- Email: [email protected]
AIDS care
Review
The direct costs of HIV/AIDS care Adrian R Levy, Douglas James, Karissa M Johnston, Robert S Hogg, P Richard Harrigan, Brian P Harrigan, Boris Sobolev, Julio S Montaner
We reviewed published studies reporting the direct medical costs of treating HIV-infected people in countries using highly active antiretroviral therapy (HAART). Of 543 potentially relevant studies, only nine provided adequate data to make a meaningful statement about costs. Within studies, people with more advanced disease incurred higher total costs. Valid comparisons of total direct medical costs between studies were not possible because of differences in the specific components included, the heterogeneous nature of study populations in terms of disease stage, the sources and methods used to estimate unit costs, and the level of aggregation at which results were reported. The advent of HAART has major implications for the cost of treating HIV-infected individuals. Although this information is important for planning purposes, only a small number of published studies provide useful estimates of the direct cost. A useful method of estimating resource use and costs is computer simulation.
Introduction AIDS is characterised by the progressive destruction of a person’s immune system and is the late and most serious stage of HIV infection. Over the past two decades, the epidemic has become a major challenge to health-care systems, with more than 20 million people dying from HIV/AIDS and a further 40·3 million people worldwide estimated to be infected in 2005.1 Recent advances in treatment, especially the use of potent combinations of nucleoside reverse transcriptase inhibitors, protease inhibitors, and non-nucleoside reverse transcriptase inhibitors (referred to as highly active antiretroviral therapy, or HAART), have resulted in dramatic reductions in the rates of HIV disease progression, opportunistic infections, hospital admissions, and deaths.2–5 In developed countries, the remarkable success of HAART has also altered the use of health-care resources for HIVinfected patients, with the nature of treatment shifting from inpatient hospital admissions to outpatient care and greater use of medications in the outpatient setting.6 Furthermore, HIV prevalence is increasing in western countries as a consequence of falling death rates.1,7,8 These changes have occurred against a background of little empirical evidence about the direct costs of treating HIV-infected people in terms of per-person annual expenditures and lifetime costs,9,10 the implications on the cost of using different treatment strategies,11,12 or the extent to which costs vary by stage of HIV infection.13 Information on the direct costs of treatment is important since it provides a basis for health planners to allocate budgets or reimburse specific categories of expenditures. It also enables policymakers, when faced with changes in prevalence—eg, that currently occurring with the spread of HIV infection among injection drug users14—to make more informed choices between programmes. To optimally allocate scarce economic resources to prevention and treatment programmes, planners require accurate, up-to-date estimates of the direct costs of treatment.15–17 Although economic evaluation is an important approach for establishing priorities for health interventions,6,18,19 in practice this type of evaluation has been of limited value in HIV/AIDS because of the paucity of accurate cost data.9 http://infection.thelancet.com Vol 6 March 2006
The purpose of this review is to identify published estimates of the direct medical costs, including hospital inpatient, outpatient, and medication costs for treating HIV-infected individuals after HAART was introduced into routine clinical practice, to determine the extent to which these estimates can be validly compared, and to make such comparisons where possible. In cases where meaningful comparisons are not possible, we explain why this is the case. We also discuss the implications for future research in this area.
Methods To be included, studies had to meet pre-specified criteria for information content. We identified studies that included an original estimate of the mean monthly or annual direct medical costs of treating an HIV-infected individual. We included studies from English language peer-reviewed published work that provided enough detail to allow meaningful comparisons by explicitly describing the study period, location and population (demographic and clinical distributions), types of treatments, data sources, and methods used for cost estimates. Use of health-care resources must have been estimated at an individual level, either through administrative or HIV clinic databases or patient questionnaires. Furthermore, studies must have analysed data in which HAART was included as routine clinical practice. This criterion eliminated a large proportion of studies published before 1999 that used data from before the advent of HAART.9 All studies were reviewed by two investigators (DJ, KMJ) and discrepancies resolved by consensus. Information on three types of expenditures—ie, inpatient, outpatient, and medications—was sought from each study. For each category, we collected information on the data sources used for resource use, the source of unit costs, and the mean monthly or annual cost. Costs were recorded at the most disaggregated level available. Two procedures were used to convert costs into a common price year and account for differences in currency. Inflation rate differences were taken into account by converting the results from each study into a common price year (2001) using country-specific health
Lancet Infect Dis 2006; 6: 171–77 ARL and KMJ are at the Department of Health Care and Epidemiology, University of British Columbia, Vancouver, BC, Canada, and also at the Centre for Health Evaluation and Outcome Sciences, St Paul’s Hospital, Vancouver. RSH is at the Department of Health Care and Epidemiology, University of British Columbia, and also at the BC Centre for Excellence in HIV/AIDS, St Paul’s Hospital. PRH and JSM are at the BC Centre for Excellence in HIV/AIDS, St Paul’s Hospital, and also at the Department of Medicine, University of British Columbia. BS is at the Department of Health Care and Epidemiology, University of British Columbia. DJ is at the Centre for Health Evaluation and Outcome Sciences, St Paul’s Hospital. BPH was at the BC Centre for Excellence in HIV/AIDS, St Paul’s Hospital. BPH is now at Oxford Outcomes Ltd, Vancouver, Canada. Correspondence to: Dr Adrian R Levy, St Paul’s Hospital, 620-1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada. Tel +1 604 806 8691; fax +1 604 806 8005; [email protected]
171
Review
Country Years
Number of patients/ Variability Data sources population based? reported?
Type of expenditure Inpatient
Outpatient
Source of unit costs
Components
Source of unit costs
Outpatient physician visits, laboratory and diagnostic tests Outpatient physician visits Outpatient physician visits, diagnostic tests Outpatient physician visits Outpatient physician visits, laboratory tests, home care Outpatient physician visits
Reimbursement rates
France6
1994–98 1232/no
Yes
HIV clinic database
Reimbursement rates
USA11 Italy21
1999 1998
5255/no 74/no
No No
HIV clinic database HIV clinic database
Hospital costing survey Hospital costing survey
England22 1996 Canada23 2000
5708/no 654/yes
Yes No
HIV clinic database Hospital costing survey Administrative databases Reimbursement rates
France24 2000
1212/no
No
695/no
Yes
Italy26
1997–98 473/no
No
USA27
1996–98 2864/no
Yes
USA
25
1997
Medications Components
Antiretrovirals, anti-infectives, all other* Hospital costing survey .. Hospital costing survey Antiretrovirals
Hospital costing survey .. Reimbursement rates Antiretrovirals, all other Administrative databases Hospital costing survey Reimbursement rates Antiretrovirals, anti-infectives† Administrative databases Reimbursement rates Outpatient physician and Reimbursement rates Antiretrovirals, emergency visits, home care all other Patient questionnaire Hospital costing survey Outpatient physician visits, Hospital costing survey Antiretrovirals laboratory and diagnostic tests Patient questionnaire Hospital costing survey Outpatient physician and Hospital costing survey Antiretrovirals, emergency visits all other
Source of unit costs Market price
NA Market price† NA Market price Market price Reimbursement rates Market price‡
Market price
..=not reported; NA=not applicable. *Included all drugs for inpatients and chemoprophylaxis for outpatients. †Anti-infective treatments were included under inpatient costs. ‡The two Italian studies used market prices but only included 50% to represent the portion paid by the Italian government.
Table 1: Characteristics of studies, types of expenditures, and costing methods included in estimating direct medical costs of treating HIV/AIDS since the introduction of HAART according to type of expenditure
expenditure inflators.20 To account for differences in the relative unit costs of health-care service across countries, health-specific purchasing power parities20 were used to express all cost estimates in US dollars. Results reported as annual costs were directly converted to monthly costs.
