Adam Peyton

Sofosbuvir and simeprevir for treatment of hepatitis C virus infection in liver transplant recipients

Recurrent hepatitis C virus (HCV) infection occurs universally in the allograft in the absence of effective antiviral therapy before liver transplantation (LT). Antiviral therapy with sofosbuvir and simeprevir has proven to be highly effective and well tolerated in the nontransplant setting for treatment of HCV genotype 1 infection; therefore, we sought to evaluate the efficacy and safety of this regimen in LT recipients with recurrent HCV infection. This was a retrospective analysis of a single‐center treatment protocol of patients with HCV genotype 1 infection who received a 12‐week combination regimen of sofosbuvir and simeprevir. Sixty‐one patients (35 with genotype 1a and 26 with genotype 1b) completed treatment with simeprevir and sofosbuvir. Three patients received additional ribavirin. Laboratory data and clinical assessments performed at the baseline, on treatment, at the end of treatment, and 12 weeks after the completion of antiviral therapy [sustained virological response at 12 weeks (SVR12)] were analyzed. The median time after LT was 5.4 years [interquartile range (IQR), 1.9‐8.4 years], and tacrolimus was the most commonly used immunosuppressive agent (80.3%). Overall, SVR12 was achieved in 93.4% [95% confidence interval (CI), 84%‐97%] of LT recipients treated with 12 weeks of sofosbuvir and simeprevir. When they were analyzed according to the HCV subtype, LT recipients with genotype 1b had a 100% SVR12 rate (95% CI, 87%‐100%), whereas SVR12 was 89% (95% CI, 74%‐95%) for those with genotype 1a. Advanced fibrosis (METAVIR F3‐F4) was associated with diminished antiviral efficacy in LT recipients with genotype 1a [SVR12, 67% (95% CI, 39%‐86%); P = 0.01]. Overall, the incidence of adverse events (AEs) was low, and no severe AEs occurred during treatment. In conclusion, treatment with a 12‐week regimen of sofosbuvir and simeprevir was well tolerated and resulted in a high SVR12 rate for LT recipients with recurrent HCV genotype 1 infection. Genotype 1a patients with advanced fibrosis of the allograft were more likely to relapse. Liver Transpl 21:823‐830, 2015.

Primary Biliary Cirrhosis: Therapeutic Advances

Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease characterized by destruction of the interlobular bile ducts, which, if untreated, leads to fibrosis, biliary cirrhosis, and liver failure. Because liver transplantation remains the only curative option for PBC, the goals of treatment are to slow the rate of progression, to alleviate related symptoms, and to prevent complications. Ursodeoxycholic acid is the only US Food and Drug Administration-approved medical treatment of PBC. Several agents are undergoing evaluation as monotherapy or as an adjuvant to ursodeoxycholic acid. This review summarizes current therapeutic advances in the care of patients with PBC.

Efficacy of Sofosbuvir Plus Ribavirin in Veterans With Hepatitis C Virus Genotype 2 Infection, Compensated Cirrhosis, and Multiple Comorbidities

BACKGROUND & AIMS: We conducted a phase 4, open‐label study with limited exclusion criteria to evaluate the safety and efficacy of sofosbuvir and ribavirin in veterans with hepatitis C virus genotype 2 infection, and compensated cirrhosis. This population is often excluded from clinical studies. METHODS: We performed a prospective study of treatment‐naive (n = 47) and treatment‐experienced (n = 19) patients with chronic hepatitis C virus genotype 2 infection and compensated cirrhosis at 15 Department of Veterans Affairs sites. All subjects were given sofosbuvir (400 mg, once daily) plus ribavirin (1000–1200 mg/day) in divided doses for 12 weeks. Patients with major psychiatric diseases or alcohol or substance use disorders were not excluded. The primary endpoint was sustained virologic response 12 weeks after therapy. RESULTS: Fifty‐two patients achieved a sustained virologic response 12 weeks after therapy (79%; 95% confidence interval, 67%–88%); 16 of these patients were treatment experienced (84%; 95% confidence interval, 60%–97%) and 36 were treatment naive (77%; 95% confidence interval, 62%–88%). All patients had at least 1 comorbidity. Thirty‐five percent had depression, 24% had posttraumatic stress disorder, and 30% had anxiety disorder. In addition, 29% had current substance use. Of the 7 patients (11%) who discontinued the study treatment prematurely, 3 did so because of adverse events. The most common adverse events were fatigue, anemia, nausea, and headache. Serious adverse events occurred in 8 patients. Only 2 of the serious adverse events (anemia and nausea) were considered to be related to study treatment. CONCLUSIONS: In a phase 4 study, 12 weeks treatment with sofosbuvir and ribavirin led to a sustained virologic response 12 weeks after therapy in almost 80% of veterans with hepatitis C virus genotype 2 infection, compensated cirrhosis, and multiple comorbidities, regardless of their treatment history. ClinicalTrials.gov, Number: NCT02128542

