Lawrence U. Liu

Survival and Risk of Recidivism in Methadone-Dependent Patients Undergoing Liver Transplantation

Cirrhosis resulting from hepatitis C virus is presently the most common indication for liver transplantation (OLT) in the United States. A number of U.S. transplant centers require cirrhotics who are using methadone to discontinue it before proceeding with OLT. We sought to examine the outcomes of those patients who had undergone OLT at the Mount Sinai Medical Center.

Marked Differences in acute cellular rejection rates between living-donor and deceased-donor liver transplant recipients.

Background. Due to ongoing organ donor shortage, an increasing number of adult live-donor liver transplants (LDLT) are being performed. The aims of this study were to compare the incidence of ACR between recipients of live- and deceased-donor liver transplants, and to note any differences in ACR among related and unrelated living-donor recipients. Methods. Sixty-four adults undergoing LDLT between 1998-2001 were closely matched with a deceased recipient. Statistical comparisons in ACR between the live- and deceased-donor groups were based on the differences between the ACR rates of each LDLT patient and the corresponding matched deceased recipient. Analyses were performed separately for pairs in which the living donor was not related to the recipient, was a nonsibling relative, or was a sibling. Results. Live- and deceased-donor recipients underwent a similar number of liver biopsies. In all, 16/50 (32%) of the biopsied LDLT patients had ACR compared to 36/49 (73%) of the deceased-donor recipients. ACR rates of living donors and their deceased-donor matches did not differ significantly for the unrelated living donors, but did differ for the nonsibling related (P=0.03) and the sibling LDLT (P=0.03). The results were similar when comparing rates of high-degree ACR for unrelated, nonsibling related, and sibling pairs. High-degree ACR differences in the sibling LDLT group were significantly greater than in the nonsibling group (P=0.05). Conclusions. Rates of ACR and high-degree ACR are decreased in living-related liver transplant recipients. This difference is likely genetically related as ACR rates are lower in recipient-donor pairs of increasing genetic similarity.

Effect of fibrosis on adverse events in patients with hepatitis C treated with telaprevir

Data about adverse events are needed to optimise telaprevir‐based therapy in a broad spectrum of patients.

Diabetes mellitus and advanced liver fibrosis are risk factors for severe anaemia during telaprevir-based triple therapy

Adding telaprevir to pegylated‐interferon and ribavirin increased both response rates and side effects of hepatitis C virus (HCV) treatment. We identified variables associated with severe anaemia during telaprevir‐based triple therapy.

Endoscopic Diagnosis of Bleeding Meckel's Diverticulum in a Multivisceral Transplant Recipient

Small bowel transplantation has become a life‐saving procedure for patients with intestinal failure who fail conventional therapy. Meckels diverticulum is a rare cause of occult gastrointestinal bleeding that has not been reported in patients receiving intestinal allografts. We report a case in which transplantation of an asymptomatic Meckels diverticulum as part of a multivisceral allograft led to intestinal bleeding requiring surgical intervention. Endoscopy identified the actual bleeding diverticulum. Diverticulectomy at the time of transplant was not performed due to the difficult operative course, and the need for frequent surveillance ileoscopy, which would be performed across a fresh intestinal anastomosis. The patient underwent resection of the diverticulum, along with 40 cm of ileum, and did not experience further bleeding.

High baseline bilirubin and low albumin predict liver decompensation and serious adverse events in HCV-infected patients treated with sofosbuvir-containing regimens

To conduct surveillance and determine the safety profile of new hepatitis C virus treatments in real‐world clinical practice. Hepatic decompensation and other serious adverse events were investigated in an observational cohort study of 511 patients treated with regimens containing sofosbuvir, December 2013–June 2014. Among 499 previously stable patients (no history of hepatic decompensation during the previous 12 months), a nested case–control study was performed to identify predictors of decompensation/serious adverse event. Cases and controls were matched 1:5 based on treatment regimen and duration. Matched conditional logistic regression was used for analysis. Providers scored the likelihood that events were treatment‐related (scale = 0–4). The cumulative incidence of decompensation/events was 6.4% for the total cohort. Among 499 previously stable patients, the incidence of decompensation/events was 4.5%; the mortality rate was 0.6%. Sixteen of the 499 experienced one or more serious complications considered to be at least potentially treatment‐related, and the sustained virological response rate was 7/16 (44%). Two cases, both on sofosbuvir/simeprevir (without interferon or ribavirin), had complications consistent with autoimmune events (score 3, ‘likely treatment‐related’), and one experienced a flare of autoimmune hepatitis. Compared to controls, cases had higher baseline median model for end‐stage liver disease scores (14 vs 8, P < 0.01). Decompensation/events was independently associated with lower baseline albumin (OR = 0.12/g/dL, P = 0.01) and higher total bilirubin (OR = 4.31/mg/dL, P = 0.01). Reduced hepatic function at baseline increased the risk of liver decompensation/events.

