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Homozygosity for UGT1A1*28/*28 (Gilbert’s variant) has been reported to be associated with atazanavir-associated hyperbilirubinemia and premature atazanavir discontinuation. We assessed the potential cost-effectiveness of UGT1A1 testing to inform choice of an initial protease inhibitor-containing regimen in antiretroviral therapy (ART)-naïve individuals.
We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) computer simulation model to project quality-adjusted life years (QALYs) and lifetime costs (2009 US dollars) for atazanavir-based ART with or without UGT1A1 testing, using darunavir rather than atazanavir when indicated. We assumed UGT1A1-associated atazanavir discontinuation rates reported in the Swiss HIV Cohort Study, a *28/*28 frequency of 14.9%, equal efficacy and cost of atazanavir and darunavir, and genetic assay cost of $107. Sensitivity analyses varied these parameters and hyperbilirubinemia impact on quality of life and loss to follow-up (LTFU). Costs and QALYs were discounted at 3% annually.
Initiating atazanavir-based ART at CD4 <500/µl without UGT1A1 testing had an average discounted life expectancy of 16.02 QALYs and $475,800 discounted lifetime cost. Testing for UGT1A1 increased QALYs by 0.49 per 10,000 patients tested, and was not cost-effective (>$100,000/QALY). Testing for UGT1A1 was cost-effective (<$100,000/QALY) if assay cost decreased to $10, or if avoiding hyperbilirubinemia by UGT1A1 testing reduced LTFU by 5%. If atazanavir and darunavir differed in cost or efficacy, testing for UGT1A1 was not cost-effective under any scenario.
Testing for UGT1A1 may be cost-effective if assay cost is low and if testing improves retention in care, but only if the comparator ART regimens have the same drug cost and efficacy.
Homozygosity for UGT1A1*28/*28 confers decreased hepatic expression of UGT1A1 (UDP-glucuronosyltransferase1 family, polypeptide A1) as compared to the *1 allele, and is required although not sufficient to manifest the mild unconjugated hyperbilirubinemia of Gilbert’s syndrome [1,2]. Such bilirubin elevations reflect decreased bilirubin clearance from plasma, not hepatic injury, but can still cause icterus. The HIV-1 protease inhibitor atazanavir is metabolized by UGT1A1, and in most patients causes plasma bilirubin concentrations to increase from pre-treatment values. Among patients prescribed atazanavir-containing antiretroviral therapy (ART), the UGT1A1*28/*28 variant is associated with greater increases from baseline in plasma bilirubin concentrations .
In a retrospective analysis of patients initiating ART in the Swiss HIV Cohort Study, UGT1A1 genotype was reported to be associated with the likelihood of atazanavir discontinuation, with discontinuation rates of 62.5% (33.3% due to toxicity), 23.8%, and 14.6% among 18 patients homozygous for *28/*28, 48 patients heterozygous for *1/*28, and 55 patients homozygous for *1/*1, respectively . The overall atazanavir discontinuation rate due to toxicity was 10.7% and due to all causes was 25.4%. This may be clinically relevant as atazanavir-containing regimens are among the preferred initial options recommended by the U.S. Department of Health and Human Services Guidelines Panel .
Genetic testing for HLA*B-5701 has been shown to be cost-effective to avoid abacavir hypersensitivity reactions in HIV-infected individuals . Cost-effectiveness of genetic testing for other ART drugs and outcomes beyond abacavir hypersensitivity have not been investigated . Among HIV-negative patients with colorectal cancer, testing for UGT1A1 may be cost-effective prior to cancer therapy with irinotecan because individuals who are homozygous for the UGT1A1*28 variant are at increased risk of irinotecan-related adverse events due to greater plasma concentrations of SN-38, the active metabolite of irinotecan .
Economic considerations increasingly affect how antiretroviral drugs are incorporated into clinical care, particularly given the availability of several initial ART options. In this context, we sought to identify factors that would most influence cost-effectiveness of UGT1A1 testing to inform first-line ART prescribing and prevent atazanavir discontinuation in the United States.
