The Effect of Shorter Treatment Regimens for Hepatitis C on Population Health and Under Fixed Budgets

The Effect of Shorter Treatment Regimens for Hepatitis C on Population Health and Under Fixed... Open Forum Infectious Diseases MAJOR ARTICLE e Eff Th ect of Shorter Treatment Regimens for Hepatitis C on Population Health and Under Fixed Budgets 1 2 3,4 1,5 Jake R. Morgan, Arthur Y. Kim, Susanna Naggie, and Benjamin P. Linas 1 2 Section of Infectious Diseases, Department of Medicine, Boston Medical Center, Boston, Massachusetts; Division of Infectious Diseases, Department of Medicine, Massachusetts General 3 4 5 Hospital, Boston, Massachusetts; School of Medicine, Duke University, Durham, North Caorlina; Duke Clinical Research Institute, Durham, North Carolina; Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts Background. Direct acting antiviral hepatitis C virus (HCV) therapies are highly effective but costly. Wider adoption of an 8-week ledipasvir/sofosbuvir treatment regimen could result in significant savings, but may be less efficacious compared with a 12-week regimen. We evaluated outcomes under a constrained budget and cost-effectiveness of 8 vs 12 weeks of therapy in treat- ment-naïve, noncirrhotic, genotype 1 HCV-infected black and nonblack individuals and considered scenarios of IL28B and NS5A resistance testing to determine treatment duration in sensitivity analyses. Methods. We developed a decision tree to use in conjunction with Monte Carlo simulation to investigate the cost-effectiveness of recommended treatment durations and the population health effect of these strategies given a constrained budget. Outcomes included the total number of individuals treated and attaining sustained virologic response (SVR) given a constrained budget and incremental cost-effectiveness ratios. Results. We found that treating eligible (treatment-naïve, noncirrhotic, HCV-RNA <6 million copies) individuals with 8 weeks rather than 12 weeks of therapy was cost-effective and allowed for 50% more individuals to attain SVR given a constrained budget among both black and nonblack individuals, and our results suggested that NS5A resistance testing is cost-effective. Conclusions. Eight-week therapy provides good value, and wider adoption of shorter treatment could allow more individuals to attain SVR on the population level given a constrained budget. This analysis provides an evidence base to justify movement of the 8-week regimen to the preferred regimen list for appropriate patients in the HCV treatment guidelines and suggests expanding that recommendation to black patients in settings where cost and relapse trade-offs are considered. Keywords. budget impact; cost-effectiveness; NS5A; IL28B. At least 3 million individuals are infected with hepatitis C virus HCV RNA <6 million copies/mL, without cirrhosi [5–8]. In (HCV) in the United States [1, 2]. New therapies to treat HCV such patients, a common treatment regimen is co-formulated are very effective, with cure rates >95%, but they are costly. ledipasvir/sofosbuvir (LDV/SOF). Per US Food and Drug Because of the high prevalence of HCV and the high cost of Administration (FDA)–approved labeled indication, short- treatment, the budgetary impact of treating HCV is high [3]. As ening the LDV/SOF treatment course in such patients from a result, many payers in the United States restrict access to HCV 12 to 8 weeks represents a savings of 33% [9]. Though real- treatment to patients with more advanced liver fibrosis and to world data suggest excellent cure rates with the 8-week regi- those without recent substance use [4]. As medication prices are men in appropriate patients [10, 11], there is concern that in coming down, some payers have loosened their HCV treatment some patients, especially those with co-factors such as black coverage restrictions, but many, especially Medicaid programs, race [12], HIV co-infection, NS5A resistance-associated sub- continue to limit access to HCV therapy [4]. stitutions (RAS), and/or hepatosteatosis, the 8-week treatment course may be inadequate. And although the recent approval A means of controlling medication cost is to shorten treat- of glecaprevir/pibrentasvir brings another 8-week regimen to ment duration. One of the most common profiles of HCV- the clinics for treatment-naïve patients with HCV infection, infected patients in the United States is HCV genotype 1 some payers will prefer LDV/SOF based on negotiated prices. infected individuals who are treatment naïve, have a serum Further, while treatment options for “salvage” HCV regimens have been recently approved, willingness of insurers to pay Received 27 October 2017; editorial decision 30 November 2017; accepted 6 December 2017. Correspondence: J. R. Morgan, PhD, 801 Massachusetts Ave, Boston, MA 02118 (jakem@ for them is uncertain. Mandated shortening of treatment to 8 bu.edu). weeks may therefore increase the pool of patients who are dif- Open Forum Infectious Diseases © The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases ficult to treat for HCV. Society of America. This is an Open Access article distributed under the terms of the Creative Understanding the trade-offs between cost and efficacy for Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ 8- and 12-week treatment courses is critical. We therefore by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work employed an existing microsimulation model of HCV infec- is properly cited. For commercial re-use, please contact journals.permissions@oup.com tion, the Hepatitis C Cost-Effectiveness Model (HEP-CE), to DOI: 10.1093/ofid/ofx267 Shorter Treatment for Hepatitis C • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx267/4712241 by Ed 'DeepDyve' Gillespie user on 16 March 2018 examine the economic value associated with 8- and 12-week treatment, summarized in greater detail in the published literature treatment regimens. We considered treatment for black patients [15–17]. The model inputs are summarized in Table 1. Where pos- and nonblack patients and considered strategies for identifying sible, inputs were informed by the relevant clinical trials. patients best treated with 12 weeks of LDV/SOF, including test- Cost-effectiveness Analysis ing for host-related factors (interleukin-28B [IL28B] genotype) In the cost-effectiveness analysis, we simulated a cohort without or virus-related factors (NS5A resistance). We identified thresh- constrained treatment capacity, evaluating the effect of treating old treatment efficacies and cost that changed conclusions, and all individuals. The model estimates of the lifetime cost and we considered the decision assuming both an open treatment QALY per person. We modeled the effect of no treatment, treat- budget and a fixed capacity system. ment with an 8-week LDV/SOF regimen, and treatment with a 12-week LDV/SOF regimen. We sorted regimens in order of METHODS increasing lifetime cost and then calculated the incremental Model Structure cost and QALYs associated with increasingly expensive strate- We first built a decision tree to describe the effectiveness of the gies compared with the next least costly strategy. We calculated 8- and 12-week strategies in black and nonblack patients (Figure incremental cost-effectiveness ratios (ICERs) by dividing the 1). The model begins with treatment eligible patients presenting incremental cost by the incremental QALYs. We used the com- for treatment. The efficacy of either the 8- or 12-week course monly cited US willingness-to-pay threshold of $100 000 per of LDV/SOF determines the sustained virologic response QALY gained to interpret ICERs [14]. (SVR) rate after the first round of therapy. Those who fail first- Budget Constrained Analysis line therapy are either retained in care with salvage therapy of We evaluated the effect of each treatment strategy by assuming sofosbuvir/velpatasvir/voxilaprevir for 12 weeks or are lost to a fixed budget constraint. This analysis assumed the budgetary follow-up [13]. Those retained either attain SVR or fail therapy perspective of a public payer, department of health, or depart- and never attain SVR. The decision tree