James R. Burton

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.).

Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers.

BACKGROUND & AIMS Excellent single-center outcomes of neoadjuvant chemoradiation and liver transplantation for unresectable perihilar cholangiocarcinoma caused the United Network of Organ Sharing to offer a standardized model of end-stage liver disease (MELD) exception for this disease. We analyzed data from multiple centers to determine the effectiveness of this treatment and the appropriateness of the MELD exception. METHODS We collected and analyzed data from 12 large-volume transplant centers in the United States. These centers met the inclusion criteria of treating 3 or more patients with perihilar cholangiocarcinoma using neoadjuvant therapy, followed by liver transplantation, from 1993 to 2010 (n = 287 total patients). Center-specific protocols and medical charts were reviewed on-site. RESULTS The patients completed external radiation (99%), brachytherapy (75%), radiosensitizing therapy (98%), and/or maintenance chemotherapy (65%). Seventy-one patients dropped out before liver transplantation (rate, 11.5% in 3 months). Intent-to-treat survival rates were 68% and 53%, 2 and 5 years after therapy, respectively; post-transplant, recurrence-free survival rates were 78% and 65%, respectively. Patients outside the United Network of Organ Sharing criteria (those with tumor mass >3 cm, transperitoneal tumor biopsy, or metastatic disease) or with a prior malignancy had significantly shorter survival times (P < .001). There were no differences in outcomes among patients based on differences in surgical staging or brachytherapy. Although most patients came from 1 center (n = 193), the other 11 centers had similar survival times after therapy. CONCLUSIONS Patients with perihilar cholangiocarcinoma who were treated with neoadjuvant therapy followed up by liver transplantation at 12 US centers had a 65% rate of recurrence-free survival after 5 years, showing this therapy to be highly effective. An 11.5% drop-out rate after 3.5 months of therapy indicates the appropriateness of the MELD exception. Rigorous selection is important for the continued success of this treatment.

Review and management of drug interactions with boceprevir and telaprevir

Boceprevir (BOC) and telaprevir (TPV), when added to pegylated interferon and ribavirin for the treatment of chronic hepatitis C virus (HCV) infection, increase the rates of sustained virologic response in treatment‐naïve persons to approximately 70%. Though these agents represent an important advance in the treatment of chronic HCV, they present new treatment challenges to the hepatology community. BOC and TPV are both substrates and inhibitors of the hepatic enzyme, cytochrome P450 3A, and the drug transporter, P‐glycoprotein, which predisposes these agents to many drug interactions. Identification and appropriate management of potential drug interactions with TPV and BOC is critical for optimizing therapeutic outcomes during hepatitis C treatment. This review highlights the pharmacologic characteristics and drug‐interaction potential of BOC and TPV and provides guidance on the management of drug interactions with these agents. (HEPATOLOGY 2012;)

Loss of IL-7 receptor alpha-chain (CD127) expression in acute HCV infection associated with viral persistence†

Interleukin‐7 (IL‐7) is required for the establishment and maintenance of memory CD4+ and CD8+ T lymphocytes, and cells lacking IL‐7Rα (CD127) demonstrate impaired IL‐2 secretion and have a short life‐span. Chronic HCV is characterized by T cells that are functionally impaired and exhibit an immature phenotype. To investigate the potential role of IL‐7/IL‐7Rα in the outcome of HCV infection, we used multiparameter flow cytometry to characterize patients with acute infection (n = 24), long‐term chronic infection (12) and normal subjects (13). HCV infection per se resulted in downregulation of CD127 on total CD4+ and CD8+ T lymphocytes as compared to normal controls. Total expression was lowest in those patients who subsequently developed persistence and intermediate in those patients with acute‐resolving infection. This reduction affected both naïve and effector/memory T cells. CD127 correlated phenotypically with upregulation of chemokine receptors CCR7 and CXCR4, expression of the anti‐apoptotic molecule B cell leukemia/lymphoma 2 (Bcl‐2), and enhanced IL‐2 production. In six HLA A2‐positive patients, we longitudinally tracked tetramer responses to HCV and CMV epitopes; at baseline, reflecting the expression of CD127 on whole T cell populations, viral‐specific CTLs in patients who became chronic demonstrated lower CD127. In conclusion, CD127 is a useful marker of functional CD4+ and CD8+ T cells and its expression correlates with virologic outcome of acute HCV. These data provide a mechanistic basis for the observation that CTLs generated in early infection rapidly decline as chronicity is established; CD127 expression should be considered in the design of novel immunotherapeutic approaches. (HEPATOLOGY 2006;44:1098–1109.)

