Fredric D. Gordon

An Interferon-free Antiviral Regimen for HCV after Liver Transplantation

BACKGROUND Hepatitis C virus (HCV) infection is the leading indication for liver transplantation worldwide, and interferon-containing regimens are associated with low response rates owing to treatment-limiting toxic effects in immunosuppressed liver-transplant recipients. We evaluated the interferon-free regimen of the NS5A inhibitor ombitasvir coformulated with the ritonavir-boosted protease inhibitor ABT-450 (ABT-450/r), the nonnucleoside NS5B polymerase inhibitor dasabuvir, and ribavirin in liver-transplant recipients with recurrent HCV genotype 1 infection. METHODS We enrolled 34 liver-transplant recipients with no fibrosis or mild fibrosis, who received ombitasvir-ABT-450/r (at a once-daily dose of 25 mg of ombitasvir, 150 mg of ABT-450, and 100 mg of ritonavir), dasabuvir (250 mg twice daily), and ribavirin for 24 weeks. Selection of the initial ribavirin dose and subsequent dose modifications for anemia were at the investigators discretion. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment. RESULTS Of the 34 study participants, 33 had a sustained virologic response at post-treatment weeks 12 and 24, for a rate of 97% (95% confidence interval, 85 to 100). The most common adverse events were fatigue, headache, and cough. Five patients (15%) required erythropoietin; no patient required blood transfusion. One patient discontinued the study drugs owing to adverse events after week 18 but had a sustained virologic response. Blood levels of calcineurin inhibitors were monitored, and dosages were modified to maintain therapeutic levels; no episode of graft rejection was observed during the study. CONCLUSIONS Treatment with the multitargeted regimen of ombitasvir-ABT-450/r and dasabuvir with ribavirin was associated with a low rate of serious adverse events and a high rate of sustained virologic response among liver-transplant recipients with recurrent HCV genotype 1 infection, a historically difficult-to-treat population. (Funded by AbbVie; CORAL-I ClinicalTrials.gov number, NCT01782495.).

Sofosbuvir and Ribavirin Prevent Recurrence of HCV Infection After Liver Transplantation: An Open-Label Study

BACKGROUND & AIMS Patients with detectable hepatitis C virus (HCV) RNA at the time of liver transplantation universally experience recurrent HCV infection. Antiviral treatment before transplantation can prevent HCV recurrence, but existing interferon-based regimens are poorly tolerated and are either ineffective or contraindicated in most patients. We performed a trial to determine whether sofosbuvir and ribavirin treatment before liver transplantation could prevent HCV recurrence afterward. METHODS In a phase 2, open-label study, 61 patients with HCV of any genotype and cirrhosis (Child-Turcotte-Pugh score, ≤7) who were on waitlists for liver transplantation for hepatocellular carcinoma, received up to 48 weeks of sofosbuvir (400 mg) and ribavirin before liver transplantation. The primary end point was the proportion of patients with HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients with this HCV-RNA level at their last measurement before transplantation. RESULTS Sixty-one patients received sofosbuvir and ribavirin, and 46 received transplanted livers. The per-protocol efficacy population consisted of 43 patients who had HCV-RNA level less than 25 IU/mL at the time of transplantation. Of these 43 patients, 30 (70%) had a post-transplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died (2 from nonfunction of the primary graft and 1 from complications of hepatic artery thrombosis). Of all 61 patients given sofosbuvir and ribavirin, 49% had a post-transplantation virologic response. Recurrence was related inversely to the number of consecutive days of undetectable HCV RNA before transplantation. The most frequently reported adverse events were fatigue (in 38% of patients), headache (23%), and anemia (21%). CONCLUSIONS Administration of sofosbuvir and ribavirin before liver transplantation can prevent post-transplant HCV recurrence. ClinicalTrials.gov: NCT01559844.

Liver regeneration and surgical outcome in donors of right-lobe liver grafts.