Factors associated with success of telaprevir- and boceprevir-based triple therapy for hepatitis C virus infection

AIM To evaluate new therapies for hepatitis C virus (HCV), data about real-world outcomes are needed. METHODS Outcomes of 223 patients with genotype 1 HCV who started telaprevir- or boceprevir-based triple therapy (May 2011-March 2012) at the Mount Sinai Medical Center were analyzed. Human immunodeficiency virus-positive patients and patients who received a liver transplant were excluded. Factors associated with sustained virological response (SVR24) and relapse were analyzed by univariable and multivariable logistic regression as well as classification and regression trees. Fast virological response (FVR) was defined as undetectable HCV RNA at week-4 (telaprevir) or week-8 (boceprevir). RESULTS The median age was 57 years, 18% were black, 44% had advanced fibrosis/cirrhosis (FIB-4 ≥ 3.25). Only 42% (94/223) of patients achieved SVR24 on an intention-to-treat basis. In a model that included platelets, SVR24 was associated with white race [odds ratio (OR) = 5.92, 95% confidence interval (CI): 2.34-14.96], HCV sub-genotype 1b (OR = 2.81, 95%CI: 1.45-5.44), platelet count (OR = 1.10, per x 104 cells/μL, 95%CI: 1.05-1.16), and IL28B CC genotype (OR = 3.54, 95%CI: 1.19-10.53). Platelet counts > 135 x 103/μL were the strongest predictor of SVR by classification and regression tree. Relapse occurred in 25% (27/104) of patients with an end-of-treatment response and was associated with non-FVR (OR = 4.77, 95%CI: 1.68-13.56), HCV sub-genotype 1a (OR = 5.20; 95%CI: 1.40-18.97), and FIB-4 ≥ 3.25 (OR = 2.77; 95%CI: 1.07-7.22). CONCLUSION The SVR rate was 42% with telaprevir- or boceprevir-based triple therapy in real-world practice. Low platelets and advanced fibrosis were associated with treatment failure and relapse.

Telaprevir, Pegylated Interferon Alfa-2a, and Ribavirin for Hepatitis C Virus Genotype 4 Infection

