Faculty Bibliography

AIM/OBJECTIVE:To assess the real-world effectiveness and cost of simeprevir (SMV), and/or sofosbuvir (SOF)-based therapy for chronic hepatitis C virus (HCV) infection. METHODS:The real-world performance of patients treated with SMV/SOF ± ribavirin (RBV), SOF/RBV, and SOF/RBV with pegylated-interferon (PEG) were analyzed in a consecutive series of 508 patients with chronic HCV infection treated at a single academic medical center. Patients with genotypes 1 through 4 were included. Rates of sustained virological response - the absence of a detectable serum HCV RNA 12 wk after the end of treatment [sustained virological response (SVR) 12] - were calculated on an intention-to-treat basis. Costs were calculated from the payer's perspective using Medicare/Medicaid fees and Redbook Wholesale Acquisition Costs. Patient-related factors associated with SVR12 were identified using multivariable logistic regression. RESULTS:SVR12 rates were as follows: 86% (95%CI: 80%-91%) among 178 patients on SMV/SOF ± RBV; 62% (95%CI: 55%-68%) among 234 patients on SOF/RBV; and 78% (95%CI: 68%-86%) among 96 patients on SOF/PEG/RBV. Mean costs-per-SVR12 were $174442 (standard deviation: ± $18588) for SMV/SOF ± RBV; $223003 (± $77946) for SOF/RBV; and $126496 (± $31052) for SOF/PEG/RBV. Among patients on SMV/SOF ± RBV, SVR12 was less likely in patients previously treated with a protease inhibitor [odds ratio (OR): 0.20, 95%CI: 0.06-0.56]. Higher bilirubin (OR: 0.47, 95%CI: 0.30-0.69) reduced the likelihood of SVR12 among patients on SOF/RBV, while FIB-4 score ≥ 3.25 reduced the likelihood of SVR12 (OR: 0.18, 95%CI: 0.05-0.59) among those on SOF/PEG/RBV. CONCLUSION/CONCLUSIONS:SVR12 rates for SMV and/or SOF-based regimens in a diverse real-world population are comparable to those in clinical trials. Treatment failure accounts for 27% of costs.

AIM: To determine the factors associated with regimen selection from currently available direct-acting antivirals (DAAs) in the treatment of genotype (GT) 1 HCV. METHODS: Data were collected from providers and specialty pharmacies through Trio Health's disease management program. Patients (n=2300) who initiated therapy for GT1 HCV from Jul to Dec 2016 were included. Variables identified as significantly associated with treatment selection through chi-square testing (p=0.1) were subsequently assessed via stepwise logistic regression. Multicollinearity between variables was assessed followed by exclusion of the variable with smaller effect on model prediction. RESULTS: 3 regimens accounted for 97% (2234/2300) of initiated treatment: 79% (1823) ledipasvir/sofosbuvir (LDV/SOF) +/-ribavirin (RBV), 11% (261) elbasvir/grazoprevir (EBR/GZR) +/-RBV, and 7% (150) sofosbuvir/velpatasvir (SOF/VEL) +/-RBV. Variables identified as significantly associated with regimen selection are indicated in the TABLE. Factors found not to be significantly associated include baseline viral load, HIV, anxiety, and payer type. NS5A resistance testing was not assessed due to small sample of patients who had resistance testing at baseline. Baseline eGFR <30 ml/min was most impactful in the selection model and was negatively associated with LDV/SOF (OR=0.025) and positively favored EBR/GZR (OR=47.449). Treatment naive (TN) favored LDV/SOF (OR=2.176) and was negatively associated with EBR/GZR (OR=0.649) and SOF/VEL (OR=0.344). Baseline platelets <=100K/mcl was negatively associated with LDV/SOF (OR=0.535) and positively with SOF/VEL (OR= 2.654). SUMMARY: Based on usage patterns in the real world, LDV/SOF is the preferred regimen in GT1 patients. In patients with severe renal impairment, EBR/GZR is preferred, and SOF/VEL is preferred for patients who previously failed treatment and/or have baseline platelet counts >100K/mcl (Table presented)