Reply: To PMID 25825070.

Recently, Tavio et al. described a distinctive approach to treat hepatitis C virus (HCV) infection in 2 individuals undergoing liver transplantation (LT): initiation of antiviral therapy during the anhepatic phase. During LT, HCV RNA diminishes substantially, with the nadir typically observed from 7 to 24 hours after revascularization of the graft. In part, this is because of the removal of the recipient liver and HCV RNA distribution in the graft, but also, it is because of massive volume shifts and replacement as part of the LT procedure. Continued production of virions after native hepatectomy has been attributed to extrahepatic HCV reservoirs, but this has not been definitively shown. Tavio et al. propose to capitalize on the low levels of HCV RNA during the anhepatic phase by initiating antiviral therapy during this time and possibly be able to avoid de novo infection of the graft. In a previous issue of Liver Transplantation, we presented the sustained virological response (SVR) rates in HCV genotype 1–infected LT recipients treated with 2 direct-acting antivirals (DAAs), sofosbuvir and simeprevir, for 12 weeks. Our treatment protocol at the University of Miami was to wait at least 3 months after LT before starting antiviral therapy, and most of the patients included in our study were years away from LT (median, 5.4 years). Overall, an SVR of 93.4% was achieved. Therapy of pretransplant patients with poorly compensated liver disease (Child-TurcottePugh class C) is still an area of ongoing investigation. In hepatocellular carcinoma, where timing of LT is more reliable, Curry et al. achieved a 96% SVR (25 of 26) in patients receiving sofosbuvir and ribavirin who had been HCV RNA undetectable for at least 30 days before LT. Thus, treatment of medically stable patients both before and after transplant has been shown to have impressive rates of SVR. Despite major improvements in surgical technique, the perioperative period of LT remains a guarded period for the patient. Complications such as delayed graft function and acute renal injury may occur unpredictably, thus the safety of using agents dependent on their function could add unneeded risk to HCV treatment. Additionally, systemic absorption and pharmacokinetics of DAAs are unknown in the immediate post-LT period and early withdrawal or gaps in treatment might potentially create emergent resistance-associated variants, which may ultimately complicate therapy or result in multidrug resistance. Although novel protocols assessing the optimal timing for starting antiviral therapy after LT will continue to emerge, we advocate delaying HCV therapy after LT until the patient’s clinical course has stabilized, at least until well-designed clinical trials demonstrate equivalence or superiority in safety and efficacy of earlier therapeutic approaches.

Primary Care of Patients with Cirrhosis – Current and Future Challenges

Cirrhosis is currently the 12th leading cause of death in the United States and also accounts for considerable morbidity. However many cirrhotic patients can remain well compensated for a protracted period of time allowing interventions to prevent or treat complications. Examples include screening for varices and prophylaxis against hemorrhage as well as screening for hepatocellular carcinoma to identify tumors which are potentially curable. Optimal management of these patients should be focused on screening and prevention of these complications. Incorporating screening for varices and hepatocellular carcinoma, as well as providing vaccinations and counseling regarding proper nutrition are vital to improve patient outcomes.

