James S. Park

Susceptibility to hepatitis A in patients with chronic liver disease due to hepatitis C virus infection: Missed opportunities for vaccination

Hepatitis A virus (HAV) superinfection is associated with a high risk of liver failure and death in patients with underlying chronic liver disease. Although HAV vaccination is recommended for all patients with chronic hepatitis C virus (HCV) infection, little is known about adherence to these recommendations in clinical practice. The aims of this study were to determine the frequency of HAV testing and vaccination among patients with chronic HCV infection. We conducted a retrospective cohort study of 1,193 patients diagnosed with chronic HCV infection over a 1‐year period. During 1,646 person‐years of follow‐up, patients were seen by their primary care provider a median of 10.0 times (interquartile range, 4.0‐20.0). HAV antibody testing was performed in 640 subjects (53.6%), and 317 (49.5%) of those tested were susceptible (HAV antibody negative). Only 94 of the 1,193 patients (7.9%) received the HAV vaccine, including 26.8% of the 317 susceptible patients, 0.9% of the 323 patients who were already immune to HAV, and 1.1% of the 553 subjects who were never tested. Among the 94 vaccinated patients, 45 received only one dose of the vaccine. Three of the unvaccinated patients developed acute HAV infection during follow‐up, and 1 of them died of acute liver failure. In conclusion, despite published recommendations to vaccinate against HAV in patients with chronic HCV infection, we found that HAV testing and vaccination rates were low in clinical practice. Public health programs to increase awareness about HAV vaccination in patients with chronic liver disease are needed. (HEPATOLOGY 2005.)

Colon Pathology Detected After a Positive Screening Flexible Sigmoidoscopy: A Prospective Study in an Ethnically Diverse Cohort

OBJECTIVES:Although the association between distal neoplasia on sigmoidoscopy and proximal colonic pathology on follow-up colonoscopy has been well-described, it is not known if these findings are consistent across ethnic groups. The aim of this study was to evaluate ethnic variations in the prevalence of proximal neoplasia on follow-up colonoscopy after a neoplastic lesion is found on sigmoidoscopy.METHODS:Consecutive asymptomatic patients at average-risk for colorectal cancer who were referred for screening flexible sigmoidoscopy were prospectively enrolled. Colonoscopy was recommended for all patients with a polyp on flexible sigmoidoscopy, regardless of size. Advanced neoplasms were defined as adenomas ≥10 mm in diameter or any adenoma, regardless of size, with villous histology, high-grade dysplasia, or cancer.RESULTS:Among the 2,207 patients who had sigmoidoscopy, 970 were Caucasian, 765 were African American, 395 were Hispanic, and 77 were Asian. The prevalence of neoplasia in the distal colon was 12.6% in Caucasians, 11.2% in African Americans, 15.9% in Hispanics, and 24.7% in Asians (p= 0.002). Of the 290 patients with neoplastic lesions on sigmoidoscopy, follow-up colonoscopy identified neoplasms in the proximal colon in 63.9% of Caucasians, 59.3% of African Americans, 66.7% of Hispanics, and 26.3% of Asians (p= 0.01). Advanced neoplasms in the proximal colon were highest in African Americans (34.9%) and lowest in Asians (10.5%).CONCLUSIONS:In our study population, Asians demonstrated a higher prevalence of distal colonic neoplasia and a lower prevalence of proximal colonic neoplasia compared to non-Asians. Future studies should explore ethnic variation in colonic neoplasia prevalence and location since ethnic variation could lead to tailored colorectal cancer screening strategies.