Results Of 543 titles initially identified, 92 were flagged as potentially relevant. Based on the abstracts, full versions of 33 were obtained. Another six relevant publications were cited within retrieved articles. After reviewing each study, nine were judged to meet the inclusion criteria. Table 1 summarises the major characteristics of each study. The studies ranged in the number of included people from 7421 to 5708,22 and one study was considered population based23 because it included all patients from an entire catchment area. Four studies provided a measure of variability for the cost estimate. All nine studies used a “bottom-up” approach18 to estimate direct medical costs, in which data were collected on the resource inputs for each patient and that service use was multiplied by unit costs to produce a monthly (or annual) direct cost per patient. Some studies used different unit costs based on the intensity of the visit,24 the clinical stage of the individual,22 or the specific treatments received.6,23,25 Different sources for unit cost measurements were used by the studies. Hospital costing surveys (including per diem rates and hospital charges) were used in six studies to obtain unit costs for inpatient services and in 172
five studies to obtain unit costs for outpatient services, with the remaining estimates of inpatient and outpatient unit costs obtained using reimbursement rates. Two of the costing surveys considered the costs incurred by a single clinic,21,26 one examined costing data from six clinics,22 and the remaining three used results from national-level surveys.11,24,27 Reimbursement rates were considered from the perspective of a private insurer25 or a publicly funded system.6,23,24 Of the seven studies that included the costs of antiretroviral medications, six used market prices,6,21,23,24,26,27 although the two Italian studies21,26 took the perspective of the Italian government and only included 50% of market cost in their estimate. The remaining study priced drugs with reimbursement rates to a private insurer.25 The components included in outpatient expenditures varied among studies, with some including only outpatient physician visits, and others also including emergency visits, laboratory and diagnostic tests, or home care. Medication expenditures were accounted for in seven studies, all of which included antiretrovirals, with anti-infective and other medications also included in some of the studies. Table 2 shows the mean monthly expenditure-specific and total direct medical costs (2001 US$) for treating HIV-infected indivuduals using HAART. A tick indicates that the category was included in the cumulative figures, but costs were aggregated to a higher level. A cross indicates that the category was not included. Seven of the nine studies stratified by prognostic laboratory variables, such as CD4 cell count (figure, A) or HIV viral RNA level, or by clinical disease http://infection.thelancet.com Vol 6 March 2006
Review
Country
Disease strata
Type of expenditure Inpatient
France6
USA11
Italy21 England22
Canada23 France24 USA25
Italy26
USA27
CD4 cell count 500 cells per L ✓ CD4 cell count 301–500 cells per L CD4 cell count 201–300 cells per L CD4 cell count 101–200 cells per L CD4 cell count 51–100 cells per L CD4 cell count 50 cells per L History of ADE Current ADE CD4 cell count 500 cells per L 260 CD4 cell count 201–500 cells per L 305 CD4 cell count 51–200 cells per L 520 CD4 cell count 50 cells per L 1325 Viral RNA 10 000 copies per L 287 Viral RNA 10 001–100 000 copies per L 540 Viral RNA 100 000 copies per L 1052 Not stratified 325 Asymptomatic HIV ✓ Symptomatic HIV, not AIDS AIDS Not stratified 97 No AIDS 211 AIDS 475 CD4 cell count 201–500 cells per L 544 CD4 cell count 50–200 cells per L 473 CD4 cell count 50 cells per L 1256 No ADE, CD4 cell count 500 cells per L 149 No ADE, CD4 cell count 200–500 cells per L 197 No ADE, CD4 cell count 200 cells per L 259 ADE at enrollment 678 CD4 cell count 500 cells per L ✓ CD4 cell count 200–499 cells per L CD4 cell count 50–199 cells per L CD4 cell count 50 cells per L Asymptomatic HIV Symptomatic HIV, not AIDS AIDS
Total direct medical costs Outpatient
Medications
✓
✓
164 171 193 223 175 181 203 129 ✓
✕
790 ✕
156 ✓ ✓ 422 700 897 92 98 106 111 ✓
679 705 850 504 647 759 174 350 456 493 ✓
1015 1209 1315 1476 1323 1391 1974 3795 424 476 713 1548 462 721 1255 1244 529 879 2370 933 916 1324 1470 1819 2912 414 645 822 1282 612 1064 1566 2697 1228 1287 2033
ADE=AIDS-defining event. Some totals are not equal to the sum of individual components due to rounding. Ticks indicate that the category was included in the monthly total, but costs were aggregated to a higher level; crosses indicate that the category was not included in the monthly total.
Table 2: Monthly total expenditure-specific and direct medical costs (2001 US$) for treating HIV/AIDS
stage (AIDS vs non-AIDS, asymptomatic vs symptomatic AIDS, or presence/absence of AIDS-defining events). Two studies presented costs for all patients combined, without any stratification.21,23 Because the studies included different categories of expenditures, it was not meaningful to compare outpatient or total costs between studies. However, the total costs could be compared within studies across disease stages, with a consistent trend towards greater costs for patients with more advanced disease. Two types of expenditures were directly comparable between studies. The figure shows the costs per patient in 2001 US$ for studies that reported antiretroviral medications21,23–26 and inpatient visits,11,21,23–26 stratified by CD4 cell count or disease stage where possible. Four studies included the monthly cost of antiretroviral medications. When these were stratified by CD4 cell count, the monthly costs were similar between USA25 and Italy26 ($401 and $350, respectively) for infected people with CD4 cell counts between 200 and 499 copies http://infection.thelancet.com Vol 6 March 2006
per L. For all levels of CD4 cell count, monthly inpatient costs were highest in the USA (figure, B), with increasing costs for lower CD4 cell count and a dramatic rise for people with CD4 cell count less than 50 copies per L. These results were generally consistent between studies. The two studies presenting unstratified estimates, from Italy21 and Canada,23 showed relatively high mean monthly costs of antiretroviral medications and low inpatient costs. Three studies reported specific costs for some cost items included under the larger components of inpatient, outpatient, and medication costs.23,25,26 Costs reported at the lowest level given in the studies are included in table 3. One study reported estimates of the cost of treating an individual during the month of an AIDS-defining event ($3795), the final month of life ($14 655), and the average lifetime cost of treatment ($241 153, discounted at 3%, as recommended by the Panel on Cost Effectiveness in Health and Medicine).6 173
Review
Discussion
A Mean monthly antiretroviral costs per patient (2001 US$)
900
USA Italy France Canada
750
24 21 24 23
600 26 25
450
26 25
25 26 300
150
26
0 B
11 25
Mean monthly inpatient costs per patient (2001 US$)
1300
1100
900
700
26 25
500
300
11
11 25
24 21
11
26 24
26 100
26
23
0 500
200–499
50–199
50
No AIDS
CD4 cell count
AIDS
Unstratified
Disease stage
Figure: Average monthly costs of antiretroviral medications per patient (A) and average monthly costs of acute inpatient hospitalisations per patient (B) Numbers within symbols refer to study citation number; for reference 20, “No AIDS” observation is restricted to individuals with CD4 cell count below 200 copies per L). Country
Disease strata
Canada23 USA25
Not stratified CD4 cell count 201–500 cells per L CD4 cell count 50–200 cells per L CD4 cell count 50 cells per L No ADE, CD4 cell count 500 cells per L No ADE, CD4 cell count 200–500 cells per L No ADE, CD4 cell count 200 cells per L ADE at enrollment
Type of expenditure Inpatient
Italy26
We found substantial variation in studies reporting the total and component-specific direct medical costs of treating HIV-infected individuals in the HAART era. Valid comparisons of the estimates from the nine studies reviewed were not possible because of differences in the specific components included, the heterogeneous nature of the study populations in terms of disease stage, the sources and methods used to estimate unit costs, and the level of aggregation at which results were reported. First, the studies differed in the range of cost components that were included. Although all of the studies reported inpatient and outpatient costs, two studies did not include the cost of medications,11,22 and only one study explicitly mentioned dispensing fees.23 Moreover, of those studies that did report medication costs, only five captured the cost of both antiretroviral and non-antiretroviral medications.6,23–25,27 Besides differences in the components included, there also existed differences between studies in the cost items captured within these components. When defining the total costs attributable to outpatient care, Yazdanpanah and colleagues6 included the mean cost of physician and nurse fees per visit, as well as the total number of laboratory tests and the total number of diagnostic procedures. By comparison, Krentz and co-workers23 included physician, laboratory, and home-care costs, whereas Crane and colleagues11 excluded the cost of laboratory testing and visits in which a healthcare provider was not consulted. Other investigators did not report the specific items of outpatient care that were included.22,24 In future, comparison of direct cost estimates would become more valuable if the components of care and specific cost items were made explicit. Second, two of the studies did not stratify their cost estimates by prognostic laboratory variables such as CD4 cell count, HIV viral RNA, or by clinical disease stage.21,23 Given that, within studies, individuals with more advanced disease incurred higher total costs, unstratified cost estimates reflect the underlying distribution of the study sample with respect to stage of illness. If this is the case, studies in which estimates are not stratified are of limited value in gauging the cost of treatment in
Outpatient
97 (54 HIV/43 non-HIV) NA
156 (128 phys/28 HC) 422 (348 phys/42 emer/33 HC) 700(486 phys/187 emer/27 HC) 897(541 phys/318 emer/38 HC) 149 (3 admissions/146 day admissions) 92 (23 phys/66 lab/2 diag) 197 (18 admissions/179 day admissions) 98 (24 phys/72 lab/1 diag) 259 (60 admissions/199 day admissions) 106 (27 phys/73 lab/7 diag) 678 (190 admissions/489 day admissions) 111 (24 phys/75 lab/11 diag)
Medications (antiretrovirals/non-antiretrovirals) 679 (646/33) 504 (401/103) 647 (455/192) 759 (407/353) NA
ADE=AIDS-defining event; diag=diagnostic tests; emer=emergency; HC=home care; lab=laboratory tests; NA=not applicable; phys=physician outpatient visits.