We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) model, a widely published state transition simulation model of HIV disease [6,9–11] to identify key determinants of cost-effectiveness of UGT1A1*28 testing to guide selection of first-line ART. We compared ‘universal testing’ with ‘no testing’ of hypothetical patients for whom atazanavir-based ART was determined by the physician and patient to be the preferred initial regimen (Figure 1). In the universal testing strategy, all patients were tested for UGT1A1*28 homozygosity prior to ART initiation, atazanavir-containing ART was prescribed for all patients who were not homozygous for UGT1A1*28/*28 or who lacked UGT1A1 test results, and darunavir-containing ART was prescribed for patients homozygous for UGT1A1*28/*28. In the no testing strategy, all patients initiated atazanavir-based ART. With both strategies, patients who discontinued atazanavir were assumed to require an extra outpatient visit, and were switched from atazanavir to darunavir. This switch was considered a medically supervised drug substitution within the first-line therapy regimen.
Results are reported as quality-adjusted life years (QALYs) and lifetime direct medical costs in 2009 US dollars, discounted to present value at a 3% annual rate . All cost-effectiveness ratios ($/QALY) are calculated by comparing the incremental costs and QALYs of the universal testing strategy to the no testing strategy. A cost-effectiveness ratio <$100,000/QALY was considered cost-effective [8,11,13].
We projected the quality-adjusted life expectancies and lifetime costs accrued by simulated cohorts of HIV-infected patients using the CEPAC state transition model. In the CEPAC model, simulated patients’ health states are characterized by CD4 cell count, plasma HIV-1 RNA level, and presence or absence of opportunistic infections [6,10,14]. Without treatment, patients’ CD4 counts decline at a rate dependent on their HIV-1 RNA level . As their CD4 counts decline, patients are more likely to develop opportunistic infections and are subject to an increased HIV-related mortality rate. Probabilities of opportunistic infections and HIV-related deaths are also dependent on prior history of opportunistic infections [9,15–17]. Patients receive quarterly CD4 and HIV-1 RNA tests and become eligible for treatment according to US guidelines. ART is initiated at CD4 ≤500 cells/µl as recommended by US guidelines, and opportunistic infection prophylaxis is initiated at the appropriate CD4 counts according to the type of prophylaxis [5,18]. Patients also face an age- and sex-based risk of non-HIV-related mortality .
Upon ART initiation, patients are subject to a probability of viral suppression and subsequent CD4 count increase, with the greatest CD4 count gain during the first two months on therapy . With increasing CD4 counts, patients are less likely to develop opportunistic infections or die of HIV-related causes. If a patient experiences virologic rebound, he or she is switched to the next available ART regimen. Table 1 specifies the six lines of therapy used in the simulation [21–25]. In the current analysis, we assume that first-line and second-line regimens are equally efficacious, and that substituting darunavir for atazanavir in the first-line regimen does not reduce or increase efficacy.
Characteristics of the hypothetical cohort including age, sex, HIV-1 RNA distribution, and baseline quality of life (QOL) are from published sources (Table 1). On this QOL scale, 0.00 is death or worst possible health, and 1.00 is equivalent to best possible health. Base case model inputs for genetic risk and associations with atazanavir discontinuation are based on results from the Swiss HIV Cohort Study . These include a 14.9% probability of testing homozygous for UGT1A1*28/*28, an 84.8% probability of testing either heterozygous for UGT1A1*28/*1 or non-carrier for UGT1A1*28, and a 0.3% probability of failed genotype testing. We assumed that the probability of discontinuing atazanavir for drug-associated toxicity is 33.3% among patients homozygous for UGT1A1*28/*28, and 6.8% among patients heterozygous for UGT1A1*28 or non-carrier for UGT1A1*28. We assumed 100% accuracy of genotyping for those with a successful test.
We applied a quality-of-life multiplier of 0.97 for patients experiencing hyperbilirubinemia so that these patients would have a QOL value equal to 97% of the QOL value they would have otherwise been assigned without the side effect, and varied the multiplier in sensitivity analyses. The multiplier had no effect on life expectancy. The multiplier was applied to baseline QOL for 14 days in the base case based on clinical judgment, and both the magnitude and the duration of this hyperbilirubinemia impact were varied in sensitivity analyses.
