Safety and Effectiveness of Tenofovir Alafenamide in Usual Clinical Practice Confirms Results of Clinical Trials: TARGET-HBV.

BACKGROUND: Nucleos(t)ide analogues, with a proven record of safety and efficacy, have been the therapy of choice for over a decade for the treatment of chronic hepatitis B. The approval of tenofovir alafenamide (TAF) in 2016 provided an additional treatment option. AIMS: The aim of this study was to evaluate the characteristics and clinical outcomes of patients treated with TAF in usual clinical practice. METHODS: Retrospective data from electronic health records was obtained from those enrolled in TARGET-HBV, a longitudinal observational cohort study of patients with chronic hepatitis B managed according to local practice standards at community and academic medical centers throughout the U.S. RESULTS: Of 500 patients enrolled, most were male (66%) and of Asian race (66%) with median age of 55 years. Cirrhosis was evident in 15%. Most patients (82%) had switched to TAF after treatment with other antivirals. The perceived safety profile of TAF was cited as the primary reason for changing therapy (32%). TAF was well tolerated and only 4 patients discontinued therapy due to adverse event during a median duration of TAF dosing of 74 weeks. Among those with paired laboratory data 12-18 months after switching to TAF, biochemical response and HBV DNA suppression was maintained. Most patients had normal renal function which was essentially unchanged throughout follow-up. CONCLUSIONS: TAF is frequently utilized in routine clinical practice due to the perception of its improved safety profile. The current study supports the growing body of evidence regarding the safety and effectiveness of TAF. Trial Registration ClinicalTrials.gov identifier: NCT03692897, https://clinicaltrials.gov/ct2/show/NCT03692897 .

Posttransplant Outcome of Lean Compared With Obese Nonalcoholic Steatohepatitis in the United States: The Obesity Paradox.

Morbid obesity is considered a relative contraindication for liver transplantation (LT). We investigated if body mass index (BMI; lean versus obese) is a risk factor for post-LT graft and overall survival in nonalcoholic steatohepatitis (NASH) and non-NASH patients. Using the United Network for Organ Sharing (UNOS) database, LT recipients from January 2002 to June 2013 (age ≥18 years) with follow-up until 2017 were included. The association of BMI categories calculated at LT with graft and overall survival after LT were examined. After adjusting for confounders, all obesity cohorts (overweight and class 1, class 2, and class 3 obesity) among LT recipients for NASH had significantly reduced risk of graft and patient loss at 10 years of follow-up compared with the lean BMI cohort. In contrast, the non-NASH group of LT recipients had no increased risk for graft and patient loss for overweight, class 1, and class 2 obesity groups but had significantly increased risk for graft (P < 0.001) and patient loss (P = 0.005) in the class 3 obesity group. In this retrospective analysis of the UNOS database, adult recipients selected for first LT and NASH patients with the lowest BMI have the worse longterm graft and patient survival as opposed to non-NASH patients where the survival was worse with higher BMI.

Impact of Nonmalignant Portal Vein Thrombosis in Transplant Recipients With Nonalcoholic Steatohepatitis.

Nonalcoholic fatty liver disease is an increasingly prevalent condition, and its more severe progressive state, nonalcoholic steatohepatitis (NASH), is currently the second most common indication for wait-listed adults in the United States. The association of portal vein thrombosis (PVT) prior to or at transplant and poor graft and patient outcomes is not well established, particularly among NASH patients who inherently have an increased hypercoagulable profile. Using the United Network for Organ Sharing data set, we analyzed graft and patient outcomes of patients transplanted for the indication of NASH with and without PVT. Of 3689 NASH transplant recipients, the prevalence of PVT was 12% (450 with PVT and 3239 without PVT). NASH transplant recipients with PVT had inferior graft and patient survival compared with NASH transplant recipients without PVT, even after adjusting for recipient and donor demographic characteristics, body mass index, synthetic dysfunction, and presence of diabetes. In a multivariate Cox regression model, NASH transplant recipients with PVT had a 37% increased risk of graft failure (hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.15-1.63; P < 0.001) and 31% increased risk of overall death (HR, 1.31; 95% CI, 1.09-1.58; P < 0.001) compared with NASH transplant recipients without PVT at transplant. This difference in graft and patient survival was most pronounced in the early posttransplant period. These results demonstrate that NASH patients with PVT have decreased graft and patient survival independent of recipient and donor factors.