Drug–drug interactions during antiviral therapy for chronic hepatitis C

The emergence of direct-acting antiviral agents (DAAs) for HCV infection represents a major advance in treatment. The NS3 protease inhibitors, boceprevir and telaprevir, were the first DAAs to receive regulatory approval. When combined with PEG-IFN and ribavirin, these agents increase rates of sustained virologic response in HCV genotype 1 to ∼70%. However, this treatment regimen is associated with several toxicities. In addition, both boceprevir and telaprevir are substrates for and inhibitors of the drug transporter P-glycoprotein and the cytochrome P450 enzyme 3A4 and are, therefore, prone to clinically relevant drug interactions. Several new DAAs for HCV are in late stages of clinical development and are likely to be approved in the near future. These include the protease inhibitors, simeprevir and faldaprevir, the NS5A inhibitor, daclatasvir, and the nucleotide polymerase inhibitor, sofosbuvir. Herein, we review the clinical pharmacology and drug interactions of boceprevir, telaprevir and these investigational DAAs. Although boceprevir and telaprevir are involved in many interactions, these interactions are manageable if health-care providers proactively identify and adjust treatments. Emerging DAAs seem to have a reduced potential for drug interactions, which will facilitate their use in the treatment of HCV.

Functional Suppression by FoxP3+CD4+CD25high Regulatory T Cells during Acute Hepatitis C Virus Infection

BACKGROUND Infection with hepatitis C virus (HCV) is characterized by impairment of viral effector T cell responses and a high propensity for viral persistence. Previous studies have demonstrated that chronic HCV infection is associated with an increased frequency of regulatory T (T(reg)) cells, compared with that in persons whose infection resolved and in healthy persons. However, all patients in prior analyses had exposures in the distant past, precluding the ability to determine whether T(reg) cells play a causal role in establishing persistence during the earliest stages of infection or whether they are expanded because of viral persistence. METHODS For the first time, we longitudinally analyzed T(reg) cells in patients with acute HCV infection (n = 27). We used a multiparameter approach, including fluorescence-activated cell sorting analysis of cell-surface and intracellular antigens, coculture experiments with highly purified CD4(+)CD25(high) regulatory and CD4(+)CD25(-) responder cell populations, and multiplex analysis of secreted cytokines. RESULTS Forkhead transcription factor 3 (FoxP3) expression and T(reg) cell suppression were greater in patients with acute HCV infection than in healthy control subjects but were not different at the first time point among patients who subsequently developed persistence or resolved HCV infection spontaneously; however, 6 months later, the resolution of disease was associated with a relative loss of functional suppression. CONCLUSIONS Collectively, these data indicate that patients with acute HCV infection who develop chronicity versus spontaneous resolution exhibit temporal changes in T(reg) cell function. It is possible that repetitive viral antigenic stimulation alters the function of T(reg) cells over time.

Retransplantation for Hepatitis C: Results of a U.S. Multicenter Retransplant Study

It is widely perceived that outcomes are relatively poor following retransplantation (reTX) for recurrent of hepatitis C virus (HCV) infection. Transplant centers debate the utility of offering another liver to these patients. A U.S. study group was formed to retrospectively compare survival after reTX in patients with recurrent HCV (histologically proven) and those transplanted for other indications greater than 90 days after first transplantation, from 1996 to 2004. Patients were divided into 3 groups; group 1: HCV reTX (n = 43), group 2: non‐HCV reTX (n = 73), and group 3: recurrent HCV but no reTX (n = 156). They were predominantly male, Caucasian, with mean age of 47.2 yr. The commonest indications for non‐HCV reTX were chronic rejection (36%), hepatic artery thrombosis (31%) and recurrent primary sclerosing cholangitis (17%). Duration of hospitalization, number of intensive care unit (ICU) days, and time interval from listing to transplantation or reTX were similar between reTX groups. The 1‐yr and 3‐yr survival rates after reTX were also similar for HCV reTX and non‐HCV reTX groups (1 yr, 69% vs. 73%; 3 yr, 49% vs. 55%). Model for End‐Stage Liver Disease (MELD) scores were not predictive of survival from reTX. However, with a MELD score of >30 in the non HCV group, survival was <50%. In the recurrent HCV not undergoing reTX group, 30% were reevaluated for reTX but only 15% were listed for reTX and the 3‐yr survival was 47%. The most common reasons for not listing for reTX were recurrent HCV within 6 months (22%), fibrosing cholestatic hepatitis (19%), and renal dysfunction (9%). In conclusion, patients retransplanted for recurrent HCV had similar 1‐yr and 3‐yr survival when compared to patients undergoing reTX for other indications. MELD scores were not predictive of post‐reTX survival. Survival was <50% in the non‐HCV reTx group with MELD score of >30. Many patients with recurrent HCV are not considered for reTX and die from recurrent disease. Liver Transpl 13:1246–1253, 2007.