We used a UGT1A1*28 test cost of $107, derived from the Medicare fee schedule and Medicare reimbursement codes . We also evaluated a hypothetical cost of $10 (as may occur if UGT1A1 testing were to be included in a multiplex testing panel). The monthly cost of antiretroviral regimens are published average wholesale prices adjusted to reflect institutional discounts [26,27]. We assumed that the darunavir-containing regimen cost was equivalent to that of the atazanavir-containing regimen, and varied this assumption in sensitivity analyses. Costs of HIV care are presented from a health system perspective and are based on HIV Research Network data and Medicare fee schedules [10,26,28–30]. For the cost of evaluating a case of drug-induced hyperbilirubinemia, we used a $114 single clinic visit cost, which includes associated laboratory tests [29,31].
We first projected quality-adjusted life expectancy and lifetime costs for hypothetical cohorts initiating a first-line ART regimen with either atazanavir or darunavir, both prescribed in combination with ritonavir, tenofovir and emtricitabine. In the base case, hypothetical patients entered the model with a CD4 count of 500/µl. These results were then applied to the universal testing and no testing strategies based on the probabilities that patients would be assigned to atazanavir-containing or darunavir-containing ART, or switch to darunavir-containing ART after experiencing hyperbilirubinemia. Finally, the quality-of-life decrement and additional cost associated with hyperbilirubinemia were applied to determine the expected outcomes for each strategy and the incremental cost-effectiveness ratio for universal testing versus no testing.
In sensitivity analyses we evaluated the assumption that atazanavir-containing ART and darunavir-containing ART had equal efficacy as first-line regimens by varying the efficacy of darunavir-containing ART, using the same efficacy when darunavir is administered initially or substituted for atazanavir. We also varied the cost of darunavir relative to atazanavir to reflect the possibility of higher or lower cost depending on negotiated discounts . In scenarios where darunavir-containing ART had superior efficacy or lower cost, we also considered initiating darunavir-containing ART in all patients and assumed that these efficacy or cost advantages might outweigh the provider considerations that led to initial prescribing of atazanavir rather than darunavir.
We examined the impact of varying the frequency of UGT1A1*28/*28 homozygosity based on known frequency variation by ancestry, from 9% (the lowest reported prevalence among Caucasians) to 33% (the highest reported prevalence among individuals of African ancestry) . We also examined the impact of lowering by one half the rates of atazanavir discontinuation due to toxicity for individuals with and without UGT1A1*28/*28 homozygosity, to reflect the overall rate of discontinuation due to toxicity without virologic failure observed in a clinical trial conducted in the US . To test the impact of the QOL multiplier associated with hyperbilirubinemia, we varied the duration of symptoms from 7 to 28 days and the QOL multiplier from 0.99 to 0.92 (equivalent to the utility decrement for all symptoms patients felt were definitely attributable to ART in the Veterans Aging Cohort Study ). In probabilistic sensitivity analyses, we varied the symptom duration and QOL multiplier across these ranges and simultaneously varied the cost of evaluating a case of drug-induced hyperbilirubinemia based on assumptions about the duration of the outpatient visit. We conducted 1,000 probabilistic simulations using triangular distributions to represent the uncertainty in these 3 parameters with the base case value considered most likely .
We also explored the possibility that hyperbilirubinemia would cause some patients to completely discontinue ART and be lost to follow-up. We conducted a sensitivity analysis in which 5% of patients experiencing hyperbilirubinemia were lost to follow up and only returned to care upon development of an opportunistic infection or at a more advanced stage of disease (represented by crossing a specified CD4 count threshold). Additional sensitivity analyses included varying baseline CD4 count, age, baseline quality of life, and likelihood of failed genotyping (Table 1).
Using the CEPAC model, we found that initiating atazanavir-containing ART without UGT1A1 testing had an average projected discounted life expectancy of 16.02 QALYs and $475,800 discounted lifetime cost. At current UGT1A1 genotyping cost of $107 per assay, UGT1A1 testing increased QALYs by 0.49 per 10,000 patients tested with a cost-effectiveness ratio of over $2 million/QALY. At a hypothetical UGT1A1 genotyping cost of $10 per assay, this cost-effectiveness ratio dropped to $88,500/QALY (Table 2). If atazanavir-containing ART had either lower efficacy or higher cost than darunavir-containing ART, then the optimal strategy was always to initiate darunavir-containing ART. If atazanavir-containing ART had higher efficacy than darunavir-containing ART, then the “no test” strategy was preferred (cost-effectiveness ratio <$100,000/QALY) because of the greater efficacy despite slightly higher cost. If atazanavir-containing ART had lower cost than darunavir-containing ART, then the cost-effectiveness ratio of UGT1A1 testing was >$100,000/QALY at any test cost (e.g. approximately $50 million/QALY with a 10% cost advantage for atazanavir-containing ART).