Glecaprevir/Pibrentasvir in patients with hepatitis C virus genotype 1 or 4 and past direct-acting antiviral treatment failure.

Patients with hepatitis C virus (HCV) who have virological failure (VF) after treatment containing a nonstructural protein 5A (NS5A) inhibitor have limited retreatment options. MAGELLAN-1 Part 2 was a randomized, open-label, phase 3 study to evaluate the efficacy and safety of ribavirin (RBV)-free glecaprevir and pibrentasvir (G/P; 300 mg/120 mg) in patients with chronic HCV and past VF on at least one NS3/4A protease and/or NS5A inhibitor-containing therapy. Patients with compensated liver disease, with or without cirrhosis, and HCV genotype (GT) 1, 4, 5, or 6 were randomized 1:1 to receive 12 or 16 weeks of G/P. The primary endpoint was sustained virological response (SVR) at 12 weeks posttreatment (SVR12). Among 91 patients treated, 87 had GT1 and 4 had GT4 infection. SVR12 was achieved by 89% (39 of 44) and 91% (43 of 47) of patients who received 12 and 16 weeks of G/P, respectively. Virological relapse occurred in 9% (4 of 44) of patients treated with 12 weeks of G/P; there were no relapses with 16 weeks of treatment. Past treatment history with one class of inhibitor (protease or NS5A) had no impact on SVR12, whereas past treatment with both classes of inhibitors was associated with lower SVR12 rate. The most common adverse event (AE) was headache (≥10% of patients), and there were no serious AEs assessed as related to study drugs or AEs leading to discontinuation. CONCLUSION: Sixteen weeks of G/P treatment achieved a high SVR12 rate in patients with HCV GT1 infection and past failure to regimens containing either NS5A inhibitors or NS3 protease inhibitors. (Hepatology 2018;67:1253-1260).

Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment.

Although direct-acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection have demonstrated high rates of sustained virologic response, virologic failure may still occur, potentially leading to the emergence of viral resistance, which can decrease the effectiveness of subsequent treatment. Treatment options for patients who failed previous DAA-containing regimens, particularly those with nonstructural protein 5A inhibitors, are limited and remain an area of unmet medical need. This phase 2, open-label study (MAGELLAN-1) evaluated the efficacy and safety of glecaprevir (GLE) + pibrentasvir (PIB) ± ribavirin (RBV) in HCV genotype 1-infected patients with prior virologic failure to HCV DAA-containing therapy. A total of 50 patients without cirrhosis were randomized to three arms: 200 mg GLE + 80 mg PIB (arm A), 300 mg GLE + 120 mg PIB with 800 mg once-daily RBV (arm B), or 300 mg GLE + 120 mg PIB without RBV (arm C). By intent-to-treat analysis, sustained virologic response at posttreatment week 12 was achieved in 100% (6/6, 95% confidence interval 61-100), 95% (21/22, 95% confidence interval 78-99), and 86% (19/22, 95% confidence interval 67-95) of patients in arms A, B, and C, respectively. Virologic failure occurred in no patients in arm A and in 1 patient each in arms B and C (two patients were lost to follow-up in arm C). The majority of adverse events were mild in severity; no serious adverse events related to study drug and no relevant laboratory abnormalities in alanine aminotransferase, total bilirubin, or hemoglobin were observed. CONCLUSION: The combination of GLE and PIB was highly efficacious and well tolerated in patients with HCV genotype 1 infection and prior failure of DAA-containing therapy; RBV coadministration did not improve efficacy. (Hepatology 2017;66:389-397).