Introduction. Previous studies of healthy live‐liver donors have suggested that complete liver regeneration occurs within a matter of weeks; however, there have been no long‐term studies evaluating liver regeneration and few studies documenting long‐term donor outcome. Materials and Methods. Fifty‐one donors who provided right‐lobe grafts underwent volumetric spiral computed tomography scans preoperatively and postoperatively at time intervals of 1 week and 1, 3, 6, and 12 months. Patient demographics, surgical data, and postoperative outcome were correlated with liver regeneration data. Donor surgical outcome was followed prospectively and recorded in a comprehensive database. Results. Thirty‐three males and 18 females (mean age 36.0±9.6 years) provided 51 right‐lobe grafts. Mean follow‐up was 9.8±3.4 months. No donor operation was aborted, and surgical morbidity and mortality rates were 39% and 0%, respectively. Donor remnant liver volume was 49.4±5.7% of the original total liver volume (TLV). Overall liver regeneration was 83.3±9.0% of the TLV by 1 year. Female donors had significantly slower liver regrowth when compared with males at 12 months (79.8±9.3% vs. 85.6±8.2%, P<0.01). There was no effect of age, body mass index, operative time, estimated blood loss, postoperative complications, or perioperative liver function tests on liver regeneration. Discussion. Liver regeneration continues throughout the first postoperative year. Only one donor achieved complete liver regeneration during this time period; however, all donors have maintained normal liver function without long‐term complications. Longer follow‐up is needed to determine whether donors ever achieve original TLV.

Liver transplantation outcomes for early‐stage hepatocellular carcinoma: Results of a multicenter study

The incidence of hepatocellular carcinoma (HCC), a frequent and incurable complication of cirrhosis, continues to rise. Orthotopic liver transplantation (OLT) has been proposed as a treatment for unresectable, intrahepatic HCC limited in extent to the Milan criteria adopted by the United Network of Organ Sharing (UNOS) in 1998. More recently, somewhat less restrictive University of California, San Francisco (UCSF) 10 , criteria were proposed. To examine the long‐term outcomes of OLT for HCC patients and to assess the UNOS policy of assigning weighted allocation points to patients with HCC, we retrospectively analyzed 144 patients (113 after 1998) with HCC who underwent OLT over an 11‐year period at 3 institutions from UNOS Region 1. We compared their outcomes with 525 patients (272 after 1998) who underwent OLT for nonmalignant liver disease. The 1‐ and 5‐year survival rates were 80.3% and 46.7%, respectively, for patients with HCC and 81.5% and 70.6%, respectively, for patients without HCC (P = .020). However, there was no difference in survival between HCC and non‐HCC patients after implementation of disease‐specific allocation for HCC in 1998. A higher proportion of the HCC cohort was older and male and had chronic HCV infection and alcoholic liver disease. In univariate analysis, having alpha‐fetoprotein (AFP) levels of 10 ng/mL or less and meeting clinical and pathologic UCSF criteria were each significant predictors of improved survival (P = .005, P = .02, and P = .03, respectively). AFP greater than 10 ng/mL and exceeding pathologic UCSF criteria were also significant predictors of recurrence (P = .003 and P = .02, respectively). In conclusion, taken together, our data suggest that OLT is an acceptable option for patients with early HCC and that UCSF criteria predict outcome better than Milan or UNOS criteria. Regardless of which criteria are adopted to define eligibility, strict adherence to the criteria is important to achieve acceptable outcomes. (Liver Transpl 2004;10:1343–1354.)

Clinical Utility of AFP-L3% Measurement in North American Patients with HCV-Related Cirrhosis