Table 3: Monthly total expenditure-specific and direct medical costs (2001 US$) for treating HIV/AIDS, reported at the most disaggregated level possible
174
http://infection.thelancet.com Vol 6 March 2006
Review
different populations, or even the same population at a different point in time, due to variation in the distributions of disease stage and related clinical measurements. Cost estimates can be made more applicable to alternative populations, or to the same cohort in the future, by stratifying cost estimates based on prognostic laboratory variables or disease stage and reporting results separately for each stratum. Third, different sources for unit cost measurement were used by the investigators. Economic theory suggests that unit cost should reflect the opportunity cost of resources used in providing a service to HIV-infected patients,13,28 although in practice, because of difficulties in quantifying this measure, charges or average costs are often used as a proxy for opportunity costs.9 Several studies used mean operating costs of one or more clinics21,22,24,26 to estimate the average costs of inpatient and outpatient visits, while the remainder based costs on hospital charges, obtained either directly from the hospital billing system,11,27 or through reimbursement rates.6,23,25 Although these unit cost measures are widely used, it is unlikely that average costs and hospital charges will reflect the opportunity cost of the resources used to treat people with HIV infection or AIDS.13 Market prices were used to estimate drug costs in six studies.6,21,23,24,26,27 Market prices of pharmaceutical products may be poor estimates of opportunity cost because they reflect the patent, the regulation of profits by governments, and the development costs of both successful and unsuccessful products.28 Subtle differences in unit costing methods between studies may induce artificial differences in results. For example, whereas some studies explicitly included overhead and hotel type costs,6 others explicitly excluded those costs for inpatient stays and outpatient visits.21 Also, both Italian studies21,26 estimated the cost of antiretroviral therapy using the tariff set by the Italian National Health Service, which is only 50% of the value of the published market price. To illustrate the implications of this latter example, in part A of the figure it appears as though, for people both with and without AIDS, antiretrovirals are roughly two-fold higher in the French study24 compared with the Italian study by Garattini and colleagues.26 However, given that Garatinni and co-workers’ study26 only represents 50% of actual acquisition costs of medications, there is likely very little difference in true antiretroviral costs between the two studies. Therefore, although estimates can be made more comparable between studies by separating into components and stratifying on disease stage, differences in unit cost measurement continues to limit comparability. For this reason, the figure provides an exploratory comparison but is insufficient for drawing inferences about differences between or among countries. Fourth, the comparability of study results was hampered by differences in the level at which cost estimates were reported. Three studies reported the total http://infection.thelancet.com Vol 6 March 2006
direct cost of treatment only,6,22,27 three studies reported costs separately for inpatient care, outpatient visits, and medications,11,21,24 while other investigators broke down these treatment components into more detailed cost categories.23,25,26 Even where the cost components in each study were similar, there was still considerable variation in the reporting of results. For example, of the five studies that included the cost of both antiretroviral and nonantiretroviral medications,6,23–25,27 two studies did not report a separate cost estimate for medication,6,27 and one study reported an estimate that combined the cost of nonantiretroviral medication with the cost of inpatient care and outpatient visits.24 This variation means that, when comparing estimates of direct medical cost between these studies, it was not possible to evaluate whether similarities and/or differences between studies were attributable to single components of care or the cost items covered within these components. These factors make international comparisons dubious, since treatment patterns and the inputs into this care may differ between countries.29,30 Reporting cost estimates at the lowest disaggregated level would help to resolve this issue. A final factor affecting the applicability of cost of illness studies, unrelated to methodology, is the timeliness of published estimates. Treatment patterns in HIV/AIDS continue to evolve, with new medications within existing classes frequently becoming available.31,32 New classes of antiretrovirals are also appearing—eg, the fusion inhibitors that recently became available.33 Given the high acquisition costs typically associated with new drugs,34,35 the introduction of new antiretroviral drugs may have substantial effects on treatment costs even when the effects on disease processes are less pronounced. As a result, even the most methodologically rigorous studies must address the fact that point estimates of treatment costs based on current guidelines may no longer accurately reflect treatment costs by the time they appear in print.36 The implication is that estimates of direct treatment costs must be regularly monitored and updated if they are to be useful to health-care managers in resource planning or in determining the cost effectiveness of preventive and treatment programmes. One method of overcoming these challenges is through computer simulation. Simulation techniques involve generating hypothetical patients who are assigned clinical characteristics based on the distribution of these characteristics in a population of interest. Individual trajectories are simulated based on existing data describing the natural history of HIV/AIDS, and monthly resource use, stratified by prognostic laboratory variables or disease stage, can be recorded. Monthly direct medical costs can be calculated by multiplying average resource use by their unit costs. The simulation can be altered to reflect alternative unit costs, different treatment strategies, or populations with different distributions of severity and can be used to produce estimates at higher or lower levels of aggregation. As a 175
Review
Search strategy and selection criteria Relevant studies were identified from Medline, the Web of Science, and additional references cited within the articles retrieved. Keywords were “HIV” or “AIDS”, cross-referenced with “cost,” “expenditure,” or “utilisation.” Dates for inclusion were between January 1996 and June 2005. Abstracts were not considered.
