Newer drugs and earlier treatment: Impact on lifetime cost of care for HIV-infected adults. Technical Appendix

Transcription

1 Technical Appendix (final) 1 Newer drugs and earlier treatment: Impact on lifetime cost of care for HIV-infected adults Technical Appendix Methods Cost and utilization of medical services Diagnosis-related groups Inpatient visit costs were derived using a macrocosting approach and the French diagnosisrelated group (DRG) classification system [1], which classifies diseases into medically and economically homogeneous groups. Each DRG cost, from the French Echelle Nationale de Coûts [2], includes physician and nurse fees as well as mean cost of clinical procedures, laboratory tests, drugs dispensed during hospitalization, and hotel/overhead. Inpatient hospitalizations were classified as DRG 25, which includes HIV-related diseases [3]. Patients were assigned to subgroups of this category according to age, severity of HIV-related diseases, surgery, and survival. For example, patients with a single AIDS-defining disease were assigned to DRG 25M02B, while patients with >1 AIDS-defining diseases were assigned to DRG 25M02C. Each subgroup of DRG 25 was assigned a different cost. Inpatient day-care visits were classified as DRG 24, regardless of the severity of disease [3]. Although this DRG is defined as HIV-infection-related diseases with a length of stay less than 48 hours, the cost assigned to the DRG ( ) represents an accurate estimate of the unit cost for a day care visit, since 99% of visits assigned to DRG 24 in our analysis were day care visits (<1 day). We subtracted the costs of antiretroviral drugs and CD4, HIV RNA and genotype tests from inpatient visit costs.

2 2 Outpatient medications In the evaluation of outpatient medication use, we assumed that patients received nonantiretroviral medications in accordance with the standard-of-care in France [4]: (1) patients continued prophylaxis against Pneumocystis jiroveci pneumonia (PCP), toxoplasmosis, and Mycobacterium avium complex, maintenance therapy for cytomegalovirus and treatment of Mycobacterium tuberculosis, HBV, HCV, hyperlipidemia and diabetes until the following scheduled visit; (2) because clinic visits occurred every three months and drugs were dispensed in four-month supplies to anticipate postponed visits, we assumed that patients who were lost to follow-up took their prescription drugs for four months following their previous clinic visit; (3) treatment of cytomegalovirus and primary and recurrent PCP treatment lasted 21 days [4], toxoplasmosis treatment lasted 42 days, and herpes zoster treatment lasted 10 days; (4) antifungal treatment lasted 10 days, except for candida esophagitis treatment, which lasted 15 days [4]; and (5) antibiotic treatments prescribed for all diseases except Mycobacterium avium complex, Mycobacterium tuberculosis and PCP lasted 10 days [4]. We assumed that treatment for AIDS-defining diseases such as Kaposi s sarcoma, lymphoma, cervical cancer, HIVassociated dementia, progressive multifocal leukoencephalopathy, recurrent bacterial pneumonia and wasting syndrome was exclusively provided in a hospital setting and therefore taken into account in the DRG costs. See Table A1 for details. To determine costs for each stage of disease, we first multiplied resource utilization per patient per stage by unit cost per resource. All healthcare utilization data were derived from the Tourcoing AIDS Reference Center database. Unit costs were taken from several sources. Overall inpatient visit costs were derived using the DRG classification system and the French Echelle

3 3 Nationale de Coûts [2]. Unit costs for outpatient laboratory tests are from the French Nomenclature des actes de biologie médicale [5], and the costs of clinical procedures are from the French Classification commune des actes médicaux [6]. Drug costs are from the Tourcoing Hospital Pharmacy database and are representative of drug costs throughout France. After adding all healthcare costs incurred in each stage, we estimated per-person monthly costs by dividing stage costs by total per-person time spent in each stage. Finally, we determined mean cost per person-month in each stage. For example, patients in Stage 1 with CD4 counts >500/µl had an average of 0.4 day-care visits at 408 each, 0.13 outpatient visits at 26 each, and 0.01 inpatient hospitalizations lasting an average of 7.5 days and costing 4,547 each. Additional monthly costs for these patients included 21 for non-art drugs and 1.7 for other laboratory tests and clinical procedures. These costs added up to 220/month, excluding antiretroviral drugs as well as CD4, HIV RNA and genotype tests. Model overview The Cost-Effectiveness of Preventing AIDS Complications (CEPAC) Model is a computerbased, state-transition, Monte Carlo simulation model of the progression and outcomes of HIV disease [7-9]. A state-transition model characterizes each patient s progression as a sequence of monthly transitions from one health state to another. A Monte Carlo simulation uses a random number generator to generate one hypothetical patient at a time and draw from a set of transition probabilities to determine the occurrence of clinical events and health-state transitions experienced by the patient. The model uses a 1-month cycle length to reflect a realistic duration in which important events occur. Clinical events (e.g., acute opportunistic infections) and health-

