Assessing Value in Medicine: - PowerPoint Presentation

1.  Assessing Value in Medicine: From Virus to Policy in HIV DiseaseKenneth A. Freedberg, MD, MScDivisions of Infectious Disease and General MedicineMassachusetts General HospitalCREST conference, Boston UniversityJune 9, 2015Supported by NIAID, NIMH, CDC, CHAI, ANRSDivisions of Infectious Disease and General MedicineMassachusetts General HospitalCo-Director, CREST Program Boston University School of Medicine1995

2. I have no financial disclosures.

3. Patient: T.C.24 year-old womanOutpatient department with sore throatThrush noted HIV test recommendedPositiveCD4 20/ul, viral load 122,000 copies/ml

4. OverviewClinical Economics: brief introductionThe Cost-effectiveness of Presenting AIDS Complications (CEPAC) Model Cost-effectiveness and policy in the United StatesCost-effectiveness in resource-limited settingsConclusions

5. HIV Clinical Policy: US

6. HIV Clinical Policy: US

7. Medical Care, 2015…Two questions… 1. Is it effective?* (Does it work?) 2. Is it cost-effective?Evidence for standards of care…*Note – if it’s not effective, it’s not cost-effective

8. Medical Care, 1991

9. CREST Take-home #1What do you want to do?Why do I say this?

10. Medical Care, 1991

11. Cost AnalysisUS$11,700 - $30,200/patient/year with CD4 counts >350/µL to < 50/µLGebo et al., AIDS 2010

12. International Funding for HIV http://www.pepfar.gov/documents

13. Cost-effectiveness AnalysisTwo different outcome measuresCost ($, rand, CFA)Effectiveness: years of life saved (YLS) QALYs or DALYsCost-effectiveness ratio: Additional Resource Use Additional Health BenefitsThe value of resources spent

14. Cost-effectiveness: Common Misconceptions“Cost-Effective” = “Cheap”“Cost-Effective” = “Saves Money”“Cost-Effective” = Additional benefit worth the additional cost ($/QALY)

15. Cost-effectiveness “Thresholds” The Commission on Macroeconomics and Health and WHO have suggested that interventions are: Very cost-effective: the CE ratio is <1 x GDP per capita for that country $43,000 for US Cost-effective: the CE ratio is <3 x GDP per capita for that countryMacroeconomics and Health: WHO 2001

16. Resources are limited

17. Resources are limitedPeriod.

18. CREST Take-home #2Find a good mentor“Mutual fund rule”

19. https://research.tufts-nemc.org/cear4/AboutUs/WhatistheCEARegistry.aspxPublications on Cost-EffectivenessNumber of StudiesYear

20. Cost-effectiveness of Preventing AIDS Complications (CEPAC)CEPAC is a simulation model of HIV disease and treatment that incorporates CD4, HIV RNA, ART, opportunistic infections Data are from public use datasets, published cohorts, and clinical trialsModel outcomes are reported in projected life expectancy and costs* Funded by NIAID, NIMH, CDC, CHAI, ANRS

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22. Is ART Cost-effective in the US?Freedberg et al, N Engl J Med 2001. CE RatioStrategy Costs ($) QALM ($/QALY)Dupont 006 (CD4 350/μl) No ART 59,790 47.52 --- AZT/3TC/EFV 94,290 79.56 13,000Johns Hopkins (CD4 217/μl) No ART 54,150 35.04 --- AZT/3TC/IDV 80,460 53.16 17,000

23. Cost-effectiveness of Genotype Testing in ART-naïve PatientsSax et al, IAS Barcelona 2002

24. CREST Take-home #3If it’s not published it doesn’t exist.

25. Cost-effectiveness of Genotype Testing in ART-naïve PatientsSax et al,IAS Barcelona 2002 Clin Inf Dis 2005

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27. Patient: T.C.24 year-old womanOutpatient department with sore throatHow many of you would recommend to her that she have an HIV test?