Incidence and Predictors of 30-Day Readmission Among Patients Hospitalized for Advanced Liver Disease

BACKGROUND & AIMS The rate of readmission to the hospital 30 days after discharge (30-day readmission rate) is used as a quality measure for hospitalized patients, but it has not been studied adequately for patients with advanced liver disease. We investigated the incidence and factors that predict this rate and its relationship with mortality at 90 days. METHODS We analyzed data from patients with advanced liver disease who were hospitalized to an inpatient hepatology service at 2 large academic medical centers in 2008. Patients with elective admission and recipients of liver transplants were not included. During the study period, there were 447 patients and a total of 554 eligible admissions. Multivariate analyses were performed to identify variables associated with 30-day readmission and to examine its relationship with mortality at 90 days. RESULTS The 30-day readmission rate was 20%. After adjusting for multiple covariates, readmission within 30 days was associated independently with model for end-stage liver disease scores at discharge (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02-1.09; P = .002), the presence of diabetes (OR, 1.78; 95% CI, 1.07-2.95; P = .027), and male sex (OR, 1.73; 95% CI, 1.03-2.89; P = .038). After adjusting for age, sex, and model for end-stage liver disease score at discharge, the 90-day mortality rate was significantly higher among patients who were readmitted to the hospital within 30 days than those who were not (26.8% vs 9.8%; OR, 2.6; 95% CI, 1.36-5.02; P = .004). CONCLUSIONS Patients with advanced liver disease frequently are readmitted to the hospital within 30 days after discharge; these patients have a higher 90-day mortality rate than those who are not readmitted in 30 days. These data might be used to develop strategies to reduce early readmission of hospitalized patients with cirrhosis.

Inhibition of Angiotensin-Converting Enzyme for Diagnosis of Renal-Artery Stenosis

To determine its utility as an aid in diagnosis of renovascular hypertension, we administered nonapeptide converting-enzyme inhibitor (CEI) (which inhibits conversion of angiotensin I to angiotensin II) (0.25 mg per kilogram) to 14 unselected hypertensive patients undergoing bilateral renal-vein catheterization. In seven (Group I) predominantly unilateral disease was discovered by angiography (renal-artery stenosis in six and hydronephrosis in one); in the remaining seven (Group II) no rennal-artery abnormality was found. In Group I, mean (+/- S.E.) ratio of involved to uninvolved renal-vein plasma renin activity (PRA) increased from 2.94 +/- 0.91 before to 8.36 +/- 2.94 after CEI (P less than 0.01). In Group II, the ratio (of the initially higher to the lower side) was 1.99 +/- 0.49 before and 1.17 +/- 0.07 after CEI (P greater 0.02). Post-CEI PRA was predicted by pretreatment PRA. Mean blood pressure fell in both groups after CEI, and the decrement was predicted by pre-CEI PRA. These data suggest that CEI can be of use at the time of renal-vein catheterization, serving to increase diagnostic accuracy by increasing the difference in PRA between the two sides when there is unilateral disease.

Interferon-free therapy for genotype 1 hepatitis C in liver transplant recipients: Real-world experience from the hepatitis C therapeutic registry and research network.

Recurrent infection with the hepatitis C virus (HCV) after liver transplantation (LT) is associated with decreased graft and patient survival. Achieving sustained virological response (SVR) with antiviral therapy improves survival. Because interferon (IFN)‐based therapy has limited efficacy and is poorly tolerated, there has been rapid transition to IFN‐free direct‐acting antiviral (DAA) regimens. This article describes the experience with DAAs in the treatment of posttransplant genotype (GT) 1 HCV from a consortium of community and academic centers (Hepatitis C Therapeutic Registry and Research Network [HCV‐TARGET]). Twenty‐one of the 54 centers contributing to the HCV‐TARGET consortium participated in this study. Enrollment criteria included positive posttransplant HCV RNA before treatment, HCV GT 1, and documentation of use of a simeprevir (SMV)/sofosbuvir (SOF) containing DAA regimen. Safety and efficacy were assessed. SVR was defined as undetectable HCV RNA 64 days or later after cessation of treatment. A total of 162 patients enrolled in HCV‐TARGET started treatment with SMV+SOF with or without ribavirin (RBV) following LT. The study population included 151 patients treated with these regimens for whom outcomes and safety data were available. The majority of the 151 patients were treated with SOF and SMV alone (n = 119; 79%) or with RBV (n = 32; 21%), The duration of therapy was 12 weeks for most patients, although 15 patients received 24 weeks of treatment. Of all patients receiving SOF/SMV with or without RBV, 133/151 (88%) achieved sustained virological response at 12 weeks after therapy and 11 relapsed (7%). One patient had virological breakthrough (n = 1), and 6 patients were lost to posttreatment follow‐up. Serious adverse events occurred in 11.9%; 3 patients (all cirrhotic) died due to aspiration pneumonia, suicide, and multiorgan failure. One experienced LT rejection. IFN‐free DAA treatment represents a major improvement over prior IFN‐based therapy. Broader application of these and other emerging DAA regimens in the treatment of posttransplant hepatitis C is warranted. Liver Transpl 22:24‐33, 2016.