AIM: To examine changes in treatment preferences with approval of new therapies for HCV and assess outcomes with preferred treatments and in subgroups that historically have reduced cure rates. METHODS: Data were collected from providers and specialty pharmacies through Trio Health's disease management program. HCV-infected patients (n=7098) who initiated anti-HCV therapy from Jan to Dec 2016 were included. RESULTS: In 2016, 6 regimens accounted for 99% (7027/7098) of initiated treatment: 67% (4730) ledipasvir/sofosbuvir (LDV/SOF) +/-ribavirin (RBV), 12% (848) SOF/velpatasvir (SOF/VEL) +/-RBV, 7% (493) daclatasvir (DCV) + SOF +/-RBV, 6% (445) elbasvir/grazoprevir (EBR/GZR) +/-RBV, 5% (371) SOF + RBV, and 2% (140) ombitasvir-paritaprevir-ritonavir, and dasabuvir (PrOD) +/-RBV. Population characteristics and per protocol (PP) SVR12 rates by time period and genotype (GT) are provided in the TABLE. The regimen distribution by GT differed between Jan-Jun (1H) and Jul-Dec (2H) of 2016. By GT, PP SVR12 rates in 2H2016 increased or remained the same as 1H2016. PP SVR12 rates in subgroups with impaired kidney function, HIV coinfection, prior treatment experience, prior transplant, or cirrhosis were <=95%. SUMMARY: PP SVR12 rates increased slightly from 1H to 2H2016 for most patients. Subgroups stratified by characteristics historically associated with reduced SVR12 rates achieved per protocol SVR12 of 95% or higher (Table presented)

Background: Lengthening EBR/GZR treatment to 16 weeks and/or adding RBV is recommended for select GT1 HCV subgroups. However, real-world utilization patterns previously reported (J Hepat 2017 66: S295) suggests utilization of this dosing recommendation is low. This study examines 12 and 16 week EBR/GZR +/-RBV in different patient subgroups. Methods: Data were collected from providers and specialty pharmacies through Trio Health's disease management program. Patients (n=442) with GT1 HCV who initiated EBR/GZR therapy between Jan 28, 2016 (FDA approval) to Dec 31, 2016 were included. Results: 401 (91%) received 12-week EBR/GZR, 12 (3%) 12-week EBR/GZR+RBV, 11 (2%) 16-week EBR/GZR, and 18 (4%) 16-week EBR/GZR+RBV. Possible baseline NS5A resistance was identified in 13/285 patients with GT1A HCV. In this subgroup, 3/13 (23%) received 12-week EBR/GZR, 1/13 (8%) received 12-week EBR/GZR+RBV, 2/13 (15%) received 16-week EBR/GZR, and 7/13 (54%) received 16-week EBR/GZR+RBV. For the complete GT1 population, the +RBV subgroup had a higher fraction of patients that were treatment experienced (TE, 43%, 13/30) compared to the-RBV group (17%, 69/412). For the complete GT1 population, the 16-week subgroup had a higher proportion of GT1A subtype (93%, 27/29) compared to the 12-week group (62% GT1A, 258/413). Other characteristics including gender, age, baseline viral load, and cirrhosis were similar between regimens or between groups defined by RBV addition or therapy duration. SVR12 results at time of abstract submission were available for 262/442 patients. Overall per protocol (PP) SVR12 was 97% (253/262). Across the GT1 subgroups (defined by subtype, prior treatment experience, and fibrosis) that received EBG/GZR for 12-week regimen without RBV, the PP was SVR12 <=94%. (TABLE) Summary: The majority of patients were treated for 12 weeks without RBV in real world practice and Zepatier was found to be highly effective. Full SVR12 data across sub populations will be presented at the conference (Table presented)

BACKGROUND: At baseline, the presence of virus with NS5A RASs has been shown to impact the efficacy of NS5A containing regimens in patients with G1a chronic HCV infection. Therefore, the purpose of the current analysis was to describe the utilization and effectiveness of EBR/GZR in G1a chronic HCV patients with or without NS5A RASs in the United States. METHODS: A subgroup analysis of an EBR/GZR treated cohort previously derived using data collected from US providers and specialty pharmacies through Trio Health's disease management platform was used. The cohort was restricted to TN chronic HCV G1a patients who initiated EBR/GZR therapy between Jan 28, 2016 (FDA approval) and Dec 31, 2016. The primary SVR analysis was a Per Protocol (PP) analysis defined as all patients that completed their intended therapy and who received an SVR testing at 12 weeks (SVR12) post therapy. RESULTS: 234 patients met the inclusion criteria for the subgroup analysis and NS5A RASs testing was conducted in 58% (135/234) of the cohort. Approximately 9% (12/135) of those tested had an NS5A RAS present. 50% (6/12) of these patients were treated for 16 weeks with ribavirin (RBV), 8% (1/12) for 12 weeks with RBV, 25% (3/12) were treated for 12 weeks without RBV, 17% (2/12) for 16 weeks without RBV. Of patients that did not have an NS5A RAS present, 95% (111/117) were treated for 12 weeks without RBV. At present, only 126 patients of the overall G1a cohort have completed therapy with an SVR12 of 98% (124/126) (TABLE). Of those with an NS5A RAS present, the SVR12 was 100% (2/2) in those treated for 16 weeks with RBV, 100% (1/1) in those treated for 12 weeks and 100% (1/1) in those treated for 16 weeks. The SVR12 was 98% (60/61) in those patients who did not have an NS5A RAS present. CONCLUSIONS: Based on preliminary data, EBR/GZR appears to be highly effective in treating G1a patients regardless of the presence of NS5A RASs. Full SVR data will be presented at the meeting (Table presented)