estimates per-person ment of corrections with a fixed pharmacy budget and there- therapy costs of first- and second-line therapy and estimates the fore considered only the costs of first- and second-line therapy. proportion of the population achieving SVR. As an example, we chose a $10 000 000 fixed budget. Using the     Next, we used the HEP-CE model to estimate the lifetime decision tree from the cost-effectiveness analysis, we found the medical costs and quality-adjusted life-years (QALYs) of each maximum number of individuals who could be treated while strategy, discounted 3% annually [14]. e Th HEP-CE Model is a keeping the budget at or below the constraint. Monte Carlo lifetime simulation of HCV infection, screening, and Scenario Analyses We also explored 2 potential testing strategies that could evalu- ate who would have success using an 8-week regimen and who Firstline therapy may benefit from longer therapy: detecting interleukin-28B 8 or 12 wk LDV/SOF (IL28B) polymorphisms and testing for the prevalence of NS5A RAS [18]. The difference in efficacy observed between black and SVR No SVR nonblack patients has been in part attributed to differences in IL28B polymorphisms [19]. While the role of IL28B in pegylated Retained Lost to interferon-alpha treatment was well established, the effect of in care follow-up IL28B polymorphisms on treatment with direct acting antivirals (DAAs) such as LDV/SOF has been attenuated; however, differ- Salvage therapy 12 wk ences in SVR rates among IL28B genotypes persist [19, 20]. Some SOF/VEL/VOX studies suggest that certain NS5A RAS can affect SVR achieve- ment, although NS5A resistance testing is rare [18]. We evaluated SVR No SVR the effect of IL28B testing and treating individuals with either an 8-week (CC genotypes) or 12-week (non-CC genotypes) course of therapy. Next, we considered a scenario in which all patients Figure 1. Decision tree evaluating 8-week vs 12-week therapy for HCV. Figure 1 is a schematic of our model. All individuals begin the analysis ready for treatment. received HCV viral genotyping for NS5A ledipasvir-specific Following firstline therapy, individuals’ chance of attaining SVR is based on the ef- RAS, including substitutions at the following positions: K24G/ ficacy of the firstline regimen. Among those failing to achieve SVR, they are either N/R, M28A/G/T, Q30E/G/H/L/K/R/T, L31I/F/M/V, P32L, S38F, retained in care or lost to follow-up. Those lost to follow-up never achieve SVR. Those retained are treated with salvage therapy and attain SVR with a probability H58D, A92K/T, and Y93C/F/H/N/S in genotype 1a patients and equal to the efficacy of the salvage therapy. At the end of each branch (SVR or L31F/I/M/V, P32L, P58D, A92K, and Y93C/H/N/S in genotype no SVR), lifetime cost and QALY outcomes are calculated via the HEP-CE model. 1b patients [18]. Our approach to parameterizing these analyses Abbreviations: HCV, hepatitis C virus; HEP-CE, Hepatitis C Cost-Effectiveness Model; QALY, quality-adjusted life-year; SVR, sustained virologic response. is covered in the Supplementary Appendix. 2 • OFID • Morgan et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx267/4712241 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 1. Model Inputs to Evaluate 8 vs 12 Weeks of Treatment of HCV evaluated the effects of retention, the age of the cohort, and the Genotype 1 availability of salvage treatment. Sensitivity RESULTS Range Input Value Evaluated Source Cost-effectiveness Analysis Cohort characteristics The cost-effectiveness was similar among black and nonblack Mean age 53 30–65 [12] patients as regimen costs were the same and efficacy rates were Proportion male, % 60 0–100 [12] similar (Table 2). Among all patients, an 8-week course of LDV/ Average age at HCV 26 16–36 [27] SOF resulted in a discounted lifetime medical cost of $226 000 infection HCV disease progression and a quality-adjusted lifetime expectancy of 15.2 QALYs, yield- Median y to cirrhosis from 25 15–35 [28, 29] ing ICERs of less than $11 000/QALY (Table 2). When employing infection the 8-week regimen, 97% of black patients ultimately attained Median y to first liver- 11 6–17 [30] related event after SVR compared with 98% of nonblack patients. Four percent cirrhosis of black patients and 3% of nonblack patients needed a second Liver-related mortality with 1.4 0.7–2.8 [30] course of therapy because they failed the 8-week regimen, 0.03% compensated cirrhosis, deaths/100 PY of black patients and 0.02% of nonblack patients were left without Liver-related mortality with 12 6–24 [30] treatment options after failing both HCV treatment regimens, decompensated cir- and 2.8% of black patients and 2.4% of nonblack patients were rhosis, deaths/100 PY lost to follow-up between the first and second lines of therapy. Reduction in liver mortality 94 81–98 [31] after SVR, % A 12-week regimen resulted in fewer patients requiring retreat- HCV therapy efficacy, % ment (1.1% vs 3.7% for black patients and 2.9% vs 3.1% for SVR of 8-wk regimen LDV/ 96.3 72–100 [12] nonblack patients), fewer patients being left without treatment SOF in black patients SVR of 8-wk regimen LDV/ 96.9 72–100 [12] options (0.01% vs 0.03% for black patients and 0.020% vs 0.022% SOF in nonblack patients for nonblack patients), and fewer patients lost to follow-up (0.8% SVR of 12-wk regimen LDV/ 98.9 72–100 [12] vs 2.8% for black patients and 2.2% vs 2.4% for nonblack patients). SOF in black patients However, the 12-week regimen increased costs by $18 000 per SVR of 12-wk regimen LDV/ 97.1 72–100 [12] SOF in nonblack patients black patient and $19 000 per nonblack patient, with a commen- SVR of 12-wk regimen 97.3 0–100 [32] surate increase in QALYs of less than 0.1 per black patient and sofosbuvir/velpatasvir/ voxilaprevir less than 0.01 per nonblack patient, yielding an ICER compared Retention to salvage treat- 24 0–100 [13] with the 8-week regimen of $212 000/QALY for black patients ment, % and $2 850 000 for nonblack patients (Table 2).     Costs Non-HCV-related medical costs, $ per mo Budget Constrained Analysis Background medical costs 110–1100 55–1650 [33] In the presence of a fixed pharmacy budget of $10 000 000, 261     (without HCV) patients could be treated with an 8-week regimen, with 254 Laboratory testing costs, $ black and 255 nonblack patients attaining SVR, while 175 could IL28B genotype test 68.52 0–200 [34] NS5A test 231.23 0–400 [34] be treated under the 12-week regimen, with 174 black and 171 HCV related medical costs, $ nonblack patients attaining SVR. While the 12-week strategy per mo yielded a higher probability of SVR among those who were No cirrhosis 245 185–305 [35] treated, using an 8-week regimen allowed for almost 50% more Mild to moderate cirrhosis 440 315–550 [35] Decompensated cirrhosis 830 620–1050 [35] individuals to be cured (Table 2). HCV therapy, $ per 4 wk IL28B Testing Scenario Analyses LDV/SOF 18 900 9000–28 000 [23] In black patients, 8-week therapy had a lifetime cost of $227 000 Sofosbuvir/velpatasvir/ 18 654 11 250–33 750 [23]     voxilaprevir and 15.0 QALYs for an ICER of $11 000 compared with no Quality of life treatment, and 93.9% of patients reached SVR (Table  3). After achieving SVR 0.74–0.92 0.60–1 [36, 37] Treating based on the IL28B polymorphism increased costs by No to moderate fibrosis 0.89 0.75–1 [38–40] $16 000 and quality of life by less than 0.1 QALYs, resulting in Cirrhosis 0.62 0.55–0.75 [38, 39]   an ICER of $190 000 compared with an 8-week regimen for all Decompensated cirrhosis 0.48 0.40–0.60 [38, 39] patients without IL28B testing (Table  3). Treating all patients with 12-week therapy was slightly more expensive, increasing To further evaluate the robustness of our results, we con- costs by $2000, and quality of life by just under 0.01 QALYs, ducted several sensitivity analyses. We varied the efficacy and cost of therapy to determine the effect of price reductions and producing an ICER of $267 000 compared with the IL28B Shorter Treatment for Hepatitis C • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx267/4712241 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Cost-effectiveness and Fixed