result, simulation tools can be used to make more valid comparisons between populations and can easily update estimates if the introduction of new medications induces changes in total direct treatment costs. Using a computer simulation tool, Yazdanpanah and colleagues6 were able to do a sensitivity analysis to incorporate multiple sources of variation when quantifying the uncertainty in their final estimates. Simulation tools can be updated as clinical practice changes. Simulation models can also aid in the estimation of lifetime treatment costs associated with HIV. For example, Yazdanpanah and colleagues6 estimated a projected lifetime cost of treating HIV-infected people in France. Simulation models can thereby assist health-care managers to plan future resource requirements. To summarise, the advent of HAART has major implications for the cost of treating people infected with HIV. To date, however, only a small number of studies have been published that provide useful estimates of the direct cost. Cost estimates can be made more generalisable by stratifying cost estimates based on prognostic laboratory variables or disease stage and reporting results separately for each stratum. One useful and underused method of estimating resource use and costs is computer simulation. Conflicts of interest ARL is supported by a Michael Smith Foundation for Health Research Scholar Award and a Canadian Institutes of Health Research New Investigator award. He is a shareholder in Oxford Outcomes, a consultancy specialising in contract research for a wide range of clients in the life sciences industry, including both public sector organisations as well as pharmaceutical and other private companies. DJ has no conflicts of interest to declare. KMJ is supported by the Michael Smith Foundation for Health Research through a Junior Fellowship Award and has no conflicts of interest to declare. RSH is partly supported by the Michael Smith Foundation for Health Research through a Senior Scholar Award. He has held grant funding from the National Institutes of Health, Canadian Institutes of Health Research National Health Research Development Program, and Health Canada. He has received grant funding and honoraria and/or reimbursement from the pharmaceutical industry for participating in continued medical education programmes and conferences from Agouron Pharmaceuticals Inc, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb, GlaxoSmithKline, and Merck Frosst Laboratories. PRH has worked as an employee in the pharmaceutical industry (Glaxo Wellcome) and HIV diagnostic industries (Virco). He has received fees for consulting, honoraria, owned stock, acted as a consultant, and received fees or grants from a wide range of pharmaceutical and HIV diagnostic and therapeutic monitoring companies, including Abbott Laboratories, Agouron Pharmaceuticals Inc, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers
176
Squibb, GlaxoSmithKline, Hoffman-La Roche, Merck Frosst Laboratories, Pfizer Inc, and Virco. BPH is employed at a contract research organisation that does work with a wide range of clients in the pharmaceutical industry, including AstraZeneca, Bayer, BristolMyers Squibb, GlaxoSmithKline, Johnson and Johnson, Novartis, Merck, Pfizer, Roche, Sanofi-Aventis, Novo Nordisk, and Schering. BS has no conflicts of interest to declare. JSM has received consulting fees, served on paid advisory boards, or received lecture fees from Avexa Ltd, Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals Inc, Borean Pharma AS, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoffman-La Roche, Immune Response Corporation, Janssen-Ortho Inc, Kucera Pharmaceutical Company, Merck Frosst Laboratories, Pfizer Canada Inc, Shire Biochem Inc, Tibotec Pharmaceuticals Inc, and Trimeris Inc. References 1 UNAIDS/WHO. AIDS epidemic update: December 2005. http:// www.unaids.org/epi2005/doc/report_pdf.html (accessed Jan 19, 2006). 2 Ledergerber B, Egger M, Opravil M, et al. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Lancet 1999; 353: 863–68. 3 Moore RD, Chaisson RE. Natural history of HIV infection in the era of combination antiretroviral therapy. AIDS 1999; 13: 1933–42. 4 Mouton Y, Alfandari S, Valette M, et al. Impact of protease inhibitors on AIDS-defining events and hospitalizations in 10 French AIDS reference centres. AIDS 1997; 11: F101–05. 5 Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338: 853–60. 6 Yazdanpanah Y, Goldie SJ, Losina E, et al. Lifetime cost of HIV care in France during the era of highly active antiretroviral therapy. Antivir Ther 2002; 7: 257–66. 7 Health Canada. Looking forward: focussing the response. Canada’s report on HIV/AIDS 2003. http://www.phac-aspc.gc.ca/aidssida/hiv_aids/report03/index.html (accessed Jan 19, 2006). 8 UNAIDS. Global summary of the HIV and AIDS epidemic in 2005. http://www.unaids.org/EN/resources/epidemiology/epicore. asp (accessed Jan 19, 2006). 9 Beck EJ, Miners AH, Tolley K. The cost of HIV treatment and care. A global review. Pharmacoeconomics 2001; 19: 13–39. 10 Hellinger FJ. HIV patients in the HCUP database: a study of hospital utilization and costs. Inquiry 2004; 41: 95–105. 11 Crane L, Crowe R, Fine S, et al. Hospital and outpatient health services utilization among HIV-infected patients in care in 1999. J Acquir Immune Defic Syndr 2002; 30: 21–26. 12 Krentz HB, Gill MJ. Impact of practice changes on an antiretroviral budget in an HIV care program. Disease Management and Health Outcomes 2005; 13: 209–17. 13 Tolley K, Gyldmark M. The treatment and care costs of people with HIV-infection or AIDS: development of a standardized cost framework for Europe. Health Policy 1993; 24: 55–70. 14 Tyndall MW, Currie S, Spittal P, et al. Intensive injection cocaine use as the primary risk factor in the Vancouver HIV-1 epidemic. AIDS 2003; 17: 887–93. 15 BC Ministry of Health Planning. Priorities for action in managing the epidemics. HIV/AIDS in BC: 2003–2007. http://www.health services.gov.bc.ca/hiv/priorities.html (accessed Jan 19, 2006). 16 Holtgrave DR, Qualls NL, Graham JD. Economic evaluation of HIV prevention programs. Annu Rev Public Health 1996; 17: 467–88. 17 Holtgrave DR, Pinkerton SD. Updates of cost of illness and quality of life estimates for use in economic evaluations of HIV prevention programs. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 16: 54–62. 18 Drummond MF, O’Brien B, Stoddart G, Torrance GW. Methods for the economic evaluation of health care programmes, 2nd edit. Oxford: Oxford Medical Publications, 1997. 19 Youle M, Trueman P, Simpson K. Health economics in HIV disease. A review of the European literature. Pharmacoeconomics 1999; 15: 1–12. 20 Organisation for Economic Co-operation and Development (OECD). Health data 2004. http://www.oecd.com (accessed Jan 31, 2006).
http://infection.thelancet.com Vol 6 March 2006
Review
21
22
23
24
25
26
27
28
Tramarin A, Campostrini S, Postma MJ, et al. A multicentre study of patient survival, disability, quality of life and cost of care: among patients with AIDS in northern Italy. Pharmacoeconomics 2004; 22: 43–53. Beck EJ, Tolley K. Financing HIV service provision in England: estimated impact of the cost of antiretroviral combination therapy. Int J STD AIDS 1998; 9: 512–17. Krentz HB, Auld MC, Gill MJ. The changing direct costs of medical care for patients with HIV/AIDS, 1995–2001. CMAJ 2003; 169: 106–10. Basuyau F, Josset V, Merle V, Czernichow P. Case fatality and health care costs in HIV-infected patients: evolution from 1992 to 2000 at Rouen University Hospital, France. Int J STD AIDS 2004; 15: 679–84. Gebo KA, Chaisson RE, Folkemer JG, Bartlett JG, Moore RD. Costs of HIV medical care in the era of highly active antiretroviral therapy. AIDS 1999; 13: 963–69. Garattini L, Tediosi F, Di Cintio E, Yin D, Parazzini F. Resource utilization and hospital cost of HIV/AIDS care in Italy in the era of highly active antiretroviral therapy. AIDS Care 2001; 13: 733–41. Bozzette SA, Joyce G, McCaffrey DF, et al. Expenditures for the care of HIV-infected patients in the era of highly active antiretroviral therapy. N Engl J Med 2001; 344: 817–23. Palmer S, Raftery J. Economics notes: opportunity cost. BMJ 1999; 318: 1551–52.
http://infection.thelancet.com Vol 6 March 2006
29
30
31
32
33
34
35 36
European AIDS Clinical Society. European guidelines for the clinical management and treatment of HIV infected adults 2005. http://www.eacs.ws/download/Euroguidelines4151105.pdf (accessed Jan 19, 2006). Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Bethesda, MD, USA: Department of Health and Human Services, 2005. US Food and Drug Administration. Drugs used in the treatment of HIV infection. http://www.fda.gov/oashi/aids/virals.html (accessed Jan 19, 2006). Yeni PG, Hammer SM, Hirsch MS, et al. Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA panel. JAMA 2004; 292: 251–65. Jamjian MC, McNicholl IR. Enfuvirtide: first fusion inhibitor for treatment of HIV infection. Am J Health Syst Phar 2004; 61: 1242–47. Shah ND, Hoffman JM, Vermeulen LC, Hunkler RJ, Hontz KM. Projecting future drug expenditures – 2003. Am J Health Syst Pharm 2003; 60: 137–49. Leao JC, Frezzini C, Porter S. Enfuvirtide: a new class of antiretroviral therapy for HIV infection. Oral Dis 2004; 10: 327–29. Rabeneck L, Menke T, Wray NP. How good are US studies of HIV costs of care? Medical Care 1999; 37: 748–59.