To the Editor—Benhamou et al demonstrated that the tolerability and pharmacokinetics of telaprevir in patients infected with hepatitis C virus (HCV) genotype 4 were similar to those found in HCV genotype 1 patients [1]. In their study, patients infected with HCV genotype 4 were randomly assigned to receive (1) telaprevir monotherapy for 15 days; (2) telaprevir, pegylated interferon alfa-2a, and ribavirin (TPR) for 15 days; or (3) placebo, pegylated interferon alfa-2a, and ribavirin (PR) for 15 days. After the initial 15-day treatment period, study drugs in each group were replaced with standard PR treatment, which was administered for an additional 46–48 weeks. Findings from the study by Benhamou et al supported the investigation of TPR for 12 weeks, followed by PR for an additional 36 weeks, in HCV genotype 4–infected patients. With institutional review board approval, we performed a chart review of HCV genotype 4–infected patients who received TPR at Mount Sinai Hospital, New York, between April 2011 and October 2012. The aim was to determine the rate of sustained virologic response at week 24 of follow-up (SVR24), which was defined as undetectable HCV RNA 24 weeks after the end of treatment. Patients who were chronically infected with HCV genotype 4 and received at least 1 dose of telaprevir were included. The demographic characteristics of our patients are described in Table ​Table1.1. Patients received the TPR regimen approved for treatment of HCV genotype 1 infection (ie, TPR for 12 weeks then PR for an additional 12 weeks [response-guided therapy] or 36 weeks), with the following exceptions [2]. Patient 1 began TPR treatment, and after 2 weeks it was discovered that he was given 200 mg ribavirin twice daily instead of 600 mg twice daily. Telaprevir therapy was mistakenly discontinued after 8 weeks, and PR treatment was discontinued because of virologic breakthrough (ie, HCV RNA was detected after the HCV RNA level had fallen below the limit of detection during treatment) that occurred after 41 weeks of treatment. Patient 3 initiated TPR therapy, decided to stop treatment 40 weeks after initiation, and achieved a SVR24. Patient 5 initiated TPR therapy and, after 11 weeks, discontinued telaprevir treatment because of adverse events. Patient 6 received nitazoxanide and PR treatment, and his HCV RNA load 4 weeks later had decreased to 5414 IU/mL. He discontinued nitazoxanide therapy at this time because of adverse events. A 12-week course of telaprevir treatment was added to the existing regimen after 22 weeks. By week 31 of treatment, the HCV RNA level in patient 6 had fallen below the limit of quantification, but HCV RNA was detectable 6 weeks after the end of treatment. Patient 7 initiated TPR treatment, but it was discontinued after 2 weeks because of adverse events (hepatic encephalopathy, ascites, thrombocytopenia, and neutropenia). Decompensation continued, and the patient was discharged to hospice 13 weeks after the end of treatment, where he died. Table 1. Demographic Characteristics, Baseline Characteristics, and Treatment Outcomes Among Patients Infected With Hepatitis C Virus (HCV) Genotype 4 Our patients experienced adverse events similar to those experienced by patients observed by Benhamou et al [1]. The most common adverse events experienced by our patients included but were not limited to influenza-like symptoms, rash, fatigue/weakness/shortness of breath, anemia, low neutrophil count, low platelet count, low white blood cell count, anorectal conditions, nausea/vomiting/diarrhea, abdominal/stomach pain, pruritus, and constipation. Two patients experienced liver decompensation (hepatic encephalopathy in patient 5 and hepatic encephalopathy, ascites, thrombocytopenia requiring platelet transfusion, and neutropenia in patient 7). One patient required epoetin alfa therapy, and 2 required epoetin alfa therapy and a blood transfusion. Less common adverse events included but were not limited to difficulty controlling diabetes until telaprevir therapy was discontinued, conjunctivitis, hypothyroidism, vision changes, and depression and moodiness. Overall, 4 patients had visits to the emergency department. Reasons for emergency care included but were not limited to hepatic encephalopathy (International Classification of Diseases, Ninth Revision–Clinical Modification code 572.2), urinary tract infection (599.0), anemia (285.9), abdominal pain (789.0), headache (784.0), back pain (724), and severe interferon reaction (995.29). Patient 1 developed hepatocellular carcinoma within a year after treatment ended, and patient 7 had a history of hepatocellular carcinoma. We observed a SVR24 in 50% of patients. All of the patients who did not obtain a SVR24 were cirrhotic and did not follow the TPR treatment protocol approved for HCV genotype 1 infection. At the time of writing, for 1 patient, 24 weeks had not passed since the end of treatment. The SVR24 rate obtained in our study reflects the same SVR24 rate that Benhamou et al found in patients treated with TPR for 15 days and then PR for 46 weeks. It is important to note that our patients differed from those in the study by Benhamou et al, as we included a patient coinfected with human immunodeficiency virus, patients with cirrhosis, and patients who were older (median age, 56 years [range, 43–68 years] vs 41 years [range, 28–52 years]). Our results reinforce the findings by Benhamou et al and support additional research of TPR therapy in patients with HCV genotype 4 infection [1].

Reply to “Telaprevir Activity in Treatment-Naive Patients Infected Hepatitis C Virus Genotype 4: A Randomized Trial” by Benhamou et al. published on July 11, 2013