Budget Analysis of Treating Noncirrhotic, Treatment-Naïve, Genotype 1 HCV-Infected Individuals Cost, $ Incr. Cost, $ QALY Incr. QALY ICER, $ % SVR No. Treated w/$10 000 000     Black patients Not treated 182 000 - 10.98 - - 0 0 8-wk 225 000 43 700 15.16 4.18 10 400 97.2 261       12-wk 244 000 18 700 15.24 0.09 218 000 99.2 175       Nonblack patients Not treated 182 000 - 10.98 - - 0 0 8-wk 225 000 43 600 15.18 4.20 10 400 97.6 261       12-wk 244 000 18 900 15.19 0.01 2 860 000 97.8 175         testing strategy (Table  3). Among nonblack patients, where rate for 8 weeks of therapy in patients with RAS conferring more the prevalence of IL28B non-CC polymorphisms is low rela- than 100-fold resistance to ledipasvir was 88% or less. tive to black patients, IL28B testing was a dominated strategy. Sensitivity Analyses In this cohort, treating all patients with an 8-week course had Two-way sensitivity analyses identified thresholds of 8-week an ICER of $11 000 compared with no treatment, while the treatment efficacy and salvage therapy efficacy where 12-week 12-week regimen had an ICER of $212 000 compared with the LDV/SOF therapy is preferred (Figure  2). Assuming that sal- 8-week regimen (Table 3). In both black and nonblack patients, vage therapy cures 97.3% of those who fail an 8-week course of an 8-week treatment course was preferred to treating patients LDV/SOF, the 8-week treatment regimen was preferred from based on the results of an IL28B test. a cost-effectiveness perspective unless 8-week treatment ef- NS5A Testing Scenario ficacy was <93.4% for black patients or <91.6% for nonblack We found that 8-week therapy cost $227 000 with 15.1 QALYs, patients. In the extreme case of a completely ineffective salvage yielding an ICER of $10 900 compared with no treatment therapy (SVR  =  0%), we found that 8-week therapy remained (Table 3). Treating patients based on NS5A RAS increased costs preferred from a cost-effectiveness perspective, as long as the by $3230 and quality of life by 0.06 QALYs, resulting in an ICER 8-week regimen resulted in an SVR greater than 94.5% for black of $56 500. Treating all patients with a 12-week regimen increased patients and 92.7% for nonblack patients. With a constrained costs by $14 400 over the NS5A testing strategy and increased budget, 8-week treatment resulted in more individuals cured QALYs by 0.09, producing an ICER of $164 000. With an ICER unless the efficacy of 8-week therapy was <65.9% for black of less than $100 000 per QALY, administering an NS5A test and patients and <64.7% for nonblack patients. treating based on RASs was preferred to treating all patients with Next, we found that when the monthly cost of LDV/ either an 8- or 12-week treatment course regardless of RAS. We SOF was $8883 (47% of the current Federal Supply Schedule found that NS5A testing was cost-effective as long as the SVR costs = $18 900) 12-week therapy was the preferred strategy for Table 3. Cost-effectiveness Scenario Treating Patients Based on an IL28B or NS5A Test Cost, $ Incr. Cost, $ QALY Incr. QALY ICER, $ % SVR IL-28B genotype test Black patients Not treated 182 000 - 10.98 - - 0 8-wk 226 000 44 100 15.02 4.04 10 900 93.9       IL28B tested 243 000 16 800 15.11 0.09 196 000 95.9       12-wk 244 000 1800 15.11 0.01 273 000 96.1     Nonblack patients Not treated 182 000 - 10.98 - - 0 8-wk 226 000 44 000 15.03 4.06 10 900 94.3       IL28B tested 243 000 16 900 15.11 0.07 Dominated 95.9     12-wk 244 000 18 700 15.12 0.09 218 000 96.2       NS5A test Not treated 182 000 - 10.98 - - 0 8-wk 226 000 43 800 15.10 4.13 10 600 95.8       NS5A tested 229 000 3570 15.16 0.06 62 300 97.2     12-wk 244 000 14 900 15.25 0.09 170 000 99.2       4 • OFID • Morgan et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx267/4712241 by Ed 'DeepDyve' Gillespie user on 16 March 2018 black patients. Because the 8-week and 12-week efficacies were health systems faced with a fixed budget such as correctional similar for nonblack patients, the 12-week regimen was not pre- systems or Medicaid, and this type of analysis could be useful to ferred unless the monthly price of LDV/SOF fell to less than 4% settings outside of the United States grappling with similar cost/ ($750) of the Federal Supply Schedule cost. efficacy trade-offs. In scenario analyses, however, we demon- When we varied retention in care aer fa ft iling an 8-week strate that NS5A testing might be a good strategy for both con- regimen, we found that at any level of follow-up for salvage trolling cost and minimizing poor outcomes. Guidelines should therapy (0%–100%), the 8-week regimen remained preferred, consider the value of NS5A testing, and future research should likely because firstline therapy is so efficacious. evaluate the real-world performance of such an individualized e Th findings were robust in all other deterministic sensitivity approach. analyses, including changing the efficacy and cost of therapy, e A Th merican Association for the Study of Liver Diseases retention, the age of the cohort, and the availability of salvage (AASLD)/Infectious Diseases Society of America (IDSA) treatment (Supplementary Appendix). HCV treatment guidance recently added the 8-week LDV/SOF regimen to the recommended regimen list for treatment-naïve, DISCUSSION genotype 1 HCV-infected individuals without cirrhosis who have a baseline HCV RNA <6 million IU/mL. However, there This cost-effectiveness analysis, both with and without a fixed are caveats regarding which individuals are best suited for budget constraint, demonstrates that among treatment-naïve, this shortened course of therapy; thus many clinicians remain genotype 1 HCV-infected individuals without cirrhosis, an concerned about mandating shortened treatment courses that 8-week treatment regimen provides good value for the money can increase the risk of relapse for their individual patients. and is preferred to a 12-week regimen in both black and non- However, early trials showing decreased efficacy did not limit black patients. While 8-week treatment results in more treat- 8-week treatment to patients with HCV RNA <6 million copies, ment failures, resources invested in extending therapy to 12 as would later be recommended. When we considered efficacy weeks would likely be more productively invested in other stratified by RNA, the relative efficacy rates of 8- and 12-week HCV-related health care interventions, such as expanding therapy in both black and nonblack patients were similar. HCV screening or improving HCV linkage to care. We found Furthermore, we provide additional strategies here that may that 8 weeks of therapy was preferred even though our rate of improve provider comfort with patient-tailored approaches. retreatment was low (24%) [13]; additional investments in link- While differences in treatment outcomes by race persist in age to care would likely increase the attractiveness if 8 weeks the era of DAA treatment, these differences are less dependent of treatment. Furthermore, when presented with a fixed budget on the IL28B polymorphism [21]. In a scenario considering constraint, the 8-week regimen results in nearly 50% more indi- the usefulness of IL28B testing to prioritize black patients for viduals attaining SVR than the 12-week regimen, yielding better 8 vs 12 weeks of LDV/SOF, we found that treating based on population outcomes. This finding is particularly relevant for Black patients Nonblack patients 96.0% 96.0% 95.5% 95.5% 8-wk preferred 95.0% 95.0% 94.5% 94.5% 94.0% 94.0% 8-wk preferred 93.5% 93.5% 93.0% 93.0% 92.5% 92.5% 12-wk preferred 92.0% 92.0% 12-wk preferred 91.5% 91.5% 91.0% 91.0% Salvage SVR Salvage SVR Figure 2. Sensitivity analysis of SVR of 8-week therapy and salvage therapy. Figure 2 depicts the results of our sensitivity analysis of the effect of 8-week regimen SVR and salvage therapy SVR. The x-axis displays the SVR range of the salvage regimen, and the y-axis depicts the SVR of the 8-week regimen. Holding constant the efficacy of the 12-week regimen, we vary the salvage SVR from 0% to 100% and find the corresponding 8-week regimen efficacy threshold that results in 12-week therapy to