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29. HIV Screening: Outpatients At a 1% prevalence of undiagnosed HIV infection, routine testing every 5 years had a cost-effectiveness ratio of $71,000/QALY gained (Paltiel et al. NEJM 2005)At a 1% prevalence of undiagnosed HIV infection, cost-effectiveness of routine screening was $41,700/QALY (Sanders et al. NEJM 2005)With the inclusion of transmission effects, routine HIV screening in a population with 0.2% prevalence of undiagnosed HIV infection, had a cost-effectiveness ratio of $50,000/QALY (Paltiel et al. Ann Intern Med 2006)

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31. Cost-effectiveness Ratiosfor Other Screening Programs C-E ratio Screening Program ($/QALY)* ReferenceHIV screening inpatients $38,600 Walensky AJM HIV screening every 5 years high risk patients $50,000 Paltiel NEJM Breast cancer screening Salzmann Annual mammogram, 50–69 y/o $57,500 Ann Intern Med Diabetes Mellitus, Type 2 Fasting plasma glucose, adults >25 y/o $70,000 CDC JAMA*All costs adjusted to 2001 US dollars

32. Life expectancy (QALY)Per-person lifetime cost* (USD 2010)ICER($/QALY)No ART4.05 131,200--Branded ART12.45 342,80025,200Generic ART in the USUSD: United States Dollars; QALY: quality-adjusted life year; ART: antiretroviral therapy*QALY and costs discounted at 3% annuallyWalensky et al, Annals 2013

33. Life expectancy (QALY)Per-person lifetime cost* (USD 2010)ICER($/QALY)No ART4.05 131,200--Generic ART12.08 300,30021,100Branded ART12.45 342,800114,800USD: United States Dollars; QALY: quality-adjusted life year; ART: antiretroviral therapy*QALY and costs discounted at 3% annually $42,500 0.37Generic ART in the USWalensky et al, Annals 2013

34. Generic ART:Cost-effectiveness Plane No ART Generic ART Branded ARTWalensky et al, Annals 2013

35. Generic ART:Cost-effectiveness Plane No ART Generic ART Branded ARTWalensky et al, Annals 2013

36. Revised May 1, 2014

37. What about HIV Cure?Recent evidence in one bone marrow recipient and (almost…) one newborn that HIV eradication, or ‘cure’, may be viable Major efforts focused on a variety of cure strategies: gene therapy and chemotherapyGoal to establish thresholds of efficacy, toxicity, relapse, and cost at which a cure strategy could be cost-effective

38. Cost = $50 000Relapse (%/month) 0.0      0.5      1.0      1.5      2.0      102030405060Efficacy(%)Cost = $200 000Relapse (%/month) 0.0      0.5      1.0      1.5      2.0      102030405060Efficacy (%) Cost-saving C/E<$100 000/QALY Not cost-effectiveGene Therapy: Efficacy, Relapse, and CostSax et al., PLoS One 2014

39. Number of People Living with HIV: USPeople Living With HIVYearU.S.

40. Number of People Living with HIV: US and GloballyPeople Living With HIV (Millions)YearU.S.Global

41. What should be the standard of care?

42. Abidjan, Côte d’Ivoire

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44. Policy Issue:Cost-effectiveness of ARTART is $270 per monthResources are limited (drug, clinic space, personnel)Who should get ART and when?

45. Strategy ART starting criteria L-E (mths)Cost ($)C-E Ratio($/YLS)No treatment--31.4 780--ART, no CD42 OIs41.41,230 600 ART, with CD4CD4<200 69.63,400 1,200Goldie et al., NEJM, 2006Côte d’Ivoire per capita GDP = $1,100

46. Abidjan, March 2011

47. 3rd-line ART in Côte d’IvoireOuattara et al., JAIDS 2014ClinicalEconomicStrategyL-E (months)Cost($)C-E Ratio ($/YLS)Routine CD4 counts for failure2nd-line ART only49.6  4,700--Adherence intervention, then restart 2nd- line ART64.2  6,0001,100Adherence intervention, then 3rd-line ART if virologic failure persists90.4 13,8003,600Immediate change to 3rd-line ART88.3 16,600Dom.