AIM: Since 2013, the fraction of patients starting prescribed curative therapies for HCV has decreased because of insurance denials and/or processes. (Gastroent 2017 152: S1089). In this study, we examine both non-start rates and time to fill by payer type to better understand the larger populations facing hurdles in access to cure. METHODS: Data collected from providers and specialty pharmacies through Trio Health's disease management program were limited to patients (n=13417) who received an anti-HCV prescription in 2016. Variables significantly different between subgroups were identified by chi-square (p=0.05). RESULTS: 3989 (30%) of 13417 patients did not start prescribed therapy. Non-start reasons were specified in 2535/3989 (64%) of patients with most indicated as insurance denial (83%, 2114/2535). Failure to start therapy occurred in 37% (1335/3590) commercial (COM), 48% (1389/2916) Medicaid (MCD), and 17% (1149/6678) Medicare (MCR). For the 9428 patients that started therapy, 1848 (20%) received first dispense <30 days after the prescription was received by the specialty pharmacy. For COM, mean (SD) time to fill was 29 (38) days with 25% (556/2255) delayed starts. For MCD, mean (SD) time to fill was 31 (44) days with 27% (408/1527) delayed starts. For MCR, mean (SD) time to fill was 19 (26) days with 14% (795/5529) delayed starts. Mean time to fill values for COM and MCD were significantly different from MCR. Time to fill by individual specialty pharmacies revealed differences by payer types largely aligned with the aggregate results. Characteristics identified as significantly different between sgroups are provided in the TABLE. Variables not significantly different between groups include baseline Hb, genotype, treatment experience, gender, anxiety, depression, and certain regimens. SUMMARY: Variables associated with non-start and delayed start populations include COM or MCD coverage and less severe disease as based on fibrosis, platelets, viral load, and reduced presence of comorbids diabetes and hypertension. Accounting for both non-starts and delayed time to fill, 53% (1891/3590) of COM, 62% (1797/2916) of MCD, and 29% (1944/6678) of MCR patients face barriers in access to cure (Table presented)

BACKGROUND Ledipasvir/sofosbuvir (LDV/SOF) and sofosbuvir/velpatasvir (SOF/VEL) are oral single-tablet regimens (STRs) with excellent efficacy, tolerability, and real-world effectiveness in treatment-naive (TN) and treatment-experienced (TE) chronic hepatitis C virus (HCV) patients. For patients previously failing direct-acting antivirals, sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) is the only STR re-treatment (RT) that has been extensively studied in patients with NS5A, NS3, and NS5A+NS3 resistance, and leads to high sustained virologic rates (SVR) regardless of patients' baseline resistance associated mutations. With the availability of SOF-based STRs as first-line and RT options, this study evaluated the health outcomes for HCV treatment using SOF-based regimens vs. no treatment (NT). METHODS A model simulated the health outcomes of a cohort of 10,000 HCV genotype (GT) 1-6 non-cirrhotic (NC) and compensated cirrhotic (CC) patients with an average age of 52 from a US payer perspective over a lifetime horizon. The model assumed 73.3% of patients were GT1; 13.1%, GT2; 12.1%, GT3; 1.3%, GT4; and, 0.1% GT5/6. 14.6% of GT1-2/4-6 patients were CC (20.4% for GT3). The proportion of TN and TE patients varied by genotype. Outcomes for LDV/SOF for 8W for GT1 TN NC patients with viral load (VL) >6 million (mn) copies and SOF/VEL for all other GT1-6 patients, with or without RT with SOF/VEL/VOX, were compared to NT. Model inputs were sourced from clinical trials, published literature, or expert opinion. RESULTS Initiation of LDV/SOF for 8W for GT1 TN NC patients with VL >6 mn copies and SOF/VEL in treatment of all other GT1-6 patients yields favorable health outcomes (Table). RT with SOF/VEL/VOX results in a higher SVR (99.94%), fewer patients developing decompensated cirrhosis (0.52%), hepatocellular carcinoma (1.3%), liver transplant (0.11%), or liver-related deaths (1.3%), and a gain of 4.04 quality-adjusted life years per patient. CONCLUSION SOF-based STRs have demonstrated high SVR rates in both clinical and real-world settings. With the addition of SOF/VEL/VOX as an efficacious RT option, close to 100% of chronic HCV patients are projected to be cured (Table presented)