be preferred. In the figure, the downward sloping line is that threshold, with the shaded region underneath representing where the 12-week regimen is preferred. Areas above each threshold shaded region indicate where the 8-week regimen is preferred. The threshold for black patients is higher compared with nonblack patients because in our primary data source [18] the 12-week efficacy of LDV/SOF was higher among black patients (98.9%) than it was among nonblack (97.1%) patients, which makes 12 weeks of therapy more attractive in general. Abbreviations: LDV, ledipasvir; SOF, sofosbuvir; SVR, sustained virologic response. Shorter Treatment for Hepatitis C • OFID • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx267/4712241 by Ed 'DeepDyve' Gillespie user on 16 March 2018 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 8-wk SVR 8-wk SVR IL28B polymorphism is not preferred from a cost-effectiveness appropriate metric. Next, due to data availability, we had to use standpoint, likely because the test does not provide adequate heterogeneous data sources for the base case and 2 scenarios. information to risk stratify. It is possible that the linked poly- Although the absolute efficacy values do not always match per - morphism IFNL4-ΔG/TT (rs368234815) may provide more fectly among the 2 scenarios and base case, the relative effica- resolution, especially in black patients [22]; however, commer- cies are internally consistent. While more research is needed cial testing is not yet available. to explore combinations of HCV viral load, IL28B genotype, In contrast, our results suggest that baseline testing for NS5A RAS presence, and fibrosis in depth, we believe our results are RAS that convey >100-fold ledipasvir phenotypic resistance is a valuable first step in understanding the potential value in dif- part of a potentially attractive treatment strategy. Work from ferent testing and treatment strategies. Finally, while there are a Sarrazin et  al. demonstrated that treating patients who are number of treatments available, we focused on LDV/SOF alone infected with a virus with baseline NS5A RAS with a 12-week as a firstline regimen. While the approval of glecaprevir/pibren- regimen increases SVR by nearly 13 percentage points (from tasvir provides another 8-week treatment option primarily in 82.8% with 8 weeks to 95.7% with 12 weeks) [18]. Our model treatment-naïve patients, we believe that LDV/SOF will have results suggest that this large gain in SVR at a modest test cost continued relevance in the clinic. Price negotiations leading provides good economic value and might be the ideal strategy to steep discounts for LDV/SOF make prices difficult to com- to reduce cost and avoid higher relapse. pare, even given the lower published wholesale acquisition cost While in the current environment we demonstrate that overall of glecaprevir/pibrentasvir ($13 200/4 weeks) compared with 8-week treatment is preferred, there are important caveats. It is LDV/SOF ($31 500/4 weeks) [1, 25]. LDV/SOF has been avail- possible that future price negotiations and market competition able since 2014, and many providers have experience with that result in the price of LDV/SOF falling to the point that an add- regimen. Given the similarity in efficacy between LDV/SOF and itional month of therapy for all patients provides good value glecaprevir/pibrentasvir and the recommendation of LDV/SOF and is cost-effective. In our analysis, we find that that occurs in the AASLD/IDSA treatment guidelines, the 2 regimens will at around $8900 for a month of therapy in black patients, ap- likely continue as competitors. As such, our findings likely apply proximately 50% of the Federal Supply Schedule price and 25% to glecaprevir/pibrentasvir as well. In particular, there are ques- of the average wholesale price of LDV/SOF [1, 23]. It is possible tions around the role of NS5A resistance in glecaprevir/pibren- that some insurers or health systems have already crossed this tasvir that clinical trials were unable to answer [26]. Our finding threshold, or may do so with the downward pressure on prices that NS5A resistance testing is likely cost-effective represents an due to competition with the release of the new 8-week regimen important research space for maximizing the efficacy of gleca- of glecaprevir/pibrentasvir. If so, those systems would secure previr/pibrentasvir in particular populations. the best possible outcomes by treating all black patients for 12 While highly efficacious therapies can cure HCV with few weeks. Among nonblack patients, the threshold price that results side effects in as little as 8 weeks, many individuals and payers in 12-week therapy being cost-effective is very low and likely not are struggling with the cost. For LDV/SOF, our results indicate realistic in the near future ($750 per month of therapy). that 8-week therapy is cost-effective and can result in bet- es Th e data support the decision by the AASLD/IDSA ter population outcomes in both black and nonblack patients Guidance Panel to recommend the 8-week regimen, regardless compared with 12-week therapy, even with lower rates of SVR. of price points, for nonblack patients. While this analysis also Future research demonstrating the real-world effectiveness of supports 8 weeks in black patients, it acknowledges a higher re- NS5A testing could improve outcomes still further, while con- lapse rate with the 8-week regimen and a need for salvage with trolling cost. This analysis provides an evidence base supporting a second course of approved therapies. Furthermore, in the set- the movement of the 8-week regimen to the preferred regimen ting where the cost of LDV/SOF is less than $8900 per month list for appropriate patients in the HCV treatment guidelines. (or $17 800 per treatment), the trade-off of higher relapse and Wider use of the similarly effective, significantly less expensive cost is not needed. The guidance panel makes recommenda- 8-week regimen could result in the ability to treat more individ- tions based on safety and efficacy and does not consider cost per uals and improve population health. se [24]. Thus, these data are more likely to support population-, Supplementary Data health system–, and health insurer–level decisions, where fixed Supplementary materials are available at Open Forum Infectious Diseases budgets imply that using an 8-week regimen could allow more online. Consisting of data provided by the authors to benefit the reader, black patients to be treated. the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corre- This analysis has several limitations. First, the price of HCV sponding author. treatment varies significantly among payers, and there is evi- dence of large price reductions following negotiations for ex- Acknowledgments clusivity [25]. We attempted to capture this lower cost by using Financial support. This study was supported by the National Institute the Federal Supply Schedule, but it is possible this is not the on Drug Abuse (grant numbers P30DA040500, R01DA031059). The 6 • OFID • Morgan et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx267/4712241 by Ed 'DeepDyve' Gillespie user on 16 March 2018 content of this article is solely the responsibility of the authors and does 20. Heim MH, Bochud PY, George J. Host - hepatitis C viral interactions: the role of genetics. J Hepatol 2016; 65:22–32. not necessarily represent the official views of the funding agencies or the 21. Su F, Green PK, Berry K, Ioannou GN. The association between race/ethnicity US government. and the effectiveness of direct antiviral agents for hepatitis C virus infection. Potential conifl cts of interest. Dr. Kim reports funding from Gilead Hepatology 2017; 65:426–38. Sciences. Dr. Naggie reports funding or support from Abbvie, Bristol 22. O’Brien TR, Kottilil S, Feld JJ, et al. Race or genetic makeup for hepatitis C virus Meyers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck, Tacere, treatment decisions? Hepatology 2017; 65:2124–5. Vertex Pharmaceuticals, Eviral Hep, IDSA, IAS-USA, Platform Q Health 23. US Department of Veterans Affairs. Pharmaceutical Prices. Available at: https:// Inc., and Practice Point Communications. Drs. Morgan and Linas have no www.va.gov/oal/business/fss/pharmPrices.asp. 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Gastroenterology 2016; 151:501–12, e1. 40. Stein K, Dalziel K, Walker A, et al. Screening for hepatitis C among injecting drug 19. Backus LI, Belperio PS, Shahoumian TA, et al. Real-world effectiveness of ledipas- users and in genitourinary medicine clinics: systematic reviews of effectiveness, vir/sofosbuvir in 4,365 treatment-naive, genotype 1 hepatitis C-infected patients. modelling study and national survey of current practice. Health Technol Assess Hepatology 2016; 64:405–14. 2002; 6:1–122. Shorter Treatment for Hepatitis C • OFID • 7 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx267/4712241 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