48. Cohen et al., NEJM 2011Early compared to delayed ART conferred a 96% relative reduction in linked HIV transmissions among serodiscordant couples

49. 5-year survival Early ART93% Delayed ART84% No ART55%Survival in South AfricaWalensky et al., NEJM 2013

50. Early ARTDelayed ART No ARTTransmission Rates, 5 yrs, South AfricaWalensky et al., NEJM 2013

51. Cost-effectiveness, Lifetime, South Africa Life expectancy (years)Costs (USD 2011)ICER†($/YLS)Delayed ART13.3 15,970--Early ART15.216,320530†Including projected survival losses and cost increases associated with 1st- and 2nd-order transmissionsper capita GDP for South Africa: $8,100 Walensky et al., NEJM 2013

52. 52nRate /1OO PYaHRpWHO ART 1114.9Early ART642.80.560.0002No IPT 1044.7IPT713.00.650.005Temprano Severe HIV morbidity: (N=2,056) No significant interaction between Early-ART and IPT44% reduction in risk with Early ART35% reduction in risk with IPTDanel et al, CROI 2015

53. The “Tutu Tester”, Cape Town, South Africa

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55. Treatment StrategySVR, %Life expectancy (QALYs)Per-person lifetime cost* (USD 2013)ICER($/QALY)Naïve No treatment---5.1 94,000--- 24 wk of PEG-RBV 6211.3150,0008,700 12 wk of SOF-RBV9014.2253,00035,500Experienced No treatment---4.1 85,000--- 12 wk of SOF-RBV589.3230,000Dominated 16 wk of SOF-RBV7710.8268,00027,300Cost-Effectiveness of HCV Rx: Genotype 2, with CirrhosisLinas et al, Annals 2015

56. Treatment StrategySVR, %Life expectancy (QALYs)Per-person lifetime cost* (USD 2013)ICER($/QALY)Naïve No treatment---13.9169,000--- 24 wk of PEG-RBV 8215.5173,0003,000 12 wk of SOF-RBV9815.8261,000238,000Experienced No treatment---12.3163,000--- 12 wk of SOF-RBV9613.8258,00063,700 16 wk of SOF-RBV9913.9288,000468,000Cost-Effectiveness of HCV Rx: Genotype 2, No CirrhosisLinas et al, Annals 2015

57. CREST Take-home #4Be at the tableBen Linas, MD, MPHAASLD/IDSA Guidelines Committee on HCV, 2015

58. Patient: T.C.24 year old womanOutpatient department with sore throatThrush noted HIV test recommendedPositiveCD4 20/ul, viral load 120,000 copies/mlOn medication since 1999 (TDF/FTC/EFV)May 2015: CD4 489/ul, RNA<20 copies/ml

59. CREST Take-Home MessagesWhat do you want to do?Find a good mentor. If it’s not published, it doesn’t exist.Be at the table.#5. Always acknowledge your funders.

60. ConclusionsCost-effectiveness is about value for money; critical if resources are limited… resources are limitedIn the US cost-effectiveness analysis has motivated policy changes supporting ART, genotype testing for naïve and experienced patients, HIV testing, and lab monitoringIn resource-limited settings, cost-effectiveness analysis even more important

61. India Nagalingsewaran Kumarasamy, MBBSKenneth H. Mayer MDSoumya Swaminathan, MDSouth AfricaLinda-Gail Bekker, MD, PhDNeil Martinson, MBBCh, MPHCatherine Orrell, MBBCh, MMedRobin Wood, MBBCh, MMedCôte d’Ivoire Xavier Anglaret, MD, PhDChristine Danel, MDEric Ouattara, MD, MPHEugène Messou, MDHapsa Toure, MDFranceYazdan Yazdanpanah, MD, PhDDelphine Gabillard, PhDLiem Luong, MDFrancois Dabis, MDZimbabweBarbara Englesmann, MD, MPH Angela Mushavi, MBchB, MMedCEPAC InvestigatorsUnited StatesIngrid Bassett, MD, MPHAndrea Ciaranello, MD, MPHKenneth Freedberg, MD, MScRochelle Walensky, MD, MPHMilton Weinstein, PhDPaul Sax, MDMarc Lipsitch, PhDEmily Hyle, MD, MPHAnne Neilan, MD, MPHMelanie GaynesTaige HouMargo JacobsonElena Losina, PhDRachel MacLeanA. David Paltiel, PhD Bruce Schackman, PhD, MBAGeorge Seage, III DSc, MPHRobert Parker, ScDJared Leff, MSMichael GirouardSarah ParkSupported by NIAID, NIMH, CDC, CHAI, ANRS