To the Editor—Benhamou et al demonstrated that the tolerability and pharmacokinetics of telaprevir in patients infected with hepatitis C virus (HCV) genotype 4 were similar to those found in HCV genotype 1 patients [1]. In their study, patients infected with HCV genotype 4 were randomly assigned to receive (1) telaprevir monotherapy for 15 days; (2) telaprevir, pegylated interferon alfa-2a, and ribavirin (TPR) for 15 days; or (3) placebo, pegylated interferon alfa-2a, and ribavirin (PR) for 15 days. After the initial 15-day treatment period, study drugs in each group were replaced with standard PR treatment, which was administered for an additional 46–48 weeks. Findings from the study by Benhamou et al supported the investigation of TPR for 12 weeks, followed by PR for an additional 36 weeks, in HCV genotype 4–infected patients. With institutional review board approval, we performed a chart review of HCV genotype 4–infected patients who received TPR at Mount Sinai Hospital, New York, between April 2011 and October 2012. The aim was to determine the rate of sustained virologic response at week 24 of follow-up (SVR24), which was defined as undetectable HCV RNA 24 weeks after the end of treatment. Patients who were chronically infected with HCV genotype 4 and received at least 1 dose of telaprevir were included. The demographic characteristics of our patients are described in Table ​Table1.1. Patients received the TPR regimen approved for treatment of HCV genotype 1 infection (ie, TPR for 12 weeks then PR for an additional 12 weeks [response-guided therapy] or 36 weeks), with the following exceptions [2]. Patient 1 began TPR treatment, and after 2 weeks it was discovered that he was given 200 mg ribavirin twice daily instead of 600 mg twice daily. Telaprevir therapy was mistakenly discontinued after 8 weeks, and PR treatment was discontinued because of virologic breakthrough (ie, HCV RNA was detected after the HCV RNA level had fallen below the limit of detection during treatment) that occurred after 41 weeks of treatment. Patient 3 initiated TPR therapy, decided to stop treatment 40 weeks after initiation, and achieved a SVR24. Patient 5 initiated TPR therapy and, after 11 weeks, discontinued telaprevir treatment because of adverse events. Patient 6 received nitazoxanide and PR treatment, and his HCV RNA load 4 weeks later had decreased to 5414 IU/mL. He discontinued nitazoxanide therapy at this time because of adverse events. A 12-week course of telaprevir treatment was added to the existing regimen after 22 weeks. By week 31 of treatment, the HCV RNA level in patient 6 had fallen below the limit of quantification, but HCV RNA was detectable 6 weeks after the end of treatment. Patient 7 initiated TPR treatment, but it was discontinued after 2 weeks because of adverse events (hepatic encephalopathy, ascites, thrombocytopenia, and neutropenia). Decompensation continued, and the patient was discharged to hospice 13 weeks after the end of treatment, where he died. Table 1. Demographic Characteristics, Baseline Characteristics, and Treatment Outcomes Among Patients Infected With Hepatitis C Virus (HCV) Genotype 4 Our patients experienced adverse events similar to those experienced by patients observed by Benhamou et al [1]. The most common adverse events experienced by our patients included but were not limited to influenza-like symptoms, rash, fatigue/weakness/shortness of breath, anemia, low neutrophil count, low platelet count, low white blood cell count, anorectal conditions, nausea/vomiting/diarrhea, abdominal/stomach pain, pruritus, and constipation. Two patients experienced liver decompensation (hepatic encephalopathy in patient 5 and hepatic encephalopathy, ascites, thrombocytopenia requiring platelet transfusion, and neutropenia in patient 7). One patient required epoetin alfa therapy, and 2 required epoetin alfa therapy and a blood transfusion. Less common adverse events included but were not limited to difficulty controlling diabetes until telaprevir therapy was discontinued, conjunctivitis, hypothyroidism, vision changes, and depression and moodiness. Overall, 4 patients had visits to the emergency department. Reasons for emergency care included but were not limited to hepatic encephalopathy (International Classification of Diseases, Ninth Revision–Clinical Modification code 572.2), urinary tract infection (599.0), anemia (285.9), abdominal pain (789.0), headache (784.0), back pain (724), and severe interferon reaction (995.29). Patient 1 developed hepatocellular carcinoma within a year after treatment ended, and patient 7 had a history of hepatocellular carcinoma. We observed a SVR24 in 50% of patients. All of the patients who did not obtain a SVR24 were cirrhotic and did not follow the TPR treatment protocol approved for HCV genotype 1 infection. At the time of writing, for 1 patient, 24 weeks had not passed since the end of treatment. The SVR24 rate obtained in our study reflects the same SVR24 rate that Benhamou et al found in patients treated with TPR for 15 days and then PR for 46 weeks. It is important to note that our patients differed from those in the study by Benhamou et al, as we included a patient coinfected with human immunodeficiency virus, patients with cirrhosis, and patients who were older (median age, 56 years [range, 43–68 years] vs 41 years [range, 28–52 years]). Our results reinforce the findings by Benhamou et al and support additional research of TPR therapy in patients with HCV genotype 4 infection [1].

Telaprevir Activity in Treatment-Naive Patients Infected With Hepatitis C Virus Genotype 4