The Effect of Shorter Treatment Regimens for Hepatitis C on Population Health and Under Fixed Budgets

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Open Forum Infectious Diseases MAJOR ARTICLE e Eff Th ect of Shorter Treatment Regimens for Hepatitis C on Population Health and Under Fixed Budgets 1 2 3,4 1,5 Jake R. Morgan, Arthur Y. Kim, Susanna Naggie, and Benjamin P. Linas 1 2 Section of Infectious Diseases, Department of Medicine, Boston Medical Center, Boston, Massachusetts; Division of Infectious Diseases, Department of Medicine, Massachusetts General 3 4 5 Hospital, Boston, Massachusetts; School of Medicine, Duke University, Durham, North Caorlina; Duke Clinical Research Institute, Durham, North Carolina; Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts Background. Direct acting antiviral hepatitis C virus (HCV) therapies are highly effective but costly. Wider adoption of an 8-week ledipasvir/sofosbuvir treatment regimen could result in significant savings, but may be less efficacious compared with a 12-week regimen. We evaluated outcomes under a constrained budget and cost-effectiveness of 8 vs 12 weeks of therapy in treat- ment-naïve, noncirrhotic, genotype 1 HCV-infected black and nonblack individuals and considered scenarios of IL28B and NS5A resistance testing to determine treatment duration in sensitivity analyses. Methods. We developed a decision tree to use in conjunction with Monte Carlo simulation to investigate the cost-effectiveness of recommended treatment durations and the population health effect of these strategies given a constrained budget. Outcomes included the total number of individuals treated and attaining sustained virologic response (SVR) given a constrained budget and incremental cost-effectiveness ratios. Results. We found that treating eligible (treatment-naïve, noncirrhotic, HCV-RNA <6 million copies) individuals with 8 weeks rather than 12 weeks of therapy was cost-effective and allowed for 50% more individuals to attain SVR given a constrained budget among both black and nonblack individuals, and our results suggested that NS5A resistance testing is cost-effective. Conclusions. Eight-week therapy provides good value, and wider adoption of shorter treatment could allow more individuals to attain SVR on the population level given a constrained budget. This analysis provides an evidence base to justify movement of the 8-week regimen to the preferred regimen list for appropriate patients in the HCV treatment guidelines and suggests expanding that recommendation to black patients in settings where cost and relapse trade-offs are considered. Keywords. budget impact; cost-effectiveness; NS5A; IL28B. At least 3 million individuals are infected with hepatitis C virus HCV RNA <6 million copies/mL, without cirrhosi [5–8]. In (HCV) in the United States [1, 2]. New therapies to treat HCV such patients, a common treatment regimen is co-formulated are very effective, with cure rates >95%, but they are costly. ledipasvir/sofosbuvir (LDV/SOF). Per US Food and Drug Because of the high prevalence of HCV and the high cost of Administration (FDA)–approved labeled indication, short- treatment, the budgetary impact of treating HCV is high [3]. As ening the LDV/SOF treatment course in such patients from a result, many payers in the United States restrict access to HCV 12 to 8 weeks represents a savings of 33% [9]. Though real- treatment to patients with more advanced liver fibrosis and to world data suggest excellent cure rates with the 8-week regi- those without recent substance use [4]. As medication prices are men in appropriate patients [10, 11], there is concern that in coming down, some payers have loosened their HCV treatment some patients, especially those with co-factors such as black coverage restrictions, but many, especially Medicaid programs, race [12], HIV co-infection, NS5A resistance-associated sub- continue to limit access to HCV therapy [4]. stitutions (RAS), and/or hepatosteatosis, the 8-week treatment course may be inadequate. And although the recent approval A means of controlling medication cost is to shorten treat- of glecaprevir/pibrentasvir brings another 8-week regimen to ment duration. One of the most common profiles of HCV- the clinics for treatment-naïve patients with HCV infection, infected patients in the United States is HCV genotype 1 some payers will prefer LDV/SOF based on negotiated prices. infected individuals who are treatment naïve, have a serum Further, while treatment options for “salvage” HCV regimens have been recently approved, willingness of insurers to pay Received 27 October 2017; editorial decision 30 November 2017; accepted 6 December 2017. Correspondence: J. R. Morgan, PhD, 801 Massachusetts Ave, Boston, MA 02118 (jakem@ for them is uncertain. Mandated shortening of treatment to 8 bu.edu). weeks may therefore increase the pool of patients who are dif- Open Forum Infectious Diseases © The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases ficult to treat for HCV. Society of America. This is an Open Access article distributed under the terms of the Creative Understanding the trade-offs between cost and efficacy for Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ 8- and 12-week treatment courses is critical. We therefore by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work employed an existing microsimulation model of HCV infec- is properly cited. For commercial re-use, please contact journals.permissions@oup.com tion, the Hepatitis C Cost-Effectiveness Model (HEP-CE), to DOI: 10.1093/ofid/ofx267 Shorter Treatment for Hepatitis C • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx267/4712241 by Ed 'DeepDyve' Gillespie user on 16 March 2018 examine the economic value associated with 8- and 12-week treatment, summarized in greater detail in the published literature treatment regimens. We considered treatment for black patients [15–17]. The model inputs are summarized in Table 1. Where pos- and nonblack patients and considered strategies for identifying sible, inputs were informed by the relevant clinical trials. patients best treated with 12 weeks of LDV/SOF, including test- Cost-effectiveness Analysis ing for host-related factors (interleukin-28B [IL28B] genotype) In the cost-effectiveness analysis, we simulated a cohort without or virus-related factors (NS5A resistance). We identified thresh- constrained treatment capacity, evaluating the effect of treating old treatment efficacies and cost that changed conclusions, and all individuals. The model estimates of the lifetime cost and we considered the decision assuming both an open treatment QALY per person. We modeled the effect of no treatment, treat- budget and a fixed capacity system. ment with an 8-week LDV/SOF regimen, and treatment with a 12-week LDV/SOF regimen. We sorted regimens in order of METHODS increasing lifetime cost and then calculated the incremental Model Structure cost and QALYs associated with increasingly expensive strate- We first built a decision tree to describe the effectiveness of the gies compared with the next least costly strategy. We calculated 8- and 12-week strategies in black and nonblack patients (Figure incremental cost-effectiveness ratios (ICERs) by dividing the 1). The model begins with treatment eligible patients