Ribavirin dose management in HCV patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin.

BACKGROUND & AIMS: Some individuals with hepatitis C virus infection treated with direct-acting antivirals require ribavirin to maximize sustained virological response rates. We describe the clinical management of ribavirin dosing in hepatitis C virus-infected patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin. METHODS: We performed a post hoc analysis of patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin for 12 or 24 weeks in six phase 3 trials. Multivariate stepwise logistic regression models assessed predictors associated with ribavirin dose adjustments and with developing anaemia. RESULTS: Of 1548 patients, 100 (6.5%) modified ribavirin dose due to haemoglobin declines, of which 99% achieved sustained virological response at 12 weeks post-treatment. Median time to first ribavirin dose reduction was 37 days. Low baseline haemoglobin was significantly associated with an increased risk of requiring ribavirin dose modification (odds ratio: 0.618 [0.518, 0.738]; P < .001) and developing anaemia (odds ratio: 0.379 [0.243, 0.593]; P < .001). CONCLUSIONS: Ribavirin dose reductions were infrequent, occurred early in treatment, and did not impact sustained virological response at 12 weeks post-treatment. Patients with low baseline haemoglobin should be monitored for on-treatment anaemia.

Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.

BACKGROUND: High rates of sustained virologic response were observed among patients with hepatitis C virus (HCV) infection who received 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor ledipasvir. This study examined 8 weeks of treatment with this regimen. METHODS: In this phase 3, open-label study, we randomly assigned 647 previously untreated patients with HCV genotype 1 infection without cirrhosis to receive ledipasvir and sofosbuvir (ledipasvir-sofosbuvir) for 8 weeks, ledipasvir-sofosbuvir plus ribavirin for 8 weeks, or ledipasvir-sofosbuvir for 12 weeks. The primary end point was sustained virologic response at 12 weeks after the end of therapy. RESULTS: The rate of sustained virologic response was 94% (95% confidence interval [CI], 90 to 97) with 8 weeks of ledipasvir-sofosbuvir, 93% (95% CI, 89 to 96) with 8 weeks of ledipasvir-sofosbuvir plus ribavirin, and 95% (95% CI, 92 to 98) with 12 weeks of ledipasvir-sofosbuvir. As compared with the rate of sustained virologic response in the group that received 8 weeks of ledipasvir-sofosbuvir, the rate in the 12-week group was 1 percentage point higher (97.5% CI, -4 to 6) and the rate in the group that received 8 weeks of ledipasvir-sofosbuvir with ribavirin was 1 percentage point lower (95% CI, -6 to 4); these results indicated noninferiority of the 8-week ledipasvir-sofosbuvir regimen, on the basis of a noninferiority margin of 12 percentage points. Adverse events were more common in the group that received ribavirin than in the other two groups. No patient who received 8 weeks of only ledipasvir-sofosbuvir discontinued treatment owing to adverse events. CONCLUSIONS: Ledipasvir-sofosbuvir for 8 weeks was associated with a high rate of sustained virologic response among previously untreated patients with HCV genotype 1 infection without cirrhosis. No additional benefit was associated with the inclusion of ribavirin in the regimen or with extension of the duration of treatment to 12 weeks. (Funded by Gilead Sciences; ION-3 ClinicalTrials.gov number, NCT01851330.).

Efficacy of Direct-Acting Antiviral Combination for Patients With Hepatitis C Virus Genotype 1 Infection and Severe Renal Impairment or End-Stage Renal Disease.