Acute Pancreatitis Associated with Interferon and Ribavirin Therapy in Patients with Chronic Hepatitis C

Acute pancreatitis is a rare complication of interferon (IFN) and ribavirin (RBV) therapy. The aimof this study was to determine the incidence, clinical presentation, and outcome of acute pancreatitisin patients with chronic hepatitis C virus (HCV) infection treated with IFN and RBV combinationtherapy. We conducted a retrospective review of 1706 HCV-infected patients treated with IFN α-2band RBV. The diagnosis of drug-induced acute pancreatitis was made based on the presence ofepigastric pain, elevated amylase and lipase levels, and the absence of other identifiable causes ofpancreatitis. Acute pancreatitis was diagnosed in 7 of 1706 HCV-infected patients (0.4%; 95% CI,0.2 to 0.8%) who were treated with IFN α-2b and RBV. The mean age of the patients (four malesand three females) was 51.4 ± 4.7 years and the median duration of therapy prior to developmentof pancreatitis was 12.0 weeks (range, 4.0-21.0 weeks). All patients presented with epigastric painassociated with nausea, vomiting, and/or fever. The median amylase and lipase values at the timeof diagnosis of pancreatitis were 330.0 U/L (range, 182.0-1813.0 U/L) and 500.0 U/L (range,171.0-2778.0 U/L), respectively. IFN and RBV were discontinued in all patients at the time ofdiagnosis and six of the seven patients were hospitalized; one patient refused hospital admission.Pancreatitis resolved in all seven patients and none of these individuals had recurrent pancreatitisduring a median follow-up of 18.0 months (range, 3.0-27.0 months). In conclusion, IFN and RBVcombination therapy is a potential cause of drug-induced pancreatitis in patients with chronic HCV.In these individuals, pancreatitis is often severe enough to warrant hospital admission, althoughsymptoms resolve promptly after discontinuation of antiviral therapy.

Fatal hepatitis B reactivation due to everolimus in metastatic breast cancer: case report and review of literature

Hepatitis B reactivation can occur with cytotoxic chemotherapy in patients with hepatitis B and cancer. Reactivation can occur in a patient with chronic hepatitis, an inactive carrier, or one with resolved hepatitis. Clinical presentation may range from subclinical elevation of liver enzymes to fatal fulminant hepatic failure. Mammalian target of rapamycin inhibitors, which include everolimus, are a new generation of targeted agents that are currently approved for many cancers (since March 2009) including advanced hormone receptor positive, human epidermal growth factor receptor 2-negative breast cancer, in conjunction with exemestane (as of July 2012). We are therefore still learning the various adverse events that occur with this new class of agents. Here, we present an unfortunate case of fatal hepatitis B reactivation in a woman with metastatic breast cancer treated with everolimus and exemestane. We have detailed the controversies around hepatitis B screening prior to immunosuppressive therapy. Clinicians and patients should be aware of this rare but fatal complication prior to everolimus use, and a detailed history, screening for hepatitis B and prophylactic antiviral treatment should be considered.

Galactosylated Liposomes for Targeted Co-Delivery of Doxorubicin/Vimentin siRNA to Hepatocellular Carcinoma

The combination of therapeutic nucleic acids and chemotherapeutic drugs has shown great promise for cancer therapy. In this study, asialoglycoprotein receptors (ASGPR) targeting-ligand-based liposomes were tested to determine whether they can co-deliver vimentin siRNA and doxorubicin to hepatocellular carcinoma (HCC) selectively. To achieve this goal, we developed an ASGPR receptor targeted co-delivery system called gal-doxorubicin/vimentin siRNA liposome (Gal-DOX/siRNA-L). The Gal-DOX/siRNA-L was created via electrostatic interaction of galactose linked-cationic liposomal doxorubicin (Gal-DOX-L) on vimentin siRNA. Previous studies have shown that Gal-DOX/siRNA-L inhibited tumor growth by combined effect of DOX and vimentin siRNA than single delivery of either DOX or vimentin siRNA. These Gal-DOX/siRNA-Ls showed stronger affinity to human hepatocellular carcinoma cells (Huh7) than other cells (lung epithelial carcinoma, A549). These liposomes also have demonstrated that novel hepatic drug/gene delivery systems composed of cationic lipid (DMKE: O,O’-dimyristyl-N-lysyl glutamate), cholesterol, galactosylated ceramide, POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), and PEG2000-DSPE (distearoyl phosphatidyl ethanolamine) at 2:1:1:1:0.2 (moral ratios) can be used as an effective drug/gene carrier specifically targeting the liver in vivo. These results suggest that Gal-DOX-siRNA-L could effectively target tumor cells, enhance transfection efficacy and subsequently achieve the co-delivery of DOX and siRNA, demonstrating great potential for synergistic anti-tumor therapy.