presenting incremental cost by the incremental QALYs. We used the com- for treatment. The efficacy of either the 8- or 12-week course monly cited US willingness-to-pay threshold of $100 000 per of LDV/SOF determines the sustained virologic response QALY gained to interpret ICERs [14]. (SVR) rate after the first round of therapy. Those who fail first- Budget Constrained Analysis line therapy are either retained in care with salvage therapy of We evaluated the effect of each treatment strategy by assuming sofosbuvir/velpatasvir/voxilaprevir for 12 weeks or are lost to a fixed budget constraint. This analysis assumed the budgetary follow-up [13]. Those retained either attain SVR or fail therapy perspective of a public payer, department of health, or depart- and never attain SVR. The decision tree estimates per-person ment of corrections with a fixed pharmacy budget and there- therapy costs of first- and second-line therapy and estimates the fore considered only the costs of first- and second-line therapy. proportion of the population achieving SVR. As an example, we chose a $10 000 000 fixed budget. Using the     Next, we used the HEP-CE model to estimate the lifetime decision tree from the cost-effectiveness analysis, we found the medical costs and quality-adjusted life-years (QALYs) of each maximum number of individuals who could be treated while strategy, discounted 3% annually [14]. e Th HEP-CE Model is a keeping the budget at or below the constraint. Monte Carlo lifetime simulation of HCV infection, screening, and Scenario Analyses We also explored 2 potential testing strategies that could evalu- ate who would have success using an 8-week regimen and who Firstline therapy may benefit from longer therapy: detecting interleukin-28B 8 or 12 wk LDV/SOF (IL28B) polymorphisms and testing for the prevalence of NS5A RAS [18]. The difference in efficacy observed between black and SVR No SVR nonblack patients has been in part attributed to differences in IL28B polymorphisms [19]. While the role of IL28B in pegylated Retained Lost to interferon-alpha treatment was well established, the effect of in care follow-up IL28B polymorphisms on treatment with direct acting antivirals (DAAs) such as LDV/SOF has been attenuated; however, differ- Salvage therapy 12 wk ences in SVR rates among IL28B genotypes persist [19, 20]. Some SOF/VEL/VOX studies suggest that certain NS5A RAS can affect SVR achieve- ment, although NS5A resistance testing is rare [18]. We evaluated SVR No SVR the effect of IL28B testing and treating individuals with either an 8-week (CC genotypes) or 12-week (non-CC genotypes) course of therapy. Next, we considered a scenario in which all patients Figure 1. Decision tree evaluating 8-week vs 12-week therapy for HCV. Figure 1 is a schematic of our model. All individuals begin the analysis ready for treatment. received HCV viral genotyping for NS5A ledipasvir-specific Following firstline therapy, individuals’ chance of attaining SVR is based on the ef- RAS, including substitutions at the following positions: K24G/ ficacy of the firstline regimen. Among those failing to achieve SVR, they are either N/R, M28A/G/T, Q30E/G/H/L/K/R/T, L31I/F/M/V, P32L, S38F, retained in care or lost to follow-up. Those lost to follow-up never achieve SVR. Those retained are treated with salvage therapy and attain SVR with a probability H58D, A92K/T, and Y93C/F/H/N/S in genotype 1a patients and equal to the efficacy of the salvage therapy. At the end of each branch (SVR or L31F/I/M/V, P32L, P58D, A92K, and Y93C/H/N/S in genotype no SVR), lifetime cost and QALY outcomes are calculated via the HEP-CE model. 1b patients [18]. Our approach to parameterizing these analyses Abbreviations: HCV, hepatitis C virus; HEP-CE, Hepatitis C Cost-Effectiveness Model; QALY, quality-adjusted life-year; SVR, sustained virologic response. is covered in the Supplementary Appendix. 2 • OFID • Morgan et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx267/4712241 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 1. Model Inputs to Evaluate 8 vs 12 Weeks of Treatment of HCV evaluated the effects of retention, the age of the cohort, and the Genotype 1 availability of salvage treatment. Sensitivity RESULTS Range Input Value Evaluated Source Cost-effectiveness Analysis Cohort characteristics The cost-effectiveness was similar among black and nonblack Mean age 53 30–65 [12] patients as regimen costs were the same and efficacy rates were Proportion male, % 60 0–100 [12] similar (Table 2). Among all patients, an 8-week course of LDV/ Average age at HCV 26 16–36 [27] SOF resulted in a discounted lifetime medical cost of $226 000 infection HCV disease progression and a quality-adjusted lifetime expectancy of 15.2 QALYs, yield- Median y to cirrhosis from 25 15–35 [28, 29] ing ICERs of less than $11 000/QALY (Table 2). When employing infection the 8-week regimen, 97% of black patients ultimately attained Median y to first liver- 11 6–17 [30] related event after SVR compared with 98% of nonblack patients. Four percent cirrhosis of black patients and 3% of nonblack patients needed a second Liver-related mortality with 1.4 0.7–2.8 [30] course of therapy because they failed the 8-week regimen, 0.03% compensated cirrhosis, deaths/100 PY of black patients and 0.02% of nonblack patients were left without Liver-related mortality with 12 6–24 [30] treatment options after failing both HCV treatment regimens, decompensated cir- and 2.8% of black patients and 2.4% of nonblack patients were rhosis, deaths/100 PY lost to follow-up between the first and second lines of therapy. Reduction in liver mortality 94 81–98 [31] after SVR, % A 12-week regimen resulted in fewer patients requiring retreat- HCV therapy efficacy, % ment (1.1% vs 3.7% for black patients and 2.9% vs 3.1% for SVR of 8-wk regimen LDV/ 96.3 72–100 [12] nonblack patients), fewer patients being left without treatment SOF in black patients SVR of 8-wk regimen LDV/ 96.9 72–100 [12] options (0.01% vs 0.03% for black patients and 0.020% vs 0.022% SOF in nonblack patients for nonblack patients), and fewer patients lost to follow-up (0.8% SVR of 12-wk regimen LDV/ 98.9 72–100 [12] vs 2.8% for black patients and 2.2% vs 2.4% for nonblack patients). SOF in black patients However, the 12-week regimen increased costs by $18 000 per SVR of 12-wk regimen LDV/ 97.1 72–100 [12] SOF in nonblack patients black patient and $19 000 per nonblack patient, with a commen- SVR of 12-wk regimen 97.3 0–100 [32] surate increase in QALYs of less than 0.1 per black patient and sofosbuvir/velpatasvir/ voxilaprevir less than 0.01 per nonblack patient, yielding an ICER compared Retention to salvage treat- 24 0–100 [13] with the 8-week regimen of $212 000/QALY for black patients ment, % and $2 850 000 for nonblack patients (Table 2).     Costs Non-HCV-related medical costs, $ per mo Budget Constrained Analysis Background medical costs 110–1100 55–1650 [33] In the presence of a fixed pharmacy budget of $10 000 000, 261     (without HCV) patients could be treated with an 8-week regimen, with 254 Laboratory testing costs, $ black and 255 nonblack patients attaining SVR, while 175 could IL28B genotype test 68.52 0–200 [34] NS5A test 231.23 0–400 [34] be treated under the 12-week regimen, with 174 black and 171 HCV related medical costs, $ nonblack patients attaining SVR. While the 12-week strategy per mo yielded a higher probability of SVR among those who were No cirrhosis 245 185–305 [35] treated, using an 8-week regimen allowed for almost 50% more Mild to moderate cirrhosis 440 315–550 [35] Decompensated cirrhosis 830 620–1050 [35] individuals to be cured (Table 2). HCV therapy, $ per 4 wk IL28B Testing Scenario Analyses LDV/SOF 18 900 9000–28 000 [23] In black patients, 8-week therapy had a lifetime cost of $227 000 Sofosbuvir/velpatasvir/ 18 654 11 250–33 750 [23]     voxilaprevir and 15.0 QALYs for an ICER of $11 000 compared with no Quality of life treatment, and 93.9% of patients reached SVR (Table  3). After achieving SVR 0.74–0.92 0.60–1 [36, 37] Treating based on the IL28B polymorphism increased costs by No to moderate fibrosis 0.89 0.75–1 [38–40] $16 000 and