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. 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

3. 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.

4. Advantages Rapid turnaround (1-2 wks) Less expensive than phenotyping Detection of mutations may precede phenotypic resistance Widely available More sensitive than phenotype for detecting mixtures of resistant and wild-type virus Disadvantages Indirect measure of resistance Relevance of some mutations unclear Unable to detect minority variants (< 20% to 25% of viral sample) Complex mutational patterns may be difficult to interpret Advantages and Disadvantages of Genotype Testing

5. Advantages Provides direct and quantitative measure of resistance Methodology can be applied to any antiretroviral agent, including new drugs, for which genotypic correlates of resistance are unclear Uses 2 clinical cutoffs (CCO) derived from clinical cohorts to define spectrum of resistance Indicates which drugs have partial activity Can assess interactions among mutations Accurate with non-B HIV subtypes Disadvantages Susceptibility cutoffs not standardized between assays Clinical cutoffs not defined for some agents May be unable to detect minority variants for some mutations (< 20% to 25% of viral sample) Complex technology with longer turnaround (~ 3 wks) More expensive than genotyping Advantages and Disadvantages of Phenotype Testing

6. Advantages Similar advantages to genotype (turnaround time, cost, sensitivity) Defines resistance based on database of in vivo responses in treated patients Uses 2 clinical cutoffs (CCO) to define spectrum of resistance Indicates which drugs have partial activity Disadvantages Is an estimated phenotype based on the patient’s genotype, not an actual measured phenotype Reliability will depend on the accuracy of the genotype Available only from 1 vendor More expensive than genotype alone Methodology of linking genotype to phenotypic database not intuitively obvious—uses a proprietary “virtual phenotype linear regression model engine” Advantages and Disadvantages of “Virtual” Phenotype Testing

7. Drug Resistance Testing in Clinical Practice: Summary • Indications for use of resistance testing have greatly expanded • Genotype preferred • Treatment naive: acute or chronic infection • Early virologic failure • Patient no longer on therapy • Phenotype, virtual phenotype, or combined phenotype/genotype preferred • High-level resistance to NRTIs or PIs on genotype • Multiple regimen failure with limited treatment options

8. Cost Issues in Resistance Testing

9. Case Presentation • 38 year-old MSM with community-acquired MRSA • Treated with doxycycline, local care; recovered uneventfully • HIV test recommended; no prior test • HIV+; initial CD4 180, HIV RNA 77,000

10. What Should be Standard of Care? • Should a resistance test be done? • If not, why not? • If so, which one? • Why do we care?

11. Who Decides? • Doctor and/or patient? • Medicaid or ADAP or VA? • Kaiser or BC/BS or Harvard University Health Plan? • USPHS or IAS or WHO guidelines? • Resistance testing vendors? • “Society”?

12. 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

13. ADAPs with waiting lists Alabama: 6 on waiting list Alaska: 10 on waiting list Indiana: 33 on waiting list Montana: 20 on waiting list South Carolina: 209 on waiting list West Virginia: 24 on waiting list ADAPs with other cost-containment strategies Mississippi: Medical eligibility restrictions Oklahoma: Annual per capita expenditure limit South Carolina: Reduced formulary Six states expecting to start cost-containment in 2007 Resources are Limited – Even Here (US) Source: www.tiicann.org, Oct 6 2006.

14. Quiz Question • Has HIV become more or less costly since the introduction of potent therapy in 1996?

16. 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.

17. Cost-Benefit Analysis • One outcome measure • Costs and benefits both valued in dollars • Difficult to assign a value to clinical outcomes (PCP, stroke, etc.) • Often viewed as morally distasteful by MDs …

18. “I’ve received your credit report, and you seem to be a person worth saving.”

