HIV Resistance Testing: Overview of Indications and Cost IssuesPaul E. Sax, MDDivision of Infectious DiseasesBrigham and Womens HospitalHarvard Medical School

DisclosuresConsultant: Abbott, BMS, Gilead, GSK

Honoraria for teaching: Abbott, BMS, Gilead, GSK, Merck, Tibotec, Virco

Grant Support: BMS, Pfizer, Merck

OutlineReview of available resistance testsWhat tests to order whenReview of cost analysesHow cost issues relate to resistance testingUSA and other developed countriesResource-limited settings

When to Use Resistance Testing1. 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 PreferredAcute (primary) HIV infectionTreatment-naveFailure of first regimenLittle or no prior resistance documentedPatient no longer on therapy

Phenotype, Virtual Phenotype, or Combined Pheno/genotype Preferred High-level resistance to NRTIs or PIs on genotypeMultiple regimen failure with limited treatment optionsViral 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 StatesZidovudine$3,300TMP-SMX$ 105Tenofovir$5,500Dapsone$ 60Lamivudine$4,000Atovaquone$ 9,560Indinavir$7,000Azithromycin$ 1,450Nelfinavir$9,125Fluconazole$ 510Efavirenz$5,900Ganciclovir$15,600Lopinavir/r$8,500Enfuvirtide$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/territory35/54: all antiretrovirals covered25/54: HCV treatment covered21/54: Hep A and Hep B vaccines coveredAs 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 2007Source: 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

Cost Analyses: HIV Care is Becoming More ExpensiveWhat does it cost/year to care for an HIV patient in the USA?HCSUS,1992: $14,700HCSUS, 1998: $20,000Johns Hopkins, 1999: $15,660CEPAC Collaboration, 2004:$26,800What 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-benefit AnalysisIve received your credit report, and you seem to be a person worth saving.

Cost-effectiveness AnalysisTwo different outcome measures:Cost in dollarsEffectiveness: years of life saved (YLS) or quality-adjusted life years (QALY)Cost-effectiveness ratio: Resource use ($)/Health benefit (QALY)

The $50,000 Threshold: Often Cited, Often Ignored$/YLSPropranolol, mild HTN14,000TPA vs streptokinase33,000Rx hypercholesterolemia47,000Dialysis, ESRD51,000Screening mammography: Annual 50-6957,500 Annual 40-49168,400YLS = years of life saved

Antiretroviral Therapy is Very Cost EffectiveFreedberg et al. NEJM 2001;344:824-31.

What Does HIV Lab Testing Cost?TestCosts in $HIV RNA 119CD4 83

Genotype355-676Virtual phenotype550Phenotype700-1148Phenotype + genotype800-1690Tropism assay1960Sources: BWH hospital lab, private vendors

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

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

Genotype versusPhenotype + GenotypeResultsCosts of GT strategy slightly lower than PTGTSurvival longer with PTGTIncremental CE ratio = $28,812/QALYLimitations: benefits of PTGT over GT likely to be much smaller in those with limited resistanceIndustry-sponsoredCoakley et al. ICAAC 2005, Abstract #H1054ICER = Incremental Cost-Effectiveness Ratio

Resistance Issues in Resource-Limited Settings

HIV Drug Resistance is Becoming More Important in Resource-Limited SettingsTreatment started with more advanced diseaseFewer agents availableSome older treatments have long-term toxicity that reduces adherenceSupply chain for medications inconsistentViral load usually not used for monitoring prolonged treatment with virologic failureResistance testing not availableHospital laboratory, Rwanda(Photo courtesy W Rodriguez)

How to Select MDR HIV: Lessons from the PastMid 90sLate 00sEarly 00sLate 90sEarly 90sLate 80sEarly 80sNo ARTZDV mono-therapySequential NRTI monotherapy and dual-NRTI therapySequential monotherapy with PIs/NNRTIsHit hard, hit earlyDeferral of therapyEarlier initiation of therapy with better rxHighly adherent, aggressively treated patients with non-suppressive regimens led to selection of multidrug-resistant HIV

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?ArgentinaBotswanaBrazilSouth AfricaVietnam

Where is Resistance Testing Being Performed in Resource-Limited Settings?BrazilAvailable at all sites after panel reviews indicationBotswanaLimited access; recommended for second-line treatment failureAll other sites surveyedHighly-limited access (e.g., private payors only) or no access at allSchechter 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 TestingFor 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 variantsRapid, low-cost screening for CCR5 vs CXCR5 viral tropismGenotype and/or phenotype testing for resistance to CCR5 antagonistsGenotype and/or phenotype testing for resistance to integrase inhibitorsNone will be widely adopted

DHHS, US Department of Health and Human Services; IAS-USA, International AIDS Society-USA; Rx, treatment.Three major organizations provide resistance testing guidelines: the International AIDS Society (IAS)-USA, the US Department of Health and Human Services (DHHS), and the European HIV Drug Resistance Panel. In general, these organizations agree about when resistance testing should be done. All agree that it should be done in primary or acute infection. The European guidelines recommend resistance testing in postexposure prophylaxis, for treatment failure, and during pregnancy. However, there is some disagreement about resistance testing in chronically infected, treatment-naive patients. In recent changes to the DHHS guidelines (5/4/06), resistance testing is recommended for these patients. According to IASUSA, resistance testing is indicated only if the background rate of resistance is 5% or, according to the European guidelines, 10%. However, these guidelines are under review and are likely to be revised.

South CarolinaPuerto RicoAlaskaMontana

Cost containment measures:Two reduced the number of drugs on their formularies Three further restricted eligibility to the program One introduced client cost-sharing Two capped enrollment An additional three ADAPs anticipate having tonewly institute cost-containment measures duringADAP FY 2007 (April 1, 2007March 31, 2008).

HIV Cost and Services Utilization Study2Moore et al. (US): $10,000 - 13,000/QALYTrueman et al. (UK): $15,000-23,000/QALYMiners et al. (UK): $27,500/QALYSendi et al. (Swiss): $22,000/YLS

CD4 $100Viral load 110

C-E RatioStrategyCosts ($) QALM($/QALY)CPCRA 046No GART92,130 65.10 ----GART95,630 67.65 16,500

CE ratio remained < $50,000/QALY until:Prevalence of resistance fell to 1% orCost of test increased to $3000 orEfficacy of test was 14% of baselineConclusionsSingle 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 withoutCurrent rates of NNRTI resistance are higher than when analysis done baseline genotype testing likely to be more cost-effective now

Industry-sponsored CE analysis Hypothetical cohort of treatment-experienced patients, CD4 50-200Susceptibility score estimated from GUESS III study higher for pheno + geno (PTGT) than geno (GT)Outcomes projected using state transition Markov model

GUESS III: GT: 44.8% hadregimens w/ SS 3PTGT: 72.5% hadregimens w/ SS 3

South Africa, Rwanda, Ethiopia, Argentina, Carribean