BACKGROUND AND AIMS:Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3%) has been reported to be useful in the early detection of hepatocellular carcinoma (HCC) in Japan. The aim of this prospective study was to compare the clinical utility of AFP-L3% with that of total AFP in North American patients.METHODS:Patients with chronic hepatitis (CH) C virus-related cirrhosis from 7 clinical sites were prospectively followed every 3–6 months for 2 yr.RESULTS:Of the 372 patients evaluated, 40 had hepatitis C virus-related HCC at entry and 332 entered the prospective trial. Of the latter, 34 developed HCC and 298 remained free of HCC. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for AFP were 60.8%, 71.1%, 34.4%, and 88.0% with a cutoff of 20 ng/mL and 21.6%, 98.7%, 80.0%, and 83.5% with a cutoff of 200 ng/mL, compared to 36.5%, 91.6%, 51.9%, and 85.3% for AFP-L3% with a cutoff of 10%. In those with an elevated AFP (20–200 ng/mL), AFP-L3% had a specificity of 86.6% and an NPV of 80.7%. Multivariate analysis identified AFP, AFP-L3%, and age as independent predictors of HCC. Elevated AFP-L3% was associated with a lower cumulative HCC-free rate at 2 yr (58.9%) than was AFP (82.0%, P = 0.01).CONCLUSIONS:The incidence of HCC was significantly higher in patients with elevated AFP-L3% than in those with elevated AFP. The high specificity of AFP-L3% persisted among patients with elevated AFP (20–200 ng/mL) and suggests that AFP-L3% has clinical utility in HCV patients with AFP of 20–200 ng/mL.

Utility of Lens culinaris Agglutinin-Reactive Fraction of α-Fetoprotein and Des-Gamma-Carboxy Prothrombin, Alone or in Combination, as Biomarkers for Hepatocellular Carcinoma

BACKGROUND & AIMS Des-gamma-carboxy prothrombin (DCP) and Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) are surveillance markers used to detect hepatocellular carcinoma (HCC) in Japan. This study evaluated their utility, alone or in combination, in a North American population. METHODS Patients with hepatitis C virus-related cirrhosis were followed up prospectively for 2 years. RESULTS Of 372 patients, HCC developed in 34 of 298 who were free of HCC at entry. The overall sensitivity, specificity, and positive and negative predictive values for only AFP (>20 ng/mL) were 61%, 71%, 34%, and 88%, respectively; for only AFP-L3% (>10) were 37%, 92%, 52%, and 85%, respectively; and for only DCP (>7.5 ng/mL) were 39%, 90%, 48%, and 86%, respectively. Values increased when AFP values were combined with AFP-L3% and DCP to 77%, 59%, 32%, and 91%, respectively. Among patients with increases in AFP levels to 20 to 200 ng/mL, AFP-L3% and DCP were highly specific markers (86.6% and 90.2%, respectively). Of 29 HCC patients with AFP levels less than 20 ng/mL, 13 had increased levels of AFP-L3% or DCP. Increased alanine aminotransferase levels were associated with increased total AFP but not AFP-L3% or DCP levels. Both AFP-L3%- and DCP-positive patients showed significant differences in lower cumulative HCC-free rates compared with the overall group (P < .0001 and P = .0005, respectively). CONCLUSIONS AFP-L3% and DCP levels have higher correlation values with an absence of HCC, as well as a higher specificity and negative predictive value, than total AFP. Although this combination of markers only marginally improves surveillance for early HCC, it could identify individuals with negative imaging results who would benefit from follow-up evaluation.

Living donor liver transplantation for hepatocellular carcinoma: Increased recurrence but improved survival.

In regions with a limited deceased donor pool, living donor adult liver transplantation (LDALT) has become an important treatment modality for patients with hepatocellular carcinoma (HCC) and cirrhosis. Studies have shown higher recurrence rates of HCC after LDALT in comparison with deceased donor liver transplantation (DDLT). The aim of our study was to examine the outcome results and recurrence rates for patients with HCC who underwent LDALT at our center. During an 8‐year period, 139 patients underwent LDALT, of whom 28 (20.1%) had HCC in their explanted livers. The median follow‐up was 40.8 months. The mean explant tumor size was 3.3 ± 1.2, and the mean number of tumors was 1.5 ± 0.8. Twenty‐one patients (75%) had tumors within the Milan criteria, 5 patients had tumors outside the Milan criteria but within the University of California San Francisco (UCSF) criteria, and 2 patients were beyond the UCSF criteria. The overall 1‐ and 5‐year patient and graft survival rates were 96% and 81%, respectively. Survival following LDALT was significantly better than survival following DDLT for HCC during the same time period (P = 0.02). Eight patients (28.6%) developed tumor recurrence. Poor differentiation of tumor cells was the most significant determinant of recurrence. Despite high recurrence rates of HCC following LDALT, overall 5‐year survival appears to be excellent. Liver Transpl 15:1861–1866, 2009.