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63. Makumbe Hospital, ZimbabweInpatients, Labor & DeliveryART Clinic, Isolation Ward

64. Preventing Mother to Child Transmission (PMTCT) in Zimbabwe Computer model of MTCTLinked to CEPAC adult and pilot infant modelsData from Zimbabwe National PMTCT programsEGPAF, OPHIDZVITAMBO trialOutcomesInfant infection risk2-year survival (mothers and infants)Life expectancy (mothers)Costs

65. Four PMTCT strategiesNo antenatal care PMTCT (reference)2009 national program (primarily single dose NVP)WHO 2010 guidelines with Option A (AZT to mothers)Infant NVP through breastfeedingWHO 2010 guidelines with Option BMaternal ART through breastfeeding

66. Genotype Testing at HIV Treatment Failure CE Ratio Strategy Costs ($) QALM ($/QALY)No Resistance Test 92,130 65.10 ---Resistance Test 95,630 67.65 16,500Weinstein et al. Ann Intern Med 2001

67. Linas et al. JAIDS 2009; NASTAD AIDS Drug Assistance Programs (ADAPs): State-Based, Uninsured8,100 on wait lists, February 2013 < 300/μL< 250/μL< 200/μL< 150/μLFCFS < 350/μL

68. Patient: T.C.24 year old womanOutpatient department with sore throatThrush noted HIV test recommendedPositiveCD4 20/ul, viral load 120,000 copies/ml

69. CREST Take-Home #5Make it a good story.

70. The Role of PrEP in the USEvidence of efficacy of TDF/FTCCurrent cost = $1,430/monthWhat will be the role?

71. Population-level ScenarioBased on:392,460 annual births in Zimbabwe16% ANC HIV prevalence ~ 63,000 HIV-infected pregnant women0.96% annual HIV incidence ~ 5,000 incident infections during breastfeeding Current ARV uptake for PMTCT: 56%Index Mundi, Zimbabwe ANC Survey 2009, National HIV Estimates 2009

72. Summary of FindingsThe transition from the 2009 national PMTCT program to Option A or B will dramatically improve pediatric outcomesSubstantial improvements in uptake of all steps of the PMTCT cascade with Option A or Option B will be necessary to approach “virtual elimination” of pediatric HIVOption A is cost-effective, compared to sdNVP

73. Expanded Screening and ART in the USInfection/20 yrsInc Cost/$ BillionsInc QALYsMillionsICER, $Status Quo1,225,400Expanded screen-82,000 (6.7%)26.91.222,400Expanded ART (75 %)-125,800 (70.3%)63.83.120,300Screen/ART-212,300 (17.3%)92.64.521,600Long et al. Ann Intern Med 2010LR-once, HR-annual

74. Patient TC: Presentation with an OI24 year old womanOutpatient department with coughHIV positiveCD4 20/ulSputum positive for PCP

75. Expanded Screening and ART in the USStarting ART at <350/μlEarlier ART, 50% decrease in high-risk behavior: 65% reductionScreening and treatment: highly cost-effectiveWill not eliminate the epidemic in USLong et al. Ann Intern Med 2010

76. Results: Cost-effectiveness, Lifetime, South Africa Life expectancy (years)Costs (USD 2011)ICER†($/YLS)Delayed ART13.3 15,970--Early ART15.216,320530†Including projected survival losses and cost increases associated with 1st- and 2nd-order transmissionsper capita GDP for South Africa: $8,100