quality of life by less than 0.1 QALYs, resulting in Cirrhosis 0.62 0.55–0.75 [38, 39]   an ICER of $190 000 compared with an 8-week regimen for all Decompensated cirrhosis 0.48 0.40–0.60 [38, 39] patients without IL28B testing (Table  3). Treating all patients with 12-week therapy was slightly more expensive, increasing To further evaluate the robustness of our results, we con- costs by $2000, and quality of life by just under 0.01 QALYs, ducted several sensitivity analyses. We varied the efficacy and cost of therapy to determine the effect of price reductions and producing an ICER of $267 000 compared with the IL28B Shorter Treatment for Hepatitis C • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx267/4712241 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Cost-effectiveness and Fixed Budget Analysis of Treating Noncirrhotic, Treatment-Naïve, Genotype 1 HCV-Infected Individuals Cost, $ Incr. Cost, $ QALY Incr. QALY ICER, $ % SVR No. Treated w/$10 000 000     Black patients Not treated 182 000 - 10.98 - - 0 0 8-wk 225 000 43 700 15.16 4.18 10 400 97.2 261       12-wk 244 000 18 700 15.24 0.09 218 000 99.2 175       Nonblack patients Not treated 182 000 - 10.98 - - 0 0 8-wk 225 000 43 600 15.18 4.20 10 400 97.6 261       12-wk 244 000 18 900 15.19 0.01 2 860 000 97.8 175         testing strategy (Table  3). Among nonblack patients, where rate for 8 weeks of therapy in patients with RAS conferring more the prevalence of IL28B non-CC polymorphisms is low rela- than 100-fold resistance to ledipasvir was 88% or less. tive to black patients, IL28B testing was a dominated strategy. Sensitivity Analyses In this cohort, treating all patients with an 8-week course had Two-way sensitivity analyses identified thresholds of 8-week an ICER of $11 000 compared with no treatment, while the treatment efficacy and salvage therapy efficacy where 12-week 12-week regimen had an ICER of $212 000 compared with the LDV/SOF therapy is preferred (Figure  2). Assuming that sal- 8-week regimen (Table 3). In both black and nonblack patients, vage therapy cures 97.3% of those who fail an 8-week course of an 8-week treatment course was preferred to treating patients LDV/SOF, the 8-week treatment regimen was preferred from based on the results of an IL28B test. a cost-effectiveness perspective unless 8-week treatment ef- NS5A Testing Scenario ficacy was <93.4% for black patients or <91.6% for nonblack We found that 8-week therapy cost $227 000 with 15.1 QALYs, patients. In the extreme case of a completely ineffective salvage yielding an ICER of $10 900 compared with no treatment therapy (SVR  =  0%), we found that 8-week therapy remained (Table 3). Treating patients based on NS5A RAS increased costs preferred from a cost-effectiveness perspective, as long as the by $3230 and quality of life by 0.06 QALYs, resulting in an ICER 8-week regimen resulted in an SVR greater than 94.5% for black of $56 500. Treating all patients with a 12-week regimen increased patients and 92.7% for nonblack patients. With a constrained costs by $14 400 over the NS5A testing strategy and increased budget, 8-week treatment resulted in more individuals cured QALYs by 0.09, producing an ICER of $164 000. With an ICER unless the efficacy of 8-week therapy was <65.9% for black of less than $100 000 per QALY, administering an NS5A test and patients and <64.7% for nonblack patients. treating based on RASs was preferred to treating all patients with Next, we found that when the monthly cost of LDV/ either an 8- or 12-week treatment course regardless of RAS. We SOF was $8883 (47% of the current Federal Supply Schedule found that NS5A testing was cost-effective as long as the SVR costs = $18 900) 12-week therapy was the preferred strategy for Table 3. Cost-effectiveness Scenario Treating Patients Based on an IL28B or NS5A Test Cost, $ Incr. Cost, $ QALY Incr. QALY ICER, $ % SVR IL-28B genotype test Black patients Not treated 182 000 - 10.98 - - 0 8-wk 226 000 44 100 15.02 4.04 10 900 93.9       IL28B tested 243 000 16 800 15.11 0.09 196 000 95.9       12-wk 244 000 1800 15.11 0.01 273 000 96.1     Nonblack patients Not treated 182 000 - 10.98 - - 0 8-wk 226 000 44 000 15.03 4.06 10 900 94.3       IL28B tested 243 000 16 900 15.11 0.07 Dominated 95.9     12-wk 244 000 18 700 15.12 0.09 218 000 96.2       NS5A test Not treated 182 000 - 10.98 - - 0 8-wk 226 000 43 800 15.10 4.13 10 600 95.8       NS5A tested 229 000 3570 15.16 0.06 62 300 97.2     12-wk 244 000 14 900 15.25 0.09 170 000 99.2       4 • OFID • Morgan et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx267/4712241 by Ed 'DeepDyve' Gillespie user on 16 March 2018 black patients. Because the 8-week and 12-week efficacies were health systems faced with a fixed budget such as correctional similar for nonblack patients, the 12-week regimen was not pre- systems or Medicaid, and this type of analysis could be useful to ferred unless the monthly price of LDV/SOF fell to less than 4% settings outside of the United States grappling with similar cost/ ($750) of the Federal Supply Schedule cost. efficacy trade-offs. In scenario analyses, however, we demon- When we varied retention in care aer fa ft iling an 8-week strate that NS5A testing might be a good strategy for both con- regimen, we found that at any level of follow-up for salvage trolling cost and minimizing poor outcomes. Guidelines should therapy (0%–100%), the 8-week regimen remained preferred, consider the value of NS5A testing, and future research should likely because firstline therapy is so efficacious. evaluate the real-world performance of such an individualized e Th findings were robust in all other deterministic sensitivity approach. analyses, including changing the efficacy and cost of therapy, e A Th merican Association for the Study of Liver Diseases retention, the age of the cohort, and the availability of salvage (AASLD)/Infectious Diseases Society of America (IDSA) treatment (Supplementary Appendix). HCV treatment guidance recently added the 8-week LDV/SOF regimen to the recommended regimen list for treatment-naïve, DISCUSSION genotype 1 HCV-infected individuals without cirrhosis who have a baseline HCV RNA <6 million IU/mL. However, there This cost-effectiveness analysis, both with and without a fixed are caveats regarding which individuals are best suited for budget constraint, demonstrates that among treatment-naïve, this shortened course of therapy; thus many clinicians remain genotype 1 HCV-infected individuals without cirrhosis, an concerned about mandating shortened treatment courses that 8-week treatment regimen provides good value for the money can increase the risk of relapse for their individual patients. and is preferred to a 12-week regimen in both black and non- However, early trials showing decreased efficacy did not limit black patients. While 8-week treatment results in more treat- 8-week treatment to patients with HCV RNA <6 million copies, ment failures, resources invested in extending therapy to 12 as would later be recommended. When we considered efficacy weeks would likely be more productively invested in other stratified by RNA, the relative efficacy rates of 8- and 12-week HCV-related health care interventions, such as expanding therapy in both black and nonblack patients were similar. HCV screening or improving HCV linkage to care. We found Furthermore, we provide additional strategies here that may that 8 weeks of therapy was preferred even though our rate of improve provider comfort with patient-tailored approaches. retreatment was low (24%) [13]; additional investments in link- While differences in treatment outcomes by race persist in age to care would likely increase the attractiveness if 8 weeks the era of DAA treatment, these differences are less dependent of treatment. Furthermore, when presented with a fixed budget on the IL28B polymorphism [21]. In a scenario considering constraint, the 8-week regimen results in nearly 50% more indi- the usefulness of IL28B testing to prioritize black patients for viduals attaining SVR than the 12-week regimen, yielding better 8 vs 12 weeks of LDV/SOF, we found that treating based on