HIV Resistance Testing: Overview of Indications and Cost

Issues

Paul E. Sax, MDDivision of Infectious DiseasesBrigham and Women’s Hospital

Harvard Medical School

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 naive 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%).

Advantages and Disadvantages of Genotype TestingAdvantages

• 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 Phenotype TestingAdvantages

• 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 “Virtual” Phenotype TestingAdvantages

• 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”

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

Cost Issues in Resistance Testing

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

What Should be Standard of Care?

• Should a resistance test be done?

• If not, why not?

• If so, which one?

• Why do we care?

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”?

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 (US)• 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

Source: www.tiicann.org, Oct 6 2006.

Quiz Question

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

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.

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 …

“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 quality-adjusted life years (QALY)

• Cost-effectiveness ratio: – Resource use ($)/Health benefit (QALY)

Incremental Cost-Effectiveness Ratio

• measure of “value” for resources• a basis for comparing options• cost-saving cost-effective

Net increase in health care cost

Net gain in health effect

The “$50,000” Threshold: Often Cited, Often Ignored

$/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

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 710)

Sources: BWH hospital lab, private vendors

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.

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

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.

Resistance Testing at Diagnosis Improves Outcome at Reasonable Cost

Sax et al. Clin Infect Dis. 2005; 41:1316-23.

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.

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

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

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

“Future directions to improve access to treatment in resource -limited settingsConsiderable 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 andaccurate CD4 cell counting widely available is a high priority. Simultaneously, thefield needs to move towards the development and implementation of affordableviral load testing. CD4 and plasma HIV-1 RNA testing are not luxuries. They areimportant tools supporting the delivery of optimal care and, in the setting of thepublic health approach, are invaluable measures of programme monitoring andperformance.”

“Future directions to improve access to treatment in resource -limited settingsConsiderable 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 andaccurate CD4 cell counting widely available is a high priority. Simultaneously, thefield needs to move towards the development and implementation of affordableviral load testing. CD4 and plasma HIV-1 RNA testing are not luxuries. They areimportant tools supporting the delivery of optimal care and, in the setting of thepublic health approach, are invaluable measures of programme monitoring andperformance.”

Slide courtesy William Rodriguez, M.D.

HIV RNA Monitoring: Desired but Unavailable

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

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.

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.

• 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/

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

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?