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)

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 $3,300 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.

$1,000,000

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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.

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

Cost-benefit Analysis

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

Resistance Issues in Resource-

Limited 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)

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