BACKGROUND & AIMS: Although hepatitis C virus (HCV) infection is common in patients with end-stage renal disease, highly efficacious, well-tolerated, direct-acting antiviral regimens have not been extensively studied in this population. We investigated the safety and efficacy of ombitasvir co-formulated with paritaprevir and ritonavir, administered with dasabuvir (with or without ribavirin) in a prospective study of patients with stage 4 or 5 chronic kidney disease (CKD). METHODS: We performed a single-arm, multicenter study of treatment-naïve adults with HCV genotype 1 infection, without cirrhosis and with CKD stage 4 (estimated glomerular filtration rate, 15-30 mL/min/1.73 m(2)) or stage 5 (estimated glomerular filtration rate, <15 mL/min/1.73 m(2) or requiring hemodialysis). Twenty patients were given ombitasvir co-formulated with paritaprevir and ritonavir, administered with dasabuvir for 12 weeks. Patients with HCV genotype 1a infections also received ribavirin (n = 13), whereas those with genotype 1b infection did not (n = 7). The primary end point was sustained virologic response (serum HCV RNA <25 IU/mL) 12 weeks after treatment ended (SVR12). We collected data on on-treatment adverse events (AEs), serious AEs, and laboratory abnormalities. RESULTS: All 20 patients completed 12 weeks of treatment. Eighteen of the 20 patients achieved SVR12 (90%; 95% confidence interval: 69.9-97.2). One patient death after the end of the treatment (unrelated to the treatment) and 1 relapse accounted for the 2 non-SVRs. Adverse events were primarily mild or moderate, and no patient discontinued treatment due to an AE. Four patients experienced serious AEs; all were considered unrelated to treatment. Ribavirin therapy was interrupted in 9 patients due to anemia; 4 received erythropoietin. No blood transfusions were performed. CONCLUSIONS: In a clinical trial, the combination of ombitasvir, paritaprevir, and ritonavir, administered with dasabuvir, led to an SVR12 in 90% of patients with HCV genotype 1 infection and stage 4 or 5 CKD. The regimen is well tolerated, though RBV use may require a reduction or interruption to manage anemia. ClinicalTrials.gov ID NCT02207088.

Sustained virologic response of 100% in HCV genotype 1b patients with cirrhosis receiving ombitasvir/paritaprevir/r and dasabuvir for 12weeks.

BACKGROUND & AIMS: Patients with chronic hepatitis C virus (HCV) infection and cirrhosis have a higher risk for liver-related complications and have historically been more difficult to cure than patients without cirrhosis. We evaluated the safety and efficacy of ombitasvir/paritaprevir/ritonavir and dasabuvir, without ribavirin, for 12weeks in patients with HCV genotype 1b infection and compensated cirrhosis. METHODS: Treatment-naïve and peginterferon/ribavirin treatment-experienced patients received 12weeks of ombitasvir/paritaprevir/ritonavir (25/150/100mg once daily) and dasabuvir (250mgtwicedaily). Key inclusion criteria were hemoglobin ⩾10g/dl, albumin ⩾2.8g/dl, platelet count ⩾25×10(9)/L, creatinine clearance ⩾30ml/min, and Child-Pugh score ⩽6. Efficacy was assessed by the percentage of patients achieving SVR (HCV RNA <25IU/ml) 12weeks post-treatment (SVR12). Efficacy and safety were assessed in all patients receiving study drug. RESULTS: Sixty patients with HCV genotype 1b infection and cirrhosis received treatment. The study population comprised 62% male, 55% treatment-experienced, 83% with IL28B non-CC genotype, 22% with platelet count <90×10(9)/L, and 17% with albumin <3.5g/dl. All 60 patients completed treatment, and SVR12 was achieved in 100% (95% CI, 94.0-100%) of patients. The most common adverse events were fatigue (22%), diarrhea (20%), and headache (18%). Only one patient (1.7%) experienced a serious adverse event. Laboratory abnormalities were infrequently observed and not clinically significant. CONCLUSIONS: The HCV regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir without ribavirin for 12weeks achieved 100% SVR12 and was well tolerated in HCV genotype 1b-infected patients with cirrhosis, suggesting that this 12-week ribavirin-free regimen is sufficient in this population.