Lower Observed Hepatocellular Carcinoma Incidence in Chronic Hepatitis B Patients Treated With Entecavir: Results of the ENUMERATE Study.

OBJECTIVES:Data from the United States are lacking regarding the impact of entecavir (ETV) on the risk of hepatocellular carcinoma (HCC). Our aim is to determine whether treatment with ETV is associated with a reduced HCC risk by calculating the expected HCC incidence based on the Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B (REACH-B) model and comparing it with the observed HCC incidence.METHODS:The incidence of HCC in US patients treated with ETV between 2005 and 2013 in a retrospective cohort was obtained. The predicted HCC incidence was calculated using the REACH-B model. The standardized incidence ratios (SIRs) were calculated as a ratio of observed over predicted HCC cases.RESULTS:Of 841 patients, 646 (65% male, 84% Asian, median age 47 years, 36% hepatitis B e antigen positive, 9.4% with cirrhosis) met the inclusion criteria. Over a median follow-up of 4 years, 17 (2.6%) cases of HCC were diagnosed, including 8 out of 61 (13.1%) patients with cirrhosis and 9 out of 585 (1.5%) without cirrhosis. Compared with those without HCC, the 17 patients with HCC were older at 53 years vs. 47 years and more likely to have cirrhosis at 47.1% vs. 8.4%. Among patients without cirrhosis, the observed HCC incidence was significantly lower than predicted by the fourth year (SIR, 0.37; 95% confidence interval: 0.166–0.82). A sensitivity analysis that comprised all patients, including those with cirrhosis, showed that at the maximum follow-up time of 8.2 years, a significantly lower than predicted HCC incidence was noted with an SIR of 0.56 (95% confidence interval: 0.35–0.905).CONCLUSIONS:Based on the REACH-B model, long-term ETV therapy was associated with a lower than predicted HCC incidence. However, the risk of HCC persisted, and careful HCC surveillance remains warranted despite the anti-viral treatment.

Current recommendations of managing HBV infection in preconception or pregnancy

Hepatitis B remains a leading cause of cirrhosis, hepatocellular carcinoma and liver transplantation worldwide. Management of chronic hepatitis B during pregnancy is challenging. Transmission of hepatitis B to infants still occurs perinatally although immunoprophylaxis is widely available for infants born to mothers with chronic hepatitis B infection. The emerging data suggest that initiation of antiviral therapy in the beginning of the third trimester in highly viremic mothers can prevent immunoprophylaxis failure in their infants. The available drug safety data show that lamivudine, telbivudine and tenofovir are generally safe to be used during the pregnancy. In order to minimize the fetal exposure to the antiviral medication, antiviral therapy during the pregnancy should be limited to a selected group of patients with cirrhosis, high hepatitis B viral load, or prior history immunoprophylaxis failure. An elective Caesarean section may reduce the risk of perinatal transmission. For those females planning for pregnancy or in early stage of pregnancy, communication and follow-up among obstetrician, gastroenterologist, and primary care physician are important. In this article, we will review the features of hepatitis B infection before, during and after the pregnancy; the risk factors that increase mother-tochild transmission; safety data on antiviral drug use during pregnancy; and the potential role of Caesarean section in selected cases.

Challenges and perspectives of direct antivirals for the treatment of hepatitis C virus infection

Treatment of chronic hepatitis C virus infection has been revolutionised by the development of direct-acting antivirals (DAAs). All-oral, once-daily, 8- to 12-week treatment regimens are now standard of care, with viral eradication possible in >95% of patients across different populations. Despite these advances, several unresolved issues remain, including treatment of patients with hepatitis C virus genotype 3, chronic kidney disease, and those in whom DAA therapy has previously failed. Glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir are the most recently approved DAA regimens. Given the overwhelming success of modern DAA-based therapies, glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir are also likely to represent the last DAAs to be approved. Both are pangenotypic, once-daily, all-oral DAA combinations that have the potential to close the gaps in the current DAA treatment portfolio. Herein, we review the challenges associated with current DAAs and how these two regimens may be implemented in existing treatment algorithms.