To the Editor—Benhamou et al demonstrated that the tolerability and pharmacokinetics of telaprevir in patients infected with hepatitis C virus (HCV) genotype 4 were similar to those found in HCV genotype 1 patients [1]. In their study, patients infected with HCV genotype 4 were randomly assigned to receive (1) telaprevir monotherapy for 15 days; (2) telaprevir, pegylated interferon alfa-2a, and ribavirin (TPR) for 15 days; or (3) placebo, pegylated interferon alfa-2a, and ribavirin (PR) for 15 days. After the initial 15-day treatment period, study drugs in each group were replaced with standard PR treatment, which was administered for an additional 46–48 weeks. Findings from the study by Benhamou et al supported the investigation of TPR for 12 weeks, followed by PR for an additional 36 weeks, in HCV genotype 4–infected patients. With institutional review board approval, we performed a chart review of HCV genotype 4–infected patients who received TPR at Mount Sinai Hospital, New York, between April 2011 and October 2012. The aim was to determine the rate of sustained virologic response at week 24 of follow-up (SVR24), which was defined as undetectable HCV RNA 24 weeks after the end of treatment. Patients who were chronically infected with HCV genotype 4 and received at least 1 dose of telaprevir were included. The demographic characteristics of our patients are described in Table ​Table1.1. Patients received the TPR regimen approved for treatment of HCV genotype 1 infection (ie, TPR for 12 weeks then PR for an additional 12 weeks [response-guided therapy] or 36 weeks), with the following exceptions [2]. Patient 1 began TPR treatment, and after 2 weeks it was discovered that he was given 200 mg ribavirin twice daily instead of 600 mg twice daily. Telaprevir therapy was mistakenly discontinued after 8 weeks, and PR treatment was discontinued because of virologic breakthrough (ie, HCV RNA was detected after the HCV RNA level had fallen below the limit of detection during treatment) that occurred after 41 weeks of treatment. Patient 3 initiated TPR therapy, decided to stop treatment 40 weeks after initiation, and achieved a SVR24. Patient 5 initiated TPR therapy and, after 11 weeks, discontinued telaprevir treatment because of adverse events. Patient 6 received nitazoxanide and PR treatment, and his HCV RNA load 4 weeks later had decreased to 5414 IU/mL. He discontinued nitazoxanide therapy at this time because of adverse events. A 12-week course of telaprevir treatment was added to the existing regimen after 22 weeks. By week 31 of treatment, the HCV RNA level in patient 6 had fallen below the limit of quantification, but HCV RNA was detectable 6 weeks after the end of treatment. Patient 7 initiated TPR treatment, but it was discontinued after 2 weeks because of adverse events (hepatic encephalopathy, ascites, thrombocytopenia, and neutropenia). Decompensation continued, and the patient was discharged to hospice 13 weeks after the end of treatment, where he died. Table 1. Demographic Characteristics, Baseline Characteristics, and Treatment Outcomes Among Patients Infected With Hepatitis C Virus (HCV) Genotype 4 Our patients experienced adverse events similar to those experienced by patients observed by Benhamou et al [1]. The most common adverse events experienced by our patients included but were not limited to influenza-like symptoms, rash, fatigue/weakness/shortness of breath, anemia, low neutrophil count, low platelet count, low white blood cell count, anorectal conditions, nausea/vomiting/diarrhea, abdominal/stomach pain, pruritus, and constipation. Two patients experienced liver decompensation (hepatic encephalopathy in patient 5 and hepatic encephalopathy, ascites, thrombocytopenia requiring platelet transfusion, and neutropenia in patient 7). One patient required epoetin alfa therapy, and 2 required epoetin alfa therapy and a blood transfusion. Less common adverse events included but were not limited to difficulty controlling diabetes until telaprevir therapy was discontinued, conjunctivitis, hypothyroidism, vision changes, and depression and moodiness. Overall, 4 patients had visits to the emergency department. Reasons for emergency care included but were not limited to hepatic encephalopathy (International Classification of Diseases, Ninth Revision–Clinical Modification code 572.2), urinary tract infection (599.0), anemia (285.9), abdominal pain (789.0), headache (784.0), back pain (724), and severe interferon reaction (995.29). Patient 1 developed hepatocellular carcinoma within a year after treatment ended, and patient 7 had a history of hepatocellular carcinoma. We observed a SVR24 in 50% of patients. All of the patients who did not obtain a SVR24 were cirrhotic and did not follow the TPR treatment protocol approved for HCV genotype 1 infection. At the time of writing, for 1 patient, 24 weeks had not passed since the end of treatment. The SVR24 rate obtained in our study reflects the same SVR24 rate that Benhamou et al found in patients treated with TPR for 15 days and then PR for 46 weeks. It is important to note that our patients differed from those in the study by Benhamou et al, as we included a patient coinfected with human immunodeficiency virus, patients with cirrhosis, and patients who were older (median age, 56 years [range, 43–68 years] vs 41 years [range, 28–52 years]). Our results reinforce the findings by Benhamou et al and support additional research of TPR therapy in patients with HCV genotype 4 infection [1].