77. ResultsCost-effectiveness Plane No ART Generic ART Branded ART

78. Amount Saved (in USD millions)Generic Drug Price Reduction (%AWP)Base case (75% reduction)Generic ART: $920 millionPotential Savings in the First-YearGeneric Prices Get CheaperZocor® (Simvastatin) ~66%Methylin® (Methylphenidate HCl) ~72%Coumadin® (Warfarin) ~85%

79. Pre-Exposure Prophylaxis (PrEP): Cost-effectiveness 2009Before trials done: 50% efficacy, 1.6% annual incidence, $753/monthC-E ratio of $298,000/YLSMore cost-effective at lower cost, higher incidence, younger age, increased efficacyPaltiel et al, CID 2009

80. C-E RatioIntervention Agent ($/QALY)* ReferencePCP/Toxo proph. TMP-SMX $2,800 Freedberg JAMA 1998ART AZT/3TC/EFV $11,700 Freedberg NEJM 2001Resistance Test --- $20,200 Weinstein Annals 2001Resistance Test (naïve) --- $23,900 Sax CID 2005Inpt HIV screening --- $38,600 Walensky AJM 2005MAC proph. Azithromycin $43,300 Freedberg JAMA 1998HIV screening q5y --- $50,000 Paltiel NEJM 2005 high risk patients Cost-effectiveness Ratios for HIV Care*All costs adjusted to 2001 US dollars

81. 5-year survivalEarly ART93%Delayed ART84%No ART55%Results: Survival for South Africa

82. Early ARTDelayed ARTNo ARTResults:Cumulative Transmissions, South Africa

83. Laboratory Monitoring in India: Benefits and CostsRoutine laboratory monitoring alone0102030405060708005001,0001,5002,0002,5003,0003,5004,000Cost ($)Life expectancy (months)No routine laboratory monitoringRoutine laboratory monitoring with confirmatory testNo ART1 line of ART alone Strategies without routine HIV RNA Strategies with routine HIV RNA X+Scott et al, IAS 2011

84. Cost-effectiveness of Co-trimoxazole Prophylaxis in Côte d’IvoireProphylaxis StrategyLife Expectancy (mo)Lifetime Costs ($)Incremental CE Ratio ($/yr life saved)Based on clinical stageNo prophylaxis38.01,260--Co-trimoxazole at WHO stage ≥340.41,290110Co-trimoxazole at WHO stage ≥242.41,320200Based on CD4 cell countNo prophylaxis38.01,260--Co-trimoxazole at CD4 ≤200/μl39.01,360DominatedCo-trimoxazole at CD4 ≤500/μl41.41,390DominatedCo-trimoxazole regardless of CD442.41,320*150Yazdanpanah et al. AIDS 2005*CD4 test costs not included

85. Cost-effectiveness of HIV Treatment in Resource-Poor SettingsStrategyCD4 TestingART Starting CriteriaART Stopping CriteriaLife Expectancy (mo)Lifetime Costs ($)Incremental C-E Ratio ($/yr life saved)No Treatment------31.4783--CTX aloneNo----32.8811240CTX + ARTNo2 ODs1 OD41.41,233590CTX + ARTNo1 OD1 OD50.71,716620CTX + ARTNo1 OD3 ODs56.82,171890CTX + ARTNo1 OD5 ODs57.92,2641,060CTX + ARTYesCD4<200, CD4<350 and 1 severe OD90% in CD4 count69.63,4231,180Goldie et al. N Engl J Med 2006

86. C-E RatioIntervention Agent ($/QALY)* ReferencePCP/Toxo proph. TMP-SMX $2,800 Freedberg JAMA 1998ART AZT/3TC/EFV $11,700 Freedberg NEJM 2001Resistance Test --- $20,200 Weinstein Annals 2001Resistance Test (naïve) --- $23,900 Sax CID 2005Inpt HIV screening --- $38,600 Walensky AJM 2005MAC proph. Azithromycin $43,300 Freedberg JAMA 1998HIV screening q5y --- $50,000 Paltiel NEJM 2005 high risk patients Cost-effectiveness Ratios for HIV Care*All costs adjusted to 2001 US dollars

87. CREST Take-home #4Be at the table