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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
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
                                           —                      —                 Recommend
 prophylaxis

 Chronic, Rx naive                   Consider*             Recommend            Strongly consider*
 Failure                            Recommend              Recommend                Recommend
 Pregnancy                          Recommend                     —                Recommend*
 Pediatric                                 —                      —                Recommend†

*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.
Advantages and Disadvantages
of Genotype Testing
Advantages                            Disadvantages
•   Rapid turnaround (1-2 wks)        • Indirect measure of resistance
•   Less expensive than phenotyping
                                      • Relevance of some mutations
•   Detection of mutations may          unclear
    precede phenotypic resistance
                                      • Unable to detect minority
•   Widely available                    variants (< 20% to 25% of viral
•   More sensitive than phenotype for   sample)
    detecting mixtures of resistant
    and wild-type virus               • Complex mutational patterns
                                        may be difficult to interpret
Advantages and Disadvantages
of Phenotype Testing
Advantages                                   Disadvantages
• Provides direct and quantitative           •   Susceptibility cutoffs not standardized
  measure of resistance                          between assays
• Methodology can be applied to any        •     Clinical cutoffs not defined for some
  antiretroviral agent, including new            agents
  drugs, for which genotypic correlates of
                                           •     May be unable to detect minority
  resistance are unclear
                                                 variants for some mutations (< 20% to
• Uses 2 clinical cutoffs (CCO) derived          25% of viral sample)
  from clinical cohorts to define spectrum
                                             •   Complex technology with longer
  of resistance
                                                 turnaround
• Indicates which drugs have partial             (~ 3 wks)
  activity
                                             •   More expensive than genotyping
• Can assess interactions among
  mutations
• Accurate with non-B HIV subtypes
Advantages and Disadvantages
of ―Virtual‖ Phenotype Testing
Advantages                               Disadvantages
•   Similar advantages to genotype       •   Is an estimated phenotype based
    (turnaround time, cost, sensitivity)     on the patient‘s genotype, not an
                                             actual measured phenotype
•   Defines resistance based on
    database of in vivo responses in     •   Reliability will depend on the
    treated patients                         accuracy of the genotype
•   Uses 2 clinical cutoffs (CCO) to     •   Available only from 1 vendor
    define spectrum of resistance
                                         •   More expensive than genotype
•   Indicates which drugs have partial       alone
    activity
                                         •   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 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    $   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                • ADAPs with other cost-
  – Alabama: 6 on waiting list              containment strategies
  – Alaska: 10 on waiting list              – Mississippi: Medical
  – Indiana: 33 on waiting list               eligibility restrictions
  – Montana: 20 on waiting list             – Oklahoma: Annual per
                                              capita expenditure limit
  – South Carolina: 209 on
    waiting list                            – South Carolina: Reduced
                                              formulary
  – West Virginia: 24 on
    waiting list                          • 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


   Net increase in health care cost
      Net gain in health effect

        • measure of ―value‖ for resources
        • a basis for comparing options
        • cost-saving cost-effective
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                  57,500
 Annual 40-49                 168,400


  YLS = years of life saved
Antiretroviral Therapy is
Very Cost Effective
                                                        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



  Freedberg et al. NEJM 2001;344:824-31.
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
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.
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 versus
Phenotype + 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 versus
Phenotype + 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
HIV RNA Monitoring: Desired
but Unavailable
        “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.”




                                   Slide courtesy William Rodriguez, M.D.
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                “Hit hard,
                    dual-NRTI therapy              hit early”
 No
 ART                                                                      Earlier initiation
            ZDV                                                           of therapy with
           mono-                   “Sequential                                better rx
                                                             Deferral
          therapy                 monotherapy”
                                                            of therapy
                                 with PIs/NNRTIs




  Early     Late         Early          Mid         Late        Early      Late
  80s       80s          90s            90s         90s         00s        00s
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?

				
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