Selection for liver transplantation

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Tu1064 Insurance Approval Patterns for IFN-Free Regimens in HCV: Impact of National Guidelines

Introduction: Patients infected with the hepatitis C virus (HCV) have long been awaiting interferon-free regimens. The possibility of using two Direct Acting Antivirals (DAAs) became a possibility in clinical practice in December 2013, albeit at a significant financial cost. Guidelines were released in part by the AASLD on January 30th, 2014 with specific treatment recommendations in various patient populations. Included in these recommendations was that patients who have received a liver transplant should be treated with 12 or 24 weeks of daily sofosbuvir and simeprevir. We examined approval patterns for DAAs and factors affecting patient access. Methods: This was an IRB approved retrospective review. Two hundred and forty-five consecutive patients whose prescriptions for IFN-free regiments submitted by the University of Miami Hepatology Faculty were included and 82 pending prescriptions were not included. Most patients (96%) were genotype 1a or 1b, and 66 were post-transplant. 86% of prescriptions were for 12 weeks of sofosbuvir and simeprevir, and the remainder was for sofosbuvir and ribavirin. Type of insurance was noted. Those who required foundation assistance were excluded from the analysis. Statistical analysis with parametric, non-parametric or multivariate analysis was performed using JMP SAS software. Results: 71% of prescriptions were filled at an estimated cost of

Tu1065 Comparative Cost-Effectiveness of Sofosbuvir Regimens for Treatment of HCV Gentotype 1 at a Single VA Hepatology Practice

26,090,000. A prior authorization was submitted to every insurance company on each case. There was a significant change in the approval pattern after the release of the AASLD guidelines (80 vs. 64%, p= 0.0057). After this date, post-liver transplant patients were also significantly more likely to have an IFN-free regimen approved (90 vs. 69%, p=0.04). There was also significant variation by medical insurance company. Patients with Medicare or Medicaid were most likely to have their drug approved compared with private insurance (85 vs. 68%, p=0.01). Conclusions: National guidelines appear to affect insurance company approval process. Approval rates in liver transplant patients significantly increased after AASLD guidelines indicated that they should be treated with interferon-free regimens. Those with public insurance were most likely to be approved compared to private insurance. National societies need to continue to make specific recommendation for the benefit of patient care.

656 Elevated Serum Alkaline Phosphatase At Follow-Up Is Associated With Worse Outcomes in Primary Sclerosing Cholangitis

Introduction: Patients infected with the hepatitis C virus (HCV) have long been awaiting interferon-free regimens. The possibility of using two Direct Acting Antivirals (DAAs) became a possibility in clinical practice in December 2013, albeit at a significant financial cost. Guidelines were released in part by the AASLD on January 30th, 2014 with specific treatment recommendations in various patient populations. Included in these recommendations was that patients who have received a liver transplant should be treated with 12 or 24 weeks of daily sofosbuvir and simeprevir. We examined approval patterns for DAAs and factors affecting patient access. Methods: This was an IRB approved retrospective review. Two hundred and forty-five consecutive patients whose prescriptions for IFN-free regiments submitted by the University of Miami Hepatology Faculty were included and 82 pending prescriptions were not included. Most patients (96%) were genotype 1a or 1b, and 66 were post-transplant. 86% of prescriptions were for 12 weeks of sofosbuvir and simeprevir, and the remainder was for sofosbuvir and ribavirin. Type of insurance was noted. Those who required foundation assistance were excluded from the analysis. Statistical analysis with parametric, non-parametric or multivariate analysis was performed using JMP SAS software. Results: 71% of prescriptions were filled at an estimated cost of

P0878 : First ribavirin-free sofosbuvir and simeprevir treatment of Hepatitis C genotype 1 patients with severe renal impairment (GFR <30 ml/min or dialysis)

26,090,000. A prior authorization was submitted to every insurance company on each case. There was a significant change in the approval pattern after the release of the AASLD guidelines (80 vs. 64%, p= 0.0057). After this date, post-liver transplant patients were also significantly more likely to have an IFN-free regimen approved (90 vs. 69%, p=0.04). There was also significant variation by medical insurance company. Patients with Medicare or Medicaid were most likely to have their drug approved compared with private insurance (85 vs. 68%, p=0.01). Conclusions: National guidelines appear to affect insurance company approval process. Approval rates in liver transplant patients significantly increased after AASLD guidelines indicated that they should be treated with interferon-free regimens. Those with public insurance were most likely to be approved compared to private insurance. National societies need to continue to make specific recommendation for the benefit of patient care.