At a cost of $10 per UGT1A1 assay, the cost-effectiveness of testing became sensitive to the frequency of UGT1A1*28/*28 homozygosity, varying from $220,600/QALY at a UGT1A1*28/*28 frequency of 9% to cost-saving at a UGT1A1*28/*28 frequency of 33% (Figure 2). When the discontinuation rates associated with the presence and absence of UGT1A1*28/*28 homozygosity were both reduced by one half, the cost-effectiveness ratio increased to $290,700/QALY at the homozygosity prevalence in the base case and varied from $560,100/QALY at 9% prevalence to $69,100/QALY at 33% prevalence. At $10 per assay, the cost-effectiveness of testing was also sensitive to the duration and magnitude of the impact of hyperbilirubinemia on quality of life and the cost of evaluating a case of drug-induced hyperbilirubinemia. The cost-effectiveness ratio for testing exceeded $100,000/QALY when the duration of hyperbilirubinemia was reduced from 14 to 7 days, when the quality-of-life multiplier for patients experiencing hyperbilirubinemia was increased from 0.97 to 0.99, and when the cost of case evaluation was reduced from $114 to $45. In contrast, the cost-effectiveness ratio for testing was $44,300/QALY when the duration of hyperbilirubinemia was increased to 28 days, $33,200/QALY when the quality-of-life multiplier was reduced to 0.92, and $49,300/QALY when the cost of case evaluation was increased to $153. In probabilistic sensitivity analyses, 76% of simulations that simultaneously varied the quality of life and cost parameters across these ranges had a cost-effectiveness ratio below $100,000/QALY (Figure 3).
When we assumed that 5% of patients experiencing hyperbilirubinemia were lost to follow up and returned after their disease had progressed further, the cost-effectiveness ratio for testing generally decreased. For example, when we assumed patients who are lost to follow up return either when they experience an opportunistic infection or when their CD4 count decreases to 200/µl, the cost-effectiveness ratio of testing was $70,000/QALY at the $107 assay cost, and $56,600/QALY at the hypothetical $10 assay cost. Results were similar for a hypothetical cohort with an initial CD4 count of 350/µl (Table 2). Results were sensitive, however, to the CD4 count at which patients return to care. When we assumed patients lost to follow up return either when experiencing an opportunistic infection or reaching a CD4 count of 350/µl, the cost-effectiveness ratio of testing was >$100,000/QALY at the current assay cost for a hypothetical cohort with initial CD4 count of 500/µl. Results were not substantially affected by varying age, baseline quality of life, or the proportion with failed genotyping.
We conducted simulation model analyses to identify factors that would determine the cost-effectiveness of UGT1A1 pharmacogenetic testing to inform prescribing of first-line protease inhibitor-containing ART in the United States. In a hypothetical cohort of patients who would otherwise initiate atazanavir-containing ART at CD4 500/µl, the cost-effectiveness of UGT1A1 testing was most sensitive to UGT1A1 assay cost and whether atazanavir-associated hyperbilirubinemia caused patients to be lost to follow-up only to return with substantially more advanced HIV disease. At low UGT1A1 assay cost, the cost-effectiveness of UGT1A1 testing was also sensitive to the population frequency of UGT1A1*28/*28. However, if atazanavir-containing ART and darunavir-containing ART differed in either cost or efficacy, UGT1A1 testing was not cost-effective under any scenario. That is, the benefits of higher efficacy or lower cost outweighed the benefits of testing. These findings highlight the areas in which model-based analyses can inform priorities for translating pharmacogenetics into HIV clinical care.
Previous model-based analyses have shown that HLA*B-5701 testing to prevent abacavir hypersensitivity reactions is cost-effective [6,34], but HLA*B-5701 testing is far more sensitive and specific for abacavir hypersensitivity than UGT1A1 testing is for atazanavir discontinuation. Moreover, abacavir hypersensitivity is potentially life-threatening, while atazanavir-associated hyperbilirubinemia is a relatively mild adverse event with minimal impact on quality of life. Our finding, that UGT1A1 testing is not cost-effective if an alternative drug that does not require pharmacogenetic testing is either more effective or less expensive, is consistent with what has been reported for HLA*B-5701 testing .