AIM: To assess variables associated with failure to complete treatment and failure to achieve SVR at 12 weeks post therapy (SVR12). METHODS: Data were collected from providers and specialty pharmacies through Trio Health's disease management program. Analyses included 7831 patients who initiated DAAs from Oct 2015 to Dec 2016 excluding lost to follow up or expired patients. Variables associated with treatment discontinuation or virologic failure through chi-square or T-tests (p=0.1) were subsequently assessed via stepwise logistic regression. Multicollinearity between variables was addressed by exclusion of the variable with smaller effect on model prediction. RESULTS: 3% (261) patients discontinued the intended therapy and did not achieve SVR. Of the 97% (7570) that completed, 79% (5996/7570) had SVR results available. 3% (186/5996) of those assessed for SVR had detectable virus and 97% (5810/5996) achieved SVR12. Variables identified as significantly associated with discontinuation and/or virologic failure across all genotypes are indicated in the TABLE. Factors found not to be significantly associated include baseline viral load, hemoglobin, GT1 subtype, GT2, GT4-6, HIV, hypertension, diabetes, anxiety, depression, certain regimens, prior transplant, and practice type. Additional assessments restricted by genotype result in shifts in significant variables relative to the overall results (data not shown). SUMMARY: Univariate analyses suggest that less complex therapy and shorter treatment duration may reduce discontinuations. Multivariate analyses are consistent with this premise, but highlight specific regimen choices and cirrhosis in addition to younger age. For patients that complete therapy, older age, male gender and more severe disease (cirrhosis, prior treatment) are associated with failure to achieve SVR12 (Table presented)

Background: An estimated 2.7 million patients are infected with CHC in the US. EBR/GZR is a fixed-dose combination direct-acting antiviral that was approved in the US in January 2016. The objective of this analysis was to evaluate real-world cost-effectiveness of 12 weeks of EBR/GZR compared to no treatment in TN GT1-infected patients, using data from the TRIO Network. Methods: A Markov model was constructed to evaluate the cost-effectiveness of EBR/GZR over a lifetime time horizon from the payer perspective. The model consists of 16 health states encompassing METAVIR fibrosis score (F0-F4), treatment success or failure, decompensated cirrhosis, hepatocellular carcinoma, liver transplant, and liver-related death. Baseline patient characteristics, discontinuation rates, and the proportion of treatment-naive GT1 patients achieving sustained virologic response were collected from a realworld study of 214 TN GT1 patients who were treated with EBR/GZR between January and October 2016, using data from the TRIO Network. Other inputs were obtained from published sources. The primary outcome was incremental cost-utility ratio (ICUR) for EBR/GZR vs. no treatment. Results are reported separately for cirrhotic and non-cirrhotic GT1a patients without resistance-associated variants (RAVs) and GT1b patients; sample size was insufficient to include GT1a patients with RAVs. Results: Treatment with EBR/GZR was associated with greater quality-adjusted life years (QALYs) and costs compared to no treatment in all subpopulations modeled (Table). ICURs ranged from $195/QALY in GT1b TN cirrhotic patients to $16,910 in GT1b TN non-cirrhotic patients. Conclusion: Using real-world patient characteristics and outcomes, EBR/GZR is cost-effective compared to no treatment in TN patients with GT1 CHC

BACKGROUND: Treatment of genotype 1 hepatitis C virus (HCV) infection with combination direct acting anti-virals is associated with very high rates of sustained virological response (SVR). Daily combination of ledipasvir and sofosbuvir for 12 weeks is approved for the treatment of genotype 1 HCV patients, though noncirrhotic patients who are naive to treatment with a baseline HCV RNA <6 million IU/mL can be treated for 8 weeks. This guidance stemmed from a post hoc analysis of the ION 3 clinical trial, which demonstrated similar SVR for patients treated with ledipasvir and sofosbuvir with or without ribavirin for 8 or 12 weeks. AIM: To compare the SVR for 8 weeks vs 12 weeks of ledipasvir and sofosbuvir in HCV infected patients in a real-world setting. METHODS: We performed an observational real-world cohort study of treatment success following 8 or 12 weeks of ledipasvir and sofosbuvir for treatment-naive genotype 1 HCV patients. RESULTS: A total of 826 patients were treated for either 8 (n=252) or 12 weeks (n=574) with ledipasvir and sofosbuvir and achieved SVR rate of 95.3% and there was no statistical difference in SVR rates in the two groups irrespective of any clinical or virological variables. CONCLUSIONS: In treatment-naive HCV genotype 1 patients, SVR was 95% in those treated for either 8 weeks or 12 weeks with ledipasvir and sofosbuvir. 8 week ledipasvir and sofosbuvir can reduce costs without compromising outcomes for those patients who qualify for such regimen.