4 4 state transitions (e.g., changes in CD4 count or HIV RNA levels) are governed by probabilities estimated from clinical trials and epidemiologic datasets [10]. At the outset of any simulation, an initial cohort size and input parameters are defined including age, sex, CD4 count, and HIV RNA distribution. Also defined are probability distributions for various clinical events such as AIDS-defining diseases and entrance to or dropping out of care for different patient states. Antiretroviral therapy (ART) can lead to increased CD4 counts, reduced HIV RNA levels, ART-related toxicities, and additional medication costs. From this distribution of demographic, clinical and cost data, each patient s clinical course is tracked from entry into the model until death. Death may be attributed to an acute AIDS-defining event, chronic HIV, or non-hiv-related causes. A running tally is maintained of all clinical events and of the cumulative cost and health-related quality of life (or utility ) associated with the months in each health state. This process is repeated until the entire cohort has passed through the model, at which point overall performance measures such as average survival, qualityadjusted life expectancy, and per-patient cost are computed [10]. Health states are descriptive of the patient s current health, relevant history, quality of life, and resource utilization patterns (Figure A1). They are designed to be predictive of clinical prognosis, including disease progression, immunologic deterioration, development and relapse of opportunistic infections, medication toxicity, response to ART, and mortality. The model defines four general categories of HIV health states: primary infection, chronic infection, acute event, and death. Patients usually reside in the chronic state, where immunologic deterioration occurs. CD4 counts are stratified into six groups: CD4 <50/µl, /µl, /µl, /µl, 301-

5 5 500/µl, and >500/µl. Patients who develop an acute event (either an opportunistic infection or medication toxicity) temporarily move to an acute health state, in which resource consumption and mortality rates increase and quality of life decreases. While death may occur from any health state, mortality rates from a given health state are based upon acute event history, CD4 cell count, and age, gender and race-specific non-hiv causes [10]. Other model specifications have been published elsewhere in detail [9, 11-14]. Sensitivity analyses The range endpoints for the sensitivity analyses reported in the main manuscript originate from published studies. The range for mean initial CD4 count represents CD4 counts from late presentation to early presentation. The range for the time interval between laboratory tests represents the French Ministry of Health s recommendation to reduce outpatient visits and laboratory tests whenever possible [15]. Because we did not find a reference for this sensitivity analysis, we chose to use a wide range. The ranges used for the efficacy of first- and second-line ART are assumptions: we increased and decreased the efficacy by 10%. ART regimens 3-6 are modeled as standard regimens represented by various recent studies [16-27]. The data on the protective effect of ART on risk of AIDS-defining diseases and death are sparse [28]. We therefore chose to use a very wide range for this sensitivity analysis. The lower bound of the sensitivity analysis range for ART costs is 50% of the base case input, to represent the potential emergence of generic drugs in the near future [29]. The upper bound of the range for first-line ART represents the raltegravir-based first-line ART scenario. The upper bound of the range for ART lines 2 and 4 represent the third-line, 90%; fourth-line, 75% sensitivity analysis. All costs

6 6 are from the Tourcoing Hospital Pharmacy [30]. Results Table A2 shows the person-time spent in each disease stage and the monthly cost of care in each HIV disease stage in the CEPAC Model.