Testing for UGT1A1 was not cost-effective at the current stand-alone test cost of $107 unless hyperbilirubinemia resulted in loss to follow-up that could be prevented by UGT1A1 testing. Loss to follow-up represents a critical gap in HIV care in the US [35,36], where currently an estimated one-third of HIV-infected individuals linked to care are not retained in care . Future evaluations of pharmacogenetic tests for HIV regimen selection should consider the clinical implications of test results for retention in care, as well as the feasibility of genetic test panels that substantially reduce the cost attributable to each marker tested. Electronic health records increase the feasibility of integrating such large scale pharmacogenetic testing with clinical care .
Our analysis is subject to several limitations. We used as model inputs reported results of a retrospective analysis of 121 patients initiating ART in the Swiss HIV Cohort Study, among whom UGT1A1 homozygosity was associated with atazanavir discontinuation rates of 62.5%, 23.8%, and 14.6% among patients homozygous for *28/*28, heterozygous for *1/*28, and homozygous for *1/*1, respectively . Such data may not be generalizable to the U.S. or other populations. When we varied genetic risk to reflect variation in UGT1A1*28 frequency by ancestry, the cost-effectiveness ratios varied considerably at a hypothetical $10 assay cost and similar variation was observed if we assumed lower discontinuation rates. Furthermore, a recent analysis of data from a clinical trial conducted in the U.S. suggested that UGT1A1*28*28 was associated with atazanavir discontinuation in Hispanics, but not in whites or blacks . In the base case, we assumed atazanavir and darunavir had equivalent efficacy and cost. A clinical trial comparing atazanavir-containing and darunavir-containing first-line ART is ongoing , and drug costs may vary depending on manufacturer discounts. Our assumption that clinicians or patients might prefer to initiate atazanavir was not captured in base case QALYs or costs. The range of quality-of-life effects of hyperbilirubinemia that we considered may not capture the full spectrum of clinical situations. For example, icterus may more adversely affect quality of life in certain groups (e.g. adolescents, or individuals in jobs where their appearance affects their ability to work). We did not consider the potential future benefit of UGT1A1 testing to inform prescribing of other non-HIV drugs.
To determine the cost-effectiveness of UGT1A1 and other pharmacogenetic testing to guide ART regimen selection, it will be important to better understand the associations between genotype, adverse events, and loss to follow-up. Cost-effectiveness of initial ART, however, will remain primarily driven by regimen efficacy and cost.
We acknowledge Jared Leff, M.S. for assistance in conducting the probabilistic sensitivity analyses and Julia Maxwell, M.P.H. for assistance in project management.
Financial Support: Funded by the National Institute of Allergy and Infectious Diseases R37 AI42006 (BRS, JEB, BKB, KAF, PES), R01 AI077505 (BRS, DWH, JEB, BKB, KAF, HJR), AI069439 (DWH), AI054999 (DWH) and A1069424 (ESD) and the National Center for Advancing Translational Sciences TR000011 (DWH).
This is the author’s version of a work accepted for publication by International Medical Press. Changes resulting from the publishing process, including peer review, editing and formatting, might not be reflected in this document. A definitive version was published in Antiviral Therapy, (Vol No 18, Issue No 3)
Presented in part at the 19th Conference on Retroviruses and Opportunistic Infections in Seattle, WA, March 5–8, 2012 and at the 34th Annual Meeting of the Society for Medical Decision Making in Phoenix, AZ, October 17–20, 2012.
Conflicts of Interest: Dr. Haas has been principal investigator on research grants to Vanderbilt University from Bristol Myers Squibb, Boehringer Ingelheim, Merck, and Gilead Sciences. Dr. Sax has been a consultant for Abbott, Aileron, Bristol Myers Squibb, Gilead, GSK, Merck, and Janssen, and has received grant support from Bristol Myers Squibb, Gilead, Merck, GSK, and Janssen. Dr. Daar has been a consultant for Bristol Myers Squibb, Gilead, Merck and ViiV, and has received grant support from Abbott, Gilead, Merck, ViiV, and Pfizer.