177
The direct costs of HIV/AIDS care Adrian R Levy, Douglas James, Karissa M Johnston, Robert S Hogg, P Richard Harrigan, Brian P Harrigan, Boris Sobolev, Julio S Montaner
We reviewed published studies reporting the direct medical costs of treating HIV-infected people in countries using highly active antiretroviral therapy (HAART). Of 543 potentially relevant studies, only nine provided adequate data to make a meaningful statement about costs. Within studies, people with more advanced disease incurred higher total costs. Valid comparisons of total direct medical costs between studies were not possible because of differences in the specific components included, the heterogeneous nature of study populations in terms of disease stage, the sources and methods used to estimate unit costs, and the level of aggregation at which results were reported. The advent of HAART has major implications for the cost of treating HIV-infected individuals. Although this information is important for planning purposes, only a small number of published studies provide useful estimates of the direct cost. A useful method of estimating resource use and costs is computer simulation.
Introduction AIDS is characterised by the progressive destruction of a person’s immune system and is the late and most serious stage of HIV infection. Over the past two decades, the epidemic has become a major challenge to health-care systems, with more than 20 million people dying from HIV/AIDS and a further 40·3 million people worldwide estimated to be infected in 2005.1 Recent advances in treatment, especially the use of potent combinations of nucleoside reverse transcriptase inhibitors, protease inhibitors, and non-nucleoside reverse transcriptase inhibitors (referred to as highly active antiretroviral therapy, or HAART), have resulted in dramatic reductions in the rates of HIV disease progression, opportunistic infections, hospital admissions, and deaths.2–5 In developed countries, the remarkable success of HAART has also altered the use of health-care resources for HIVinfected patients, with the nature of treatment shifting from inpatient hospital admissions to outpatient care and greater use of medications in the outpatient setting.6 Furthermore, HIV prevalence is increasing in western countries as a consequence of falling death rates.1,7,8 These changes have occurred against a background of little empirical evidence about the direct costs of treating HIV-infected people in terms of per-person annual expenditures and lifetime costs,9,10 the implications on the cost of using different treatment strategies,11,12 or the extent to which costs vary by stage of HIV infection.13 Information on the direct costs of treatment is important since it provides a basis for health planners to allocate budgets or reimburse specific categories of expenditures. It also enables policymakers, when faced with changes in prevalence—eg, that currently occurring with the spread of HIV infection among injection drug users14—to make more informed choices between programmes. To optimally allocate scarce economic resources to prevention and treatment programmes, planners require accurate, up-to-date estimates of the direct costs of treatment.15–17 Although economic evaluation is an important approach for establishing priorities for health interventions,6,18,19 in practice this type of evaluation has been of limited value in HIV/AIDS because of the paucity of accurate cost data.9 http://infection.thelancet.com Vol 6 March 2006
The purpose of this review is to identify published estimates of the direct medical costs, including hospital inpatient, outpatient, and medication costs for treating HIV-infected individuals after HAART was introduced into routine clinical practice, to determine the extent to which these estimates can be validly compared, and to make such comparisons where possible. In cases where meaningful comparisons are not possible, we explain why this is the case. We also discuss the implications for future research in this area.
Methods To be included, studies had to meet pre-specified criteria for information content. We identified studies that included an original estimate of the mean monthly or annual direct medical costs of treating an HIV-infected individual. We included studies from English language peer-reviewed published work that provided enough detail to allow meaningful comparisons by explicitly describing the study period, location and population (demographic and clinical distributions), types of treatments, data sources, and methods used for cost estimates. Use of health-care resources must have been estimated at an individual level, either through administrative or HIV clinic databases or patient questionnaires. Furthermore, studies must have analysed data in which HAART was included as routine clinical practice. This criterion eliminated a large proportion of studies published before 1999 that used data from before the advent of HAART.9 All studies were reviewed by two investigators (DJ, KMJ) and discrepancies resolved by consensus. Information on three types of expenditures—ie, inpatient, outpatient, and medications—was sought from each study. For each category, we collected information on the data sources used for resource use, the source of unit costs, and the mean monthly or annual cost. Costs were recorded at the most disaggregated level available. Two procedures were used to convert costs into a common price year and account for differences in currency. Inflation rate differences were taken into account by converting the results from each study into a common price year (2001) using country-specific health
Lancet Infect Dis 2006; 6: 171–77 ARL and KMJ are at the Department of Health Care and Epidemiology, University of British Columbia, Vancouver, BC, Canada, and also at the Centre for Health Evaluation and Outcome Sciences, St Paul’s Hospital, Vancouver. RSH is at the Department of Health Care and Epidemiology, University of British Columbia, and also at the BC Centre for Excellence in HIV/AIDS, St Paul’s Hospital. PRH and JSM are at the BC Centre for Excellence in HIV/AIDS, St Paul’s Hospital, and also at the Department of Medicine, University of British Columbia. BS is at the Department of Health Care and Epidemiology, University of British Columbia. DJ is at the Centre for Health Evaluation and Outcome Sciences, St Paul’s Hospital. BPH was at the BC Centre for Excellence in HIV/AIDS, St Paul’s Hospital. BPH is now at Oxford Outcomes Ltd, Vancouver, Canada. Correspondence to: Dr Adrian R Levy, St Paul’s Hospital, 620-1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada. Tel +1 604 806 8691; fax +1 604 806 8005; [email protected]
171
Review
Country Years
Number of patients/ Variability Data sources population based? reported?
Type of expenditure Inpatient
Outpatient
Source of unit costs
Components
Source of unit costs
Outpatient physician visits, laboratory and diagnostic tests Outpatient physician visits Outpatient physician visits, diagnostic tests Outpatient physician visits Outpatient physician visits, laboratory tests, home care Outpatient physician visits
Reimbursement rates
France6
1994–98 1232/no
Yes
HIV clinic database
Reimbursement rates
USA11 Italy21
1999 1998
5255/no 74/no
No No
HIV clinic database HIV clinic database
Hospital costing survey Hospital costing survey
England22 1996 Canada23 2000
5708/no 654/yes
Yes No
HIV clinic database Hospital costing survey Administrative databases Reimbursement rates
France24 2000
1212/no
No
695/no
Yes
Italy26
1997–98 473/no
No
USA27
1996–98 2864/no
Yes
USA
25
1997
Medications Components
Antiretrovirals, anti-infectives, all other* Hospital costing survey .. Hospital costing survey Antiretrovirals
Hospital costing survey .. Reimbursement rates Antiretrovirals, all other Administrative databases Hospital costing survey Reimbursement rates Antiretrovirals, anti-infectives† Administrative databases Reimbursement rates Outpatient physician and Reimbursement rates Antiretrovirals, emergency visits, home care all other Patient questionnaire Hospital costing survey Outpatient physician visits, Hospital costing survey Antiretrovirals laboratory and diagnostic tests Patient questionnaire Hospital costing survey Outpatient physician and Hospital costing survey Antiretrovirals, emergency visits all other
Source of unit costs Market price
NA Market price† NA Market price Market price Reimbursement rates Market price‡
Market price
..=not reported; NA=not applicable. *Included all drugs for inpatients and chemoprophylaxis for outpatients. †Anti-infective treatments were included under inpatient costs. ‡The two Italian studies used market prices but only included 50% to represent the portion paid by the Italian government.
Table 1: Characteristics of studies, types of expenditures, and costing methods included in estimating direct medical costs of treating HIV/AIDS since the introduction of HAART according to type of expenditure
expenditure inflators.20 To account for differences in the relative unit costs of health-care service across countries, health-specific purchasing power parities20 were used to express all cost estimates in US dollars. Results reported as annual costs were directly converted to monthly costs.