7 7 References 1. Manuel des groupes homogènes de malades. 10ème version de la classification, version de la fonction groupage. Fascicule spécial n 2006/3 bis. 1 March (Accessed 9 February 2011 at 2. Echelle nationale de coûts par GHM, données (Accessed 9 February 2011 at 3. Le programme de médicalisation des systèmes d information en soins de courte durée: médecine, chirurgie et obstétrique. L algorithme de la classification des GHM (Accessed 9 February 2011 at 4. Prise en charge thérapeutique des personnes infectées par le VIH: Rapport (Accessed 9 February 2011 at 5. Nomenclature Générale des Actes Professionnels December (Accessed 8 July 2009 at 6. Classification commune des actes médicaux. (Accessed 9 February 2011 at 7. Freedberg KA, Losina E, Weinstein MC, Paltiel AD, Cohen CJ, Seage GR, et al. The cost effectiveness of combination antiretroviral therapy for HIV disease. N Engl J Med 2001,344: Weinstein MC, Goldie SJ, Losina E, Cohen CJ, Baxter JD, Zhang H, et al. Use of genotypic resistance testing to guide hiv therapy: clinical impact and cost-effectiveness. Ann Intern Med 2001,134:

8 8 9. Yazdanpanah Y, Goldie SJ, Paltiel AD, Losina E, Coudeville L, Weinstein MC, et al. Prevention of human immunodeficiency virus-related opportunistic infections in France: a costeffectiveness analysis. Clin Infect Dis 2003,36: CEPAC: Cost Effectiveness of Preventing AIDS Complications. (Accessed at temid=78) 11. Yazdanpanah Y, Goldie SJ, Losina E, Weinstein MC, Lebrun T, Paltiel AD, et al. Lifetime cost of HIV care in France during the era of highly active antiretroviral therapy. Antivir Ther 2002,7: Schackman BR, Scott CA, Walensky RP, Losina E, Freedberg KA, Sax PE. The costeffectiveness of HLA-B*5701 genetic screening to guide initial antiretroviral therapy for HIV. AIDS 2008,22: Losina E, Toure H, Uhler LM, Anglaret X, Paltiel AD, Balestre E, et al. Costeffectiveness of preventing loss to follow-up in HIV treatment programs: a Cote d'ivoire appraisal. PLoS Med 2009,6:e Walensky RP, Wood R, Ciaranello AL, Paltiel AD, Lorenzana SB, Anglaret X, et al. Scaling up the 2010 World Health Organization HIV Treatment Guidelines in resource-limited settings: a model-based analysis. PLoS Med 2010, Ministère de la Santé et des Solidarités, Direction de l Hospitalisation et de l Organisation des Soins. Circulaire nºdhos/f1/mtaa/2006/376 relative aux conditions de facturation d un GHS pour les prises en charge hospitalières en zone de surveillance de très courte durée ainsi que pour les prises en charge de moins d une journée. 31 August 2006.

9 9 16. Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz M, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008,359: Cooper DA, Steigbigel RT, Gatell JM, Rockstroh JK, Katlama C, Yeni P, et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008,359: Yazdanpanah Y, Fagard C, Descamps D, Taburet AM, Colin C, Roquebert B, et al. High rate of virologic suppression with raltegravir plus etravirine and darunavir/ritonavir among treatment-experienced patients infected with multidrug-resistant HIV: results of the ANRS 139 TRIO trial. Clin Infect Dis 2009,49: Grinsztejn B, Nguyen BY, Katlama C, Gatell JM, Lazzarin A, Vittecoq D, et al. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet 2007,369: Madruga JV, Cahn P, Grinsztejn B, Haubrich R, Lalezari J, Mills A, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24- week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007,370: Lazzarin A, Campbell T, Clotet B, Johnson M, Katlama C, Moll A, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24- week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007,370: Gulick RM, Lalezari J, Goodrich J, Clumeck N, DeJesus E, Horban A, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008,359:

10 Nelson M, Arasteh K, Clotet B, Cooper DA, Henry K, Katlama C, et al. Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experienced HIV-1-infected patients in the T- 20 versus optimized background regimen only 1 and 2 clinical trials. J Acquir Immune Defic Syndr 2005,40: Lalezari J, Goodrich J, DeJesus E, Lampiris H, Gulick R, Saag M, et al. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1: 24-week results of a phase 2b/3 study in the US and Canada [abstract 104bLB]. 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, CA; Reynes J, Arasteh K, Clotet B, Cohen C, Cooper DA, Delfraissy JF, et al. TORO: ninetysix-week virologic and immunologic response and safety evaluation of enfuvirtide with an optimized background of antiretrovirals. AIDS Patient Care STDS 2007,21: Gallant JE, DeJesus E, Arribas JR, Pozniak AL, Gazzard B, Campo RE, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 2006,354: Johnson M, Grinsztejn B, Rodriguez C, Coco J, DeJesus E, Lazzarin A, et al. Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS 2005,19: Cole S, Hernan M, Robins J, Anastos K, Chmiel J, Detels R, et al. Effect of Highly Active Antiretroviral Therapy on Time to Acquired Immunodeficiency Syndrome or Death using Marginal Structural Models. Am J Epidemiol 2003,158:

11 Verpillot E. La régulation du prix des médicaments et le marché des génériques (unpublished). Université de Franche-Comté, Ecole Doctorale Louis Pasteur.; (Accessed at Tourcoing Hospital Pharmacy

12 12 Table A1. Drugs included in the analysis to estimate outpatient drug use Antiretroviral therapy abacavir amprenavir atazanavir Darunavir delavirdine didanosine efavirenz emtricitabine enfuvirtide fosamprenavir indinavir lamivudine lopinavir nelfinavir nevirapine pentafuside ritonavir saquinavir stavudine tenofovir tipranavir zalcitabine zidovudine Treatment against hepatitis B virus and hepatitis C virus adefovir interferon alpha-2b lamivudine pegylated interferon alpha-2a ribavirin tenofovir pegylated interferon alpha-2b AIDS-defining disease prophylaxis and treatment Pneumocystis carinii pneumonia atovaquone cotrimoxazole dapsone Cytomegalovirus ganciclovir valganciclovir Fungal infections amphotericin ethambutol fluconazole flucytosine itraconazole ketoconazole metronidazole nitazoxamide nystatin paromomycin Herpes zoster and herpes simplex acyclovir valacyclovir

13 13 Table A1. (continued) Toxoplasmosis atovaquone clindamycin pyrimethamine + folic or folinic acid sulfadiazine sulfadoxine Mycobacterium tuberculosis isoniazid pyrazinamide rifampicin Mycobacterium avium complex amikacin azithromycin ciprofloxacin clarithromycin clofazimine ethambutol levofloxacin rifabutin Other antibiotics amoxicillin cefixime ceftriaxone cefuroxime clavulanic acid doxycycline moxifloxacin norfloxacin ofloxacin oxacillin phenoxymethylpenicillin pristinamycin spyramycin Roxythromycin Hyperlipidemia treatment atorvastatin benfluorex bezafibrate ciprofibrate colestyramin ezetimibe fenobibrate fluvastatin gemfibrozil pravastatin rosuvastatin simvastatin Diabetes treatment acarbose glibenclamide glicazide glimepiride glipizide insulin (all types) metformin pioglitazone rosiglitazone

14 14 Table A1. (continued) Other daunorubicine doxorubicine hydroxyurea Some drugs were used for multiple indications. Drugs that are recommended for a listed disease but were never administered in the Tourcoing cohort are not in the table. All drugs that were administered intravenously, except for ceftriaxone, were administered during inpatient care. These drugs are not included in outpatient costs.

15 15 Table A2. Undiscounted person-time spent in each disease stage and monthly cost of care in each HIV health state in a model of HIV disease and treatment in France Disease state Time in stage (months) Cost / month, 2010 a Total cost / state, 2010 Stage 1: No history of AIDS-defining events by CD4 count, cells/μl > , , ,133 36, ,578 11, ,058 9, ,212 3,659 <50 4 2,675 11,814 Stage 2: Acute AIDS-defining disease 2 8,360 20,153 Stage 3: History of at least one AIDS-defining event by CD4 count, cells/μl > , , ,625 26, ,030 13, ,367 12, ,433 4,609 <50 4 2,598 9,231 Stage 4: Death 1 10,873 10,873 Total 319 1, ,048 a Cost/month may not always equal total cost/state divided by time in stage, due to rounding.

16 16 Figure legend Figure A1. General structure of the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) Model.

17 Figure A1. 17