19. 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)

20. measure of “value” for resources a basis for comparing options cost-saving cost-effective Incremental Cost-Effectiveness Ratio Net increase in health care cost Net gain in health effect

21. $/YLS Propanolol, 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

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

23. Test Costs in $ HIV RNA 119 CD4 83 Genotype 355-676 “Virtual” phenotype 550 Phenotype 700-1148 Phenotype + genotype 800-1690 (Tropism assay 710) What Does HIV Lab Testing Cost? • Sources: BWH hospital lab, private vendors

24. 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.

25. Why is this Expensive Test So Cost-Effective? “The cost of the resistance test itself is, in effect, ‘amortized’ over several months of added survival. Compared with the cost of HAART and other HIV-related care in the added months of survival, the cost of the resistance test is modest. Even if each resistance test cost $1000, resistance testing would be relatively good value for money.” Weinstein et al. Ann Int Med. 2001;134:440-50

26. Should Resistance Testing be Done in Antiretroviral-naïve Patients? • Hypothetical cohort of HIV+ patients, newly diagnosed • Outcomes compared with and without initial genotype resistance testing • Sensitivity analyses: • Rate of resistance • Cost of test • Efficacy of test • Proportion starting NNRTI vs PI-based therapy Sax et al.Clin Infect Dis.2005; 41:1316-23.

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

28. Resistance Testing in Naives: Conclusions • CE ratio remained < $50,000/QALY until: • Prevalence of resistance fell to 1% or • Cost of test increased to $3000 or • Efficacy of test was 14% of baseline • Conclusions • Single test that improves outcome over lifetime of patient is highly cost-effective ($23,900/QALY) • Substantial benefit for those with resistance (esp NNRTI) overrides no benefit for those without • Current rates of NNRTI resistance are higher than when analysis done – baseline genotype testing likely to be more cost-effective now Sax et al.Clin Infect Dis.2005; 41:1316-23.

29. Genotype versusPhenotype + Genotype • Industry-sponsored CE analysis • Hypothetical cohort of treatment-experienced patients, CD4 50-200 • Susceptibility score estimated from “GUESS III” study – higher for pheno + geno (PTGT) than geno (GT) • Outcomes projected using state transition Markov model Coakley et al.ICAAC 2005, Abstract #H1054

30. Genotype versusPhenotype + Genotype: Results • 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

31. Resistance Issues in Resource-limited Settings

32. 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

33. “Future directions to improve access to treatment in resource -limited settings Considerable progress has been made in the past four years towards making ART scale-up in the developing world a reality. However, much remains to be done.... There are immediate needs in the area of diagnostics. Making affordable and accurate CD4 cell counting widely available is a high priority. Simultaneously, the field needs to move towards the development and implementation of affordable viral load testing. CD4 and plasma HIV-1 RNA testing are not luxuries. They are important tools supporting the delivery of optimal care and, in the setting of the public health approach, are invaluable measures of programme monitoring and performance.” HIV RNA Monitoring: Desired but Unavailable Slide courtesy William Rodriguez, M.D.

34. 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

35. 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.

36. Botswana: Guidelines for Resistance Testing 4.2 Role of Resistance Testing Since resistance testing is costly and background level resistance is probably still negligible in our setting, resistance testing at first failure is not justifiable. However, genotypic resistance testing should be definitely done to guide choice of drugs for third line regimen as it may then be possible to recycle some of the drugs used in previous regimens. Pregnant women who have taken monotherapy for PMTCT purposes may be considered for resistance testing. Botswana Antiretroviral Treatment Guidelines, 2005 Revision.

37. WHO plan for setting up labs and sentinel surveillance sites Goal is to describe both transmitted and on-treatment prevalence of resistance No recommendations for the use of resistance testing in clinical practice http://www.who.int/hiv/drugresistance/en/

38. 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

39. Resistance Testing and Cost: Conclusions and Future Directions • Resistance testing: costly but cost-effective • Major challenge: how can we apply our understanding of resistance prevention and management to resource-limited settings? • Additional questions • What is the clinical utility and cost-effectiveness of looking for minority variants? • How will existing testing be adapted to new drug classes?