Results Of 543 titles initially identified, 92 were flagged as potentially relevant. Based on the abstracts, full versions of 33 were obtained. Another six relevant publications were cited within retrieved articles. After reviewing each study, nine were judged to meet the inclusion criteria. Table 1 summarises the major characteristics of each study. The studies ranged in the number of included people from 7421 to 5708,22 and one study was considered population based23 because it included all patients from an entire catchment area. Four studies provided a measure of variability for the cost estimate. All nine studies used a “bottom-up” approach18 to estimate direct medical costs, in which data were collected on the resource inputs for each patient and that service use was multiplied by unit costs to produce a monthly (or annual) direct cost per patient. Some studies used different unit costs based on the intensity of the visit,24 the clinical stage of the individual,22 or the specific treatments received.6,23,25 Different sources for unit cost measurements were used by the studies. Hospital costing surveys (including per diem rates and hospital charges) were used in six studies to obtain unit costs for inpatient services and in 172
five studies to obtain unit costs for outpatient services, with the remaining estimates of inpatient and outpatient unit costs obtained using reimbursement rates. Two of the costing surveys considered the costs incurred by a single clinic,21,26 one examined costing data from six clinics,22 and the remaining three used results from national-level surveys.11,24,27 Reimbursement rates were considered from the perspective of a private insurer25 or a publicly funded system.6,23,24 Of the seven studies that included the costs of antiretroviral medications, six used market prices,6,21,23,24,26,27 although the two Italian studies21,26 took the perspective of the Italian government and only included 50% of market cost in their estimate. The remaining study priced drugs with reimbursement rates to a private insurer.25 The components included in outpatient expenditures varied among studies, with some including only outpatient physician visits, and others also including emergency visits, laboratory and diagnostic tests, or home care. Medication expenditures were accounted for in seven studies, all of which included antiretrovirals, with anti-infective and other medications also included in some of the studies. Table 2 shows the mean monthly expenditure-specific and total direct medical costs (2001 US$) for treating HIV-infected indivuduals using HAART. A tick indicates that the category was included in the cumulative figures, but costs were aggregated to a higher level. A cross indicates that the category was not included. Seven of the nine studies stratified by prognostic laboratory variables, such as CD4 cell count (figure, A) or HIV viral RNA level, or by clinical disease http://infection.thelancet.com Vol 6 March 2006
Review
Country
Disease strata
Type of expenditure Inpatient
France6
USA11
Italy21 England22
Canada23 France24 USA25
Italy26
USA27
CD4 cell count 500 cells per L ✓ CD4 cell count 301–500 cells per L CD4 cell count 201–300 cells per L CD4 cell count 101–200 cells per L CD4 cell count 51–100 cells per L CD4 cell count 50 cells per L History of ADE Current ADE CD4 cell count 500 cells per L 260 CD4 cell count 201–500 cells per L 305 CD4 cell count 51–200 cells per L 520 CD4 cell count 50 cells per L 1325 Viral RNA 10 000 copies per L 287 Viral RNA 10 001–100 000 copies per L 540 Viral RNA 100 000 copies per L 1052 Not stratified 325 Asymptomatic HIV ✓ Symptomatic HIV, not AIDS AIDS Not stratified 97 No AIDS 211 AIDS 475 CD4 cell count 201–500 cells per L 544 CD4 cell count 50–200 cells per L 473 CD4 cell count 50 cells per L 1256 No ADE, CD4 cell count 500 cells per L 149 No ADE, CD4 cell count 200–500 cells per L 197 No ADE, CD4 cell count 200 cells per L 259 ADE at enrollment 678 CD4 cell count 500 cells per L ✓ CD4 cell count 200–499 cells per L CD4 cell count 50–199 cells per L CD4 cell count 50 cells per L Asymptomatic HIV Symptomatic HIV, not AIDS AIDS
Total direct medical costs Outpatient
Medications
✓
✓
164 171 193 223 175 181 203 129 ✓
✕
790 ✕
156 ✓ ✓ 422 700 897 92 98 106 111 ✓
679 705 850 504 647 759 174 350 456 493 ✓
1015 1209 1315 1476 1323 1391 1974 3795 424 476 713 1548 462 721 1255 1244 529 879 2370 933 916 1324 1470 1819 2912 414 645 822 1282 612 1064 1566 2697 1228 1287 2033
ADE=AIDS-defining event. Some totals are not equal to the sum of individual components due to rounding. Ticks indicate that the category was included in the monthly total, but costs were aggregated to a higher level; crosses indicate that the category was not included in the monthly total.
Table 2: Monthly total expenditure-specific and direct medical costs (2001 US$) for treating HIV/AIDS
stage (AIDS vs non-AIDS, asymptomatic vs symptomatic AIDS, or presence/absence of AIDS-defining events). Two studies presented costs for all patients combined, without any stratification.21,23 Because the studies included different categories of expenditures, it was not meaningful to compare outpatient or total costs between studies. However, the total costs could be compared within studies across disease stages, with a consistent trend towards greater costs for patients with more advanced disease. Two types of expenditures were directly comparable between studies. The figure shows the costs per patient in 2001 US$ for studies that reported antiretroviral medications21,23–26 and inpatient visits,11,21,23–26 stratified by CD4 cell count or disease stage where possible. Four studies included the monthly cost of antiretroviral medications. When these were stratified by CD4 cell count, the monthly costs were similar between USA25 and Italy26 ($401 and $350, respectively) for infected people with CD4 cell counts between 200 and 499 copies http://infection.thelancet.com Vol 6 March 2006
per L. For all levels of CD4 cell count, monthly inpatient costs were highest in the USA (figure, B), with increasing costs for lower CD4 cell count and a dramatic rise for people with CD4 cell count less than 50 copies per L. These results were generally consistent between studies. The two studies presenting unstratified estimates, from Italy21 and Canada,23 showed relatively high mean monthly costs of antiretroviral medications and low inpatient costs. Three studies reported specific costs for some cost items included under the larger components of inpatient, outpatient, and medication costs.23,25,26 Costs reported at the lowest level given in the studies are included in table 3. One study reported estimates of the cost of treating an individual during the month of an AIDS-defining event ($3795), the final month of life ($14 655), and the average lifetime cost of treatment ($241 153, discounted at 3%, as recommended by the Panel on Cost Effectiveness in Health and Medicine).6 173
Review
Discussion
A Mean monthly antiretroviral costs per patient (2001 US$)
900
USA Italy France Canada
750
24 21 24 23
600 26 25
450
26 25
25 26 300
150
26
0 B
11 25
Mean monthly inpatient costs per patient (2001 US$)
1300
1100
900
700
26 25
500
300
11
11 25
24 21
11
26 24
26 100
26
23
0 500
200–499
50–199
50
No AIDS
CD4 cell count
AIDS
Unstratified
Disease stage
Figure: Average monthly costs of antiretroviral medications per patient (A) and average monthly costs of acute inpatient hospitalisations per patient (B) Numbers within symbols refer to study citation number; for reference 20, “No AIDS” observation is restricted to individuals with CD4 cell count below 200 copies per L). Country
Disease strata
Canada23 USA25
Not stratified CD4 cell count 201–500 cells per L CD4 cell count 50–200 cells per L CD4 cell count 50 cells per L No ADE, CD4 cell count 500 cells per L No ADE, CD4 cell count 200–500 cells per L No ADE, CD4 cell count 200 cells per L ADE at enrollment
Type of expenditure Inpatient
Italy26
We found substantial variation in studies reporting the total and component-specific direct medical costs of treating HIV-infected individuals in the HAART era. Valid comparisons of the estimates from the nine studies reviewed were not possible because of differences in the specific components included, the heterogeneous nature of the study populations in terms of disease stage, the sources and methods used to estimate unit costs, and the level of aggregation at which results were reported. First, the studies differed in the range of cost components that were included. Although all of the studies reported inpatient and outpatient costs, two studies did not include the cost of medications,11,22 and only one study explicitly mentioned dispensing fees.23 Moreover, of those studies that did report medication costs, only five captured the cost of both antiretroviral and non-antiretroviral medications.6,23–25,27 Besides differences in the components included, there also existed differences between studies in the cost items captured within these components. When defining the total costs attributable to outpatient care, Yazdanpanah and colleagues6 included the mean cost of physician and nurse fees per visit, as well as the total number of laboratory tests and the total number of diagnostic procedures. By comparison, Krentz and co-workers23 included physician, laboratory, and home-care costs, whereas Crane and colleagues11 excluded the cost of laboratory testing and visits in which a healthcare provider was not consulted. Other investigators did not report the specific items of outpatient care that were included.22,24 In future, comparison of direct cost estimates would become more valuable if the components of care and specific cost items were made explicit. Second, two of the studies did not stratify their cost estimates by prognostic laboratory variables such as CD4 cell count, HIV viral RNA, or by clinical disease stage.21,23 Given that, within studies, individuals with more advanced disease incurred higher total costs, unstratified cost estimates reflect the underlying distribution of the study sample with respect to stage of illness. If this is the case, studies in which estimates are not stratified are of limited value in gauging the cost of treatment in
Outpatient
97 (54 HIV/43 non-HIV) NA
156 (128 phys/28 HC) 422 (348 phys/42 emer/33 HC) 700(486 phys/187 emer/27 HC) 897(541 phys/318 emer/38 HC) 149 (3 admissions/146 day admissions) 92 (23 phys/66 lab/2 diag) 197 (18 admissions/179 day admissions) 98 (24 phys/72 lab/1 diag) 259 (60 admissions/199 day admissions) 106 (27 phys/73 lab/7 diag) 678 (190 admissions/489 day admissions) 111 (24 phys/75 lab/11 diag)
Medications (antiretrovirals/non-antiretrovirals) 679 (646/33) 504 (401/103) 647 (455/192) 759 (407/353) NA
ADE=AIDS-defining event; diag=diagnostic tests; emer=emergency; HC=home care; lab=laboratory tests; NA=not applicable; phys=physician outpatient visits.
