9 90 360 – Genotypic antiretroviral resistance testing 63.1 93 650 17 900 No genotypic antiretroviral resistance testing 62.2 91 980 – Genotypic antiretroviral resistance testing 66.4 97 790 16 300 Trial (Reference) CPCRA 046 (10) VIRADAPT (6) 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. Resistance Testing at Diagnosis Improves Outcome at Reasonable Cost Test cost of $400 Prevalence of primary resistance in population, % Cost-effectiveness by test cost, $/QALY Incremental cost,$ 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 Sax et al. Clin Infect Dis. 2005; 41:1316-23. Genotype versus Phenotype + Genotype Description GT PTGT Costs $160,040 $161,299 QALYs 4.54 4.59 $35,326 $35,175 Cost per QALY ICER, PTGT to GT $28,812 per QALY ICER = Incremental Cost-Effectiveness Ratio • 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 Resistance Issues in ResourceLimited Settings 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) 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 No ART ZDV monotherapy Early 80s Late 80s “Hit hard, hit early” Earlier initiation of therapy with better rx “Sequential monotherapy” with PIs/NNRTIs Early 90s Mid 90s Deferral of therapy Late 90s Early 00s Late 00s 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