Safety and Effectiveness of Ledipasvir and Sofosbuvir, With or Without Ribavirin, in Treatment-Experienced Patients with Genotype 1 Hepatitis C Virus Infection and Cirrhosis

BACKGROUND & AIMS: We aimed to evaluate the safety and effectiveness of 12 or 24 weeks treatment with ledipasvir and sofosbuvir, with or without ribavirin, in treatment‐experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis in routine clinical practice. Patients were followed in a multi‐center, prospective, observational cohort study (HCV‐TARGET). METHODS: We collected data from 667 treatment‐experienced adults with chronic genotype 1 HCV infection who began treatment with ledipasvir and sofosbuvir, with or without ribavirin, from 2011 through September 15, 2016, according to the regional standards of care, at academic (n = 39) and community (n = 18) centers in the United States, Canada, Germany, and Israel. Information was collected from medical records and abstracted into a unique centralized data core. Independent monitors systematically reviewed data entries for completeness and accuracy. Demographic, clinical, adverse event, and virologic data were collected every 12 weeks during treatment and during the follow‐up period. The primary efficacy endpoint was sustained virologic response, defined as a level of HCV RNA below the lower limit of quantification or undetectable at a minimum 64 days after the end of treatment (SVR12). The per‐protocol population (n = 610) was restricted to patients who completed 12 or 24 weeks of treatment (±2 weeks) and had final virologic outcomes available. RESULTS: The per‐protocol analysis revealed that 579 patients (93.8%) achieved an SVR12, including 50/51 patients who received ledipasvir and sofosbuvir for 12 weeks (98%), 384/408 patients who received ledipasvir and sofosbuvir for 24 weeks (94.1%), 68/70 patients who received ledipasvir and sofosbuvir with ribavirin for 12 weeks (97.1%), and 57/60 patients who received ledipasvir and sofosbuvir with ribavirin for 24 weeks (95%). On multivariate analysis, neither treatment duration nor the addition of ribavirin was associated with SVR12. Compensated cirrhosis (odds ratio [OR] compared to decompensated cirrhosis, 2.41; 95% CI, 1.16‐5.02), albumin ≥ 3.5 g/dL (OR, 3.15; 95% CI 1.46–6.80), or total bilirubin ≤ 1.2 mg/dL (OR 3.34; 95% CI, 1.59–7.00) were associated with SVR12. CONCLUSIONS: In an analysis of safety and effectiveness data from the HCV‐TARGET study, we found treatment with ledipasvir and sofosbuvir, with or without ribavirin, to be effective and well tolerated by treatment‐experienced patients with genotype 1 HCV infection and compensated cirrhosis. There were no significant differences in rate of SVR12 among patients treated with ledipasvir and sofosbuvir for 12 or 24 weeks, with or without ribavirin. Patients with decompensated cirrhosis appear to benefit from the addition of ribavirin or extension of ledipasvir and sofosbuvir treatment to 24 weeks. ClinicalTrials.gov no: NCT10474811.

Enhanced Anti-cancer Efficacy in MCF-7 Breast Cancer Cells by Combined Drugs of Metformin and Sodium Salicylate

Metformin or sodium salicylate is known to induce apoptosis and G0/G1 phase arrest in a variety of cancer cells. However, the anti-cancer effects of the combined treatments for these drugs-induced apoptosis are yet unclear. Here, we found that the combined treatment of metformin and sodium salicylate increased the efficacy of chemotherapeutics against breast cancer cells. These combined drugs significantly inhibited cellular proliferation and induced apoptosis at an earlier stage in human MCF-7 breast cancer cells. Also, co-treatments of metformin and sodium salicylate induced G1 cell cycle arrest in MCF-7 cells more effectively than either agent alone. Taken together, these results demonstrate that dual metformin/ sodium salicylate treatment prevents proliferation of MCF-7 cells by inducing apoptosis and G1 cell cycle arrest.