Table 3: Monthly total expenditure-specific and direct medical costs (2001 US$) for treating HIV/AIDS, reported at the most disaggregated level possible
174
http://infection.thelancet.com Vol 6 March 2006
Review
different populations, or even the same population at a different point in time, due to variation in the distributions of disease stage and related clinical measurements. Cost estimates can be made more applicable to alternative populations, or to the same cohort in the future, by stratifying cost estimates based on prognostic laboratory variables or disease stage and reporting results separately for each stratum. Third, different sources for unit cost measurement were used by the investigators. Economic theory suggests that unit cost should reflect the opportunity cost of resources used in providing a service to HIV-infected patients,13,28 although in practice, because of difficulties in quantifying this measure, charges or average costs are often used as a proxy for opportunity costs.9 Several studies used mean operating costs of one or more clinics21,22,24,26 to estimate the average costs of inpatient and outpatient visits, while the remainder based costs on hospital charges, obtained either directly from the hospital billing system,11,27 or through reimbursement rates.6,23,25 Although these unit cost measures are widely used, it is unlikely that average costs and hospital charges will reflect the opportunity cost of the resources used to treat people with HIV infection or AIDS.13 Market prices were used to estimate drug costs in six studies.6,21,23,24,26,27 Market prices of pharmaceutical products may be poor estimates of opportunity cost because they reflect the patent, the regulation of profits by governments, and the development costs of both successful and unsuccessful products.28 Subtle differences in unit costing methods between studies may induce artificial differences in results. For example, whereas some studies explicitly included overhead and hotel type costs,6 others explicitly excluded those costs for inpatient stays and outpatient visits.21 Also, both Italian studies21,26 estimated the cost of antiretroviral therapy using the tariff set by the Italian National Health Service, which is only 50% of the value of the published market price. To illustrate the implications of this latter example, in part A of the figure it appears as though, for people both with and without AIDS, antiretrovirals are roughly two-fold higher in the French study24 compared with the Italian study by Garattini and colleagues.26 However, given that Garatinni and co-workers’ study26 only represents 50% of actual acquisition costs of medications, there is likely very little difference in true antiretroviral costs between the two studies. Therefore, although estimates can be made more comparable between studies by separating into components and stratifying on disease stage, differences in unit cost measurement continues to limit comparability. For this reason, the figure provides an exploratory comparison but is insufficient for drawing inferences about differences between or among countries. Fourth, the comparability of study results was hampered by differences in the level at which cost estimates were reported. Three studies reported the total http://infection.thelancet.com Vol 6 March 2006
direct cost of treatment only,6,22,27 three studies reported costs separately for inpatient care, outpatient visits, and medications,11,21,24 while other investigators broke down these treatment components into more detailed cost categories.23,25,26 Even where the cost components in each study were similar, there was still considerable variation in the reporting of results. For example, of the five studies that included the cost of both antiretroviral and nonantiretroviral medications,6,23–25,27 two studies did not report a separate cost estimate for medication,6,27 and one study reported an estimate that combined the cost of nonantiretroviral medication with the cost of inpatient care and outpatient visits.24 This variation means that, when comparing estimates of direct medical cost between these studies, it was not possible to evaluate whether similarities and/or differences between studies were attributable to single components of care or the cost items covered within these components. These factors make international comparisons dubious, since treatment patterns and the inputs into this care may differ between countries.29,30 Reporting cost estimates at the lowest disaggregated level would help to resolve this issue. A final factor affecting the applicability of cost of illness studies, unrelated to methodology, is the timeliness of published estimates. Treatment patterns in HIV/AIDS continue to evolve, with new medications within existing classes frequently becoming available.31,32 New classes of antiretrovirals are also appearing—eg, the fusion inhibitors that recently became available.33 Given the high acquisition costs typically associated with new drugs,34,35 the introduction of new antiretroviral drugs may have substantial effects on treatment costs even when the effects on disease processes are less pronounced. As a result, even the most methodologically rigorous studies must address the fact that point estimates of treatment costs based on current guidelines may no longer accurately reflect treatment costs by the time they appear in print.36 The implication is that estimates of direct treatment costs must be regularly monitored and updated if they are to be useful to health-care managers in resource planning or in determining the cost effectiveness of preventive and treatment programmes. One method of overcoming these challenges is through computer simulation. Simulation techniques involve generating hypothetical patients who are assigned clinical characteristics based on the distribution of these characteristics in a population of interest. Individual trajectories are simulated based on existing data describing the natural history of HIV/AIDS, and monthly resource use, stratified by prognostic laboratory variables or disease stage, can be recorded. Monthly direct medical costs can be calculated by multiplying average resource use by their unit costs. The simulation can be altered to reflect alternative unit costs, different treatment strategies, or populations with different distributions of severity and can be used to produce estimates at higher or lower levels of aggregation. As a 175
Review
Search strategy and selection criteria Relevant studies were identified from Medline, the Web of Science, and additional references cited within the articles retrieved. Keywords were “HIV” or “AIDS”, cross-referenced with “cost,” “expenditure,” or “utilisation.” Dates for inclusion were between January 1996 and June 2005. Abstracts were not considered.
