Faculty Bibliography

Background: Few studies have evaluated the treatment landscape of chronic HBV in the US, where estimates range from 850,000 to 2.2 million people living with HBV. TRIO analytics has developed a national HBV network consisting of 7 academic and 4 community-based centers serving 17 States in the US, with the goal of understanding the realworld treatment of HBV in US clinical practice. We report here the demographic and clinical characteristics of this large cohort at enrollment. Methods: This is an observational, retrospective and prospective study of HBV patients which started in Nov 2016 and is planning to enroll 1000 patients and follow them for up to 2 years. At enrollment HBV data are retrospectively obtained from patient records through an electronic registry which collects patient demographics, treatment experience, disease characteristics, comorbidities, and lab measures. Results: 884 patients have been enrolled and data are available for this analysis on 601 patients. Select characteristics are shown in the TABLE. The majority were Asian and 8% were African or African-American. Mean age was 51 years and over 75% were HBeAg negative. Any evidence of fibrosis (measured by Fib-4 > 1.45) was 29% and cirrhosis (Fib-4 > 3.25) was 5%. At enrollment 540 patients (90%) were on treatment: 363/540 (67%) tenofovir disoproxil fumarate (TDF), 129/540 (24%) entecavir (ETV), 24/540 (4%) TDF + emtricitabine (FTC), 12/540 (2%) lamivudine (3TC), 9/540 (2%) initiated tenofovir alafenamide (TAF), and 3/540 (1%) adefovir dipivoxil (ADV). Overall 32 of 540 (6%) treated patients had viral loads >=2000 IU/ml at entry. Providerreported reasons for non-treatment of 61 patients were: 51/61 (84%) lack of clinical indication (HBeAg-/Ab+, normal liver function, and/or undetected viral load), 5/61 (8%) patient refusal, and 5/61 (8%) reason unspecified. Comorbidities of interest for risk of renal disease included hypertension (25%), diabetes (12%), and overall 51% had evidence of eGFR < 90 ml/min which was more common in treated patients. Conclusion: The HBV population in this US cohort is older, HBeAg negative, predominantly non-advanced liver disease and with significant co-morbidities. Current treatment is dominated by TDF and ETV with a high level of virological suppression. Full enrollment and prospective data over 2 years is ongoing. (Table Presented)

Background: TAF provides similar efficacy to tenofovir disoproxil fumarate (TDF) but with an improved safety profile particularly for renal injury and bone loss. Here, we evaluate clinical characteristics for patients switching to TAF during the first year of availability in US. Methods: TRIO has developed a national HBV network consisting of 7 academic and 4 community-based centers serving 17 US States to understand real-world HBV treatment. This study started Nov 2016 and is planning to enroll 1000 patients. HBV data is obtained retrospectively from patient records and then followed for 2 years through an electronic registry. To assess early TAF adoption, data are presented for 320 patients who switched nucleos(t)ide (NUC) therapy Nov 2016 to Oct 2017 or who did not switch but were followed during the same period. Results: Treatment for 320 patients at enrollment: 227 (71%) TDF, 72 (23%) entecavir (ETV), 12 (4%) TDF + emtricitabine (FTC), 10/375 (3%) lamivudine (3TC), and 2/375 (1%) adefovir dipivoxil (ADV). Of 320, 156 (49%) switched NUCs to: 144/156 (92%) TAF, 5/156 (3%) TDF, 3/156 (2%) 3TC, 2/156 (1%) ETV + TDF, 1/156 (1%) ETV, and 1/156 (1%) 3TC + TDF. Physician-provided reasons for switching to TAF included: 83/144 (58%) safety concerns or side effects, 46/144 (32%) physician preference, and 7/144 (5%) lack of efficacy. TAF switchers previously received: 131/144 (91%) TDF, 8/144 (6%) ETV, 4/144 (3%) TDF + FTC, and 1/144 (1%) ADV. TAF switchers did not significantly differ from the non-switchers for demographics, select comorbidities, HBeAg status, HBV DNA, nor degree of fibrosis [TABLE]. In the non-switch group, 7/164 (4.3%) patients had eGFR <60 ml/min vs 12/122 (9.8%) for TAF switchers; however, these results were not significantly different. Within the TAF switch group, from the time of enrollment to the date of switch, 52/122 (43%) patients had a 14% mean eGFR reduction. Bone density scans were available for 102/320 (32%) patients. A Z score of-1 or less indicating bone disease was recorded for 62, of which 40/62 (65%) switched to TAF. Conclusion: In the first year after TAF approval, almost 50% of study patients switched to TAF, predominantly for safety concerns or physician preference. For some who switched, renal (43%) and bone changes (65% of those tested) were shown. Many patients who did not switch had similar bone and renal findings. Further follow up will evaluate prospective criteria for switch strategies. (Figure Presented)

Objective The primary study objective is to determine which measures of depression are associated with early discontinuation of hepatitis C virus infection treatment and to determine which measure best characterizes the depression that develops during treatment. Methods Seventy-eight treatment-naïve subjects who initiated pegylated interferon/ribavirin treatment for hepatitis C virus infection were included. Baseline depression was assessed with the Structured Interview for the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), the Hamilton Depression Rating Scale, and the Beck Depression Inventory-II. The latter two measures were repeated at treatment weeks 12 and 24. Results Depression scores, as measured by the three instruments, lacked adequate consistency. Baseline depression as measured by the Beck Depression Inventory-II, but not by the other scales, was associated with early treatment discontinuation at weeks 12 and 24. Changes in depression during treatment were restricted to somatic symptoms. Of those who completed treatment, those who were not depressed at baseline tended to demonstrate significant depression increases during treatment. Conclusion The Beck Depression Inventory-II is recommended to assess depression prior to hepatitis C virus infection treatment. Somatic symptoms of depression should be monitored during treatment. Baseline depression as measured by the Beck Depression Inventory-II was associated with early treatment discontinuation. The Beck Depression Inventory-II, Structured Interview for DSM-IV, and Hamilton Depression Rating Scale yielded results that were not consistent with each other in this sample. Future research should focus on standardizing depression assessment in medically ill populations to identify measures that predict treatment discontinuation.

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 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: 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)

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)