population outcomes. This finding is particularly relevant for Black patients Nonblack patients 96.0% 96.0% 95.5% 95.5% 8-wk preferred 95.0% 95.0% 94.5% 94.5% 94.0% 94.0% 8-wk preferred 93.5% 93.5% 93.0% 93.0% 92.5% 92.5% 12-wk preferred 92.0% 92.0% 12-wk preferred 91.5% 91.5% 91.0% 91.0% Salvage SVR Salvage SVR Figure 2. Sensitivity analysis of SVR of 8-week therapy and salvage therapy. Figure 2 depicts the results of our sensitivity analysis of the effect of 8-week regimen SVR and salvage therapy SVR. The x-axis displays the SVR range of the salvage regimen, and the y-axis depicts the SVR of the 8-week regimen. Holding constant the efficacy of the 12-week regimen, we vary the salvage SVR from 0% to 100% and find the corresponding 8-week regimen efficacy threshold that results in 12-week therapy to be preferred. In the figure, the downward sloping line is that threshold, with the shaded region underneath representing where the 12-week regimen is preferred. Areas above each threshold shaded region indicate where the 8-week regimen is preferred. The threshold for black patients is higher compared with nonblack patients because in our primary data source [18] the 12-week efficacy of LDV/SOF was higher among black patients (98.9%) than it was among nonblack (97.1%) patients, which makes 12 weeks of therapy more attractive in general. Abbreviations: LDV, ledipasvir; SOF, sofosbuvir; SVR, sustained virologic response. Shorter Treatment for Hepatitis C • OFID • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx267/4712241 by Ed 'DeepDyve' Gillespie user on 16 March 2018 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 8-wk SVR 8-wk SVR IL28B polymorphism is not preferred from a cost-effectiveness appropriate metric. Next, due to data availability, we had to use standpoint, likely because the test does not provide adequate heterogeneous data sources for the base case and 2 scenarios. information to risk stratify. It is possible that the linked poly- Although the absolute efficacy values do not always match per - morphism IFNL4-ΔG/TT (rs368234815) may provide more fectly among the 2 scenarios and base case, the relative effica- resolution, especially in black patients [22]; however, commer- cies are internally consistent. While more research is needed cial testing is not yet available. to explore combinations of HCV viral load, IL28B genotype, In contrast, our results suggest that baseline testing for NS5A RAS presence, and fibrosis in depth, we believe our results are RAS that convey >100-fold ledipasvir phenotypic resistance is a valuable first step in understanding the potential value in dif- part of a potentially attractive treatment strategy. Work from ferent testing and treatment strategies. Finally, while there are a Sarrazin et  al. demonstrated that treating patients who are number of treatments available, we focused on LDV/SOF alone infected with a virus with baseline NS5A RAS with a 12-week as a firstline regimen. While the approval of glecaprevir/pibren- regimen increases SVR by nearly 13 percentage points (from tasvir provides another 8-week treatment option primarily in 82.8% with 8 weeks to 95.7% with 12 weeks) [18]. Our model treatment-naïve patients, we believe that LDV/SOF will have results suggest that this large gain in SVR at a modest test cost continued relevance in the clinic. Price negotiations leading provides good economic value and might be the ideal strategy to steep discounts for LDV/SOF make prices difficult to com- to reduce cost and avoid higher relapse. pare, even given the lower published wholesale acquisition cost While in the current environment we demonstrate that overall of glecaprevir/pibrentasvir ($13 200/4 weeks) compared with 8-week treatment is preferred, there are important caveats. It is LDV/SOF ($31 500/4 weeks) [1, 25]. LDV/SOF has been avail- possible that future price negotiations and market competition able since 2014, and many providers have experience with that result in the price of LDV/SOF falling to the point that an add- regimen. Given the similarity in efficacy between LDV/SOF and itional month of therapy for all patients provides good value glecaprevir/pibrentasvir and the recommendation of LDV/SOF and is cost-effective. In our analysis, we find that that occurs in the AASLD/IDSA treatment guidelines, the 2 regimens will at around $8900 for a month of therapy in black patients, ap- likely continue as competitors. As such, our findings likely apply proximately 50% of the Federal Supply Schedule price and 25% to glecaprevir/pibrentasvir as well. In particular, there are ques- of the average wholesale price of LDV/SOF [1, 23]. It is possible tions around the role of NS5A resistance in glecaprevir/pibren- that some insurers or health systems have already crossed this tasvir that clinical trials were unable to answer [26]. Our finding threshold, or may do so with the downward pressure on prices that NS5A resistance testing is likely cost-effective represents an due to competition with the release of the new 8-week regimen important research space for maximizing the efficacy of gleca- of glecaprevir/pibrentasvir. If so, those systems would secure previr/pibrentasvir in particular populations. the best possible outcomes by treating all black patients for 12 While highly efficacious therapies can cure HCV with few weeks. Among nonblack patients, the threshold price that results side effects in as little as 8 weeks, many individuals and payers in 12-week therapy being cost-effective is very low and likely not are struggling with the cost. For LDV/SOF, our results indicate realistic in the near future ($750 per month of therapy). that 8-week therapy is cost-effective and can result in bet- es Th e data support the decision by the AASLD/IDSA ter population outcomes in both black and nonblack patients Guidance Panel to recommend the 8-week regimen, regardless compared with 12-week therapy, even with lower rates of SVR. of price points, for nonblack patients. While this analysis also Future research demonstrating the real-world effectiveness of supports 8 weeks in black patients, it acknowledges a higher re- NS5A testing could improve outcomes still further, while con- lapse rate with the 8-week regimen and a need for salvage with trolling cost. This analysis provides an evidence base supporting a second course of approved therapies. Furthermore, in the set- the movement of the 8-week regimen to the preferred regimen ting where the cost of LDV/SOF is less than $8900 per month list for appropriate patients in the HCV treatment guidelines. (or $17 800 per treatment), the trade-off of higher relapse and Wider use of the similarly effective, significantly less expensive cost is not needed. The guidance panel makes recommenda- 8-week regimen could result in the ability to treat more individ- tions based on safety and efficacy and does not consider cost per uals and improve population health. se [24]. Thus, these data are more likely to support population-, Supplementary Data health system–, and health insurer–level decisions, where fixed Supplementary materials are available at Open Forum Infectious Diseases budgets imply that using an 8-week regimen could allow more online. Consisting of data provided by the authors to benefit the reader, black patients to be treated. the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corre- This analysis has several limitations. First, the price of HCV sponding author. treatment varies significantly among payers, and there is evi- dence of large price reductions following negotiations for ex- Acknowledgments clusivity [25]. We attempted to capture this lower cost by using Financial support. This study was supported by the National Institute the Federal Supply Schedule, but it is possible this is not the on Drug Abuse (grant numbers P30DA040500, R01DA031059). The 6 • OFID • Morgan et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx267/4712241 by Ed 'DeepDyve' Gillespie user on 16 March 2018 content of this article is solely the responsibility of the authors and does 20. Heim MH, Bochud PY, George J. 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