result, simulation tools can be used to make more valid comparisons between populations and can easily update estimates if the introduction of new medications induces changes in total direct treatment costs. Using a computer simulation tool, Yazdanpanah and colleagues6 were able to do a sensitivity analysis to incorporate multiple sources of variation when quantifying the uncertainty in their final estimates. Simulation tools can be updated as clinical practice changes. Simulation models can also aid in the estimation of lifetime treatment costs associated with HIV. For example, Yazdanpanah and colleagues6 estimated a projected lifetime cost of treating HIV-infected people in France. Simulation models can thereby assist health-care managers to plan future resource requirements. To summarise, the advent of HAART has major implications for the cost of treating people infected with HIV. To date, however, only a small number of studies have been published that provide useful estimates of the direct cost. Cost estimates can be made more generalisable by stratifying cost estimates based on prognostic laboratory variables or disease stage and reporting results separately for each stratum. One useful and underused method of estimating resource use and costs is computer simulation. Conflicts of interest ARL is supported by a Michael Smith Foundation for Health Research Scholar Award and a Canadian Institutes of Health Research New Investigator award. He is a shareholder in Oxford Outcomes, a consultancy specialising in contract research for a wide range of clients in the life sciences industry, including both public sector organisations as well as pharmaceutical and other private companies. DJ has no conflicts of interest to declare. KMJ is supported by the Michael Smith Foundation for Health Research through a Junior Fellowship Award and has no conflicts of interest to declare. RSH is partly supported by the Michael Smith Foundation for Health Research through a Senior Scholar Award. He has held grant funding from the National Institutes of Health, Canadian Institutes of Health Research National Health Research Development Program, and Health Canada. He has received grant funding and honoraria and/or reimbursement from the pharmaceutical industry for participating in continued medical education programmes and conferences from Agouron Pharmaceuticals Inc, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb, GlaxoSmithKline, and Merck Frosst Laboratories. PRH has worked as an employee in the pharmaceutical industry (Glaxo Wellcome) and HIV diagnostic industries (Virco). He has received fees for consulting, honoraria, owned stock, acted as a consultant, and received fees or grants from a wide range of pharmaceutical and HIV diagnostic and therapeutic monitoring companies, including Abbott Laboratories, Agouron Pharmaceuticals Inc, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers
176
Squibb, GlaxoSmithKline, Hoffman-La Roche, Merck Frosst Laboratories, Pfizer Inc, and Virco. BPH is employed at a contract research organisation that does work with a wide range of clients in the pharmaceutical industry, including AstraZeneca, Bayer, BristolMyers Squibb, GlaxoSmithKline, Johnson and Johnson, Novartis, Merck, Pfizer, Roche, Sanofi-Aventis, Novo Nordisk, and Schering. BS has no conflicts of interest to declare. JSM has received consulting fees, served on paid advisory boards, or received lecture fees from Avexa Ltd, Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals Inc, Borean Pharma AS, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoffman-La Roche, Immune Response Corporation, Janssen-Ortho Inc, Kucera Pharmaceutical Company, Merck Frosst Laboratories, Pfizer Canada Inc, Shire Biochem Inc, Tibotec Pharmaceuticals Inc, and Trimeris Inc. References 1 UNAIDS/WHO. AIDS epidemic update: December 2005. http:// www.unaids.org/epi2005/doc/report_pdf.html (accessed Jan 19, 2006). 2 Ledergerber B, Egger M, Opravil M, et al. Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study. Lancet 1999; 353: 863–68. 3 Moore RD, Chaisson RE. Natural history of HIV infection in the era of combination antiretroviral therapy. AIDS 1999; 13: 1933–42. 4 Mouton Y, Alfandari S, Valette M, et al. Impact of protease inhibitors on AIDS-defining events and hospitalizations in 10 French AIDS reference centres. AIDS 1997; 11: F101–05. 5 Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338: 853–60. 6 Yazdanpanah Y, Goldie SJ, Losina E, et al. Lifetime cost of HIV care in France during the era of highly active antiretroviral therapy. Antivir Ther 2002; 7: 257–66. 7 Health Canada. Looking forward: focussing the response. Canada’s report on HIV/AIDS 2003. http://www.phac-aspc.gc.ca/aidssida/hiv_aids/report03/index.html (accessed Jan 19, 2006). 8 UNAIDS. Global summary of the HIV and AIDS epidemic in 2005. http://www.unaids.org/EN/resources/epidemiology/epicore. asp (accessed Jan 19, 2006). 9 Beck EJ, Miners AH, Tolley K. The cost of HIV treatment and care. A global review. Pharmacoeconomics 2001; 19: 13–39. 10 Hellinger FJ. HIV patients in the HCUP database: a study of hospital utilization and costs. Inquiry 2004; 41: 95–105. 11 Crane L, Crowe R, Fine S, et al. Hospital and outpatient health services utilization among HIV-infected patients in care in 1999. J Acquir Immune Defic Syndr 2002; 30: 21–26. 12 Krentz HB, Gill MJ. Impact of practice changes on an antiretroviral budget in an HIV care program. Disease Management and Health Outcomes 2005; 13: 209–17. 13 Tolley K, Gyldmark M. The treatment and care costs of people with HIV-infection or AIDS: development of a standardized cost framework for Europe. Health Policy 1993; 24: 55–70. 14 Tyndall MW, Currie S, Spittal P, et al. Intensive injection cocaine use as the primary risk factor in the Vancouver HIV-1 epidemic. AIDS 2003; 17: 887–93. 15 BC Ministry of Health Planning. Priorities for action in managing the epidemics. HIV/AIDS in BC: 2003–2007. http://www.health services.gov.bc.ca/hiv/priorities.html (accessed Jan 19, 2006). 16 Holtgrave DR, Qualls NL, Graham JD. Economic evaluation of HIV prevention programs. Annu Rev Public Health 1996; 17: 467–88. 17 Holtgrave DR, Pinkerton SD. Updates of cost of illness and quality of life estimates for use in economic evaluations of HIV prevention programs. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 16: 54–62. 18 Drummond MF, O’Brien B, Stoddart G, Torrance GW. Methods for the economic evaluation of health care programmes, 2nd edit. Oxford: Oxford Medical Publications, 1997. 19 Youle M, Trueman P, Simpson K. Health economics in HIV disease. A review of the European literature. Pharmacoeconomics 1999; 15: 1–12. 20 Organisation for Economic Co-operation and Development (OECD). Health data 2004. http://www.oecd.com (accessed Jan 31, 2006).
http://infection.thelancet.com Vol 6 March 2006
Review
21
22
23
24
25
26
27
28
Tramarin A, Campostrini S, Postma MJ, et al. A multicentre study of patient survival, disability, quality of life and cost of care: among patients with AIDS in northern Italy. Pharmacoeconomics 2004; 22: 43–53. Beck EJ, Tolley K. Financing HIV service provision in England: estimated impact of the cost of antiretroviral combination therapy. Int J STD AIDS 1998; 9: 512–17. Krentz HB, Auld MC, Gill MJ. The changing direct costs of medical care for patients with HIV/AIDS, 1995–2001. CMAJ 2003; 169: 106–10. Basuyau F, Josset V, Merle V, Czernichow P. Case fatality and health care costs in HIV-infected patients: evolution from 1992 to 2000 at Rouen University Hospital, France. Int J STD AIDS 2004; 15: 679–84. Gebo KA, Chaisson RE, Folkemer JG, Bartlett JG, Moore RD. Costs of HIV medical care in the era of highly active antiretroviral therapy. AIDS 1999; 13: 963–69. Garattini L, Tediosi F, Di Cintio E, Yin D, Parazzini F. Resource utilization and hospital cost of HIV/AIDS care in Italy in the era of highly active antiretroviral therapy. AIDS Care 2001; 13: 733–41. Bozzette SA, Joyce G, McCaffrey DF, et al. Expenditures for the care of HIV-infected patients in the era of highly active antiretroviral therapy. N Engl J Med 2001; 344: 817–23. Palmer S, Raftery J. Economics notes: opportunity cost. BMJ 1999; 318: 1551–52.
http://infection.thelancet.com Vol 6 March 2006
29
30
31
32
33
34
35 36
European AIDS Clinical Society. European guidelines for the clinical management and treatment of HIV infected adults 2005. http://www.eacs.ws/download/Euroguidelines4151105.pdf (accessed Jan 19, 2006). Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Bethesda, MD, USA: Department of Health and Human Services, 2005. US Food and Drug Administration. Drugs used in the treatment of HIV infection. http://www.fda.gov/oashi/aids/virals.html (accessed Jan 19, 2006). Yeni PG, Hammer SM, Hirsch MS, et al. Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA panel. JAMA 2004; 292: 251–65. Jamjian MC, McNicholl IR. Enfuvirtide: first fusion inhibitor for treatment of HIV infection. Am J Health Syst Phar 2004; 61: 1242–47. Shah ND, Hoffman JM, Vermeulen LC, Hunkler RJ, Hontz KM. Projecting future drug expenditures – 2003. Am J Health Syst Pharm 2003; 60: 137–49. Leao JC, Frezzini C, Porter S. Enfuvirtide: a new class of antiretroviral therapy for HIV infection. Oral Dis 2004; 10: 327–29. Rabeneck L, Menke T, Wray NP. How good are US studies of HIV costs of care? Medical Care 1999; 37: 748–59.
177