Human monoclonal antibody MBL-HCV1 delays HCV viral rebound following liver transplantation: a randomized controlled study.

Rapid allograft infection complicates liver transplantation (LT) in patients with hepatitis C virus (HCV). Pegylated interferon‐α and ribavirin therapy after LT has significant toxicity and limited efficacy. The effect of a human monoclonal antibody targeting the HCV E2 glycoprotein (MBL‐HCV1) on viral clearance was examined in a randomized, double‐blind, placebo‐controlled pilot study in patients infected with HCV genotype 1a undergoing LT. Subjects received 11 infusions of 50 mg/kg MBL‐HCV1 (n = 6) or placebo (n = 5) intravenously with three infusions on day of transplant, a single infusion on days 1 through 7 and one infusion on day 14 after LT. MBL‐HCV1 was well‐tolerated and reduced viral load for a period ranging from 7 to 28 days. Median change in viral load (log10 IU/mL) from baseline was significantly greater (p = 0.02) for the antibody‐treated group (range −3.07 to −3.34) compared to placebo group (range −0.331 to −1.01) on days 3 through 6 posttransplant. MBL‐HCV1 treatment significantly delayed median time to viral rebound compared to placebo treatment (18.7 days vs. 2.4 days, p < 0.001). As with other HCV monotherapies, antibody‐treated subjects had resistance‐associated variants at the time of viral rebound. A combination study of MBL‐HCV1 with a direct‐acting antiviral is underway.

Native liver xanthogranulomatous cholangiopathy in primary sclerosing cholangitis: Impact on posttransplant outcome

A retrospective analysis of 51 primary sclerosing cholangitis (PSC) patients who underwent liver transplant (LT) identified 16 with xanthogranulomatous cholangiopathy (XGC) at the native liver hilum. Pre‐LT clinical and laboratory data and post‐LT course and outcome of patients with XGC were compared with the 35 PSC patients without XGC. The XGC and non‐XGC groups were similar with respect to age and laboratory data at the time of LT. Pre‐LT cholecystectomy was performed in 44% versus 26% and biliary bypass procedure in 38% versus 26% of patients with and without XGC, respectively (P = NS). Peri‐operative complications resulted in six (38%) deaths or retransplantation within 60 days of LT in the XGC group compared with 4 (11%) in the non‐XGC group (P = .05). Patient survival at 60 and 100 days post‐LT was better in the non‐XGC group (P = .01). The causes of death or retransplantation within 60 days post‐LT in the patients with XGC included primary nongraft function (1), uncontrolled bleeding (3), and sepsis (2), while in the non‐XGC group these were uncontrolled bleeding (2), sepsis (1), and primary nongraft function (1). Mean graft survival ± SD was 1,081 ± 1,584 days in patients with XGC versus 2,149 ± 1,679 days in patients without XGC. The presence of XGC in the native liver hilum of PSC patients undergoing LT was associated with a higher rate of early post‐LT mortality or retransplantation. In conclusion, no pre‐LT clinical features or laboratory tests were identified that predicted the presence of XGC in PSC patients. (Liver Transpl 2004;10:115–122.)

Cost-effectiveness of screening patients for hepatitis C

This review discusses the benefits and drawbacks of public health screening for hepatitis C, its cost effectiveness, and the various strategies to identify individuals infected with the hepatitis C virus (HCV). Of the estimated 4 million people infected with hepatitis C in the United States, approximately 50% are unaware of their infection. Both the high incidence and recent improvements in the treatment of hepatitis C make it likely that a screening program for this disease would be beneficial to patients, their families, and to the public. Testing for anti-HCV antibody is now widely available, automated, sensitive (>95%), and relatively inexpensive (approximately