Radhika Kumari

Sofosbuvir and simeprevir combination therapy in the setting of liver transplantation and hemodialysis

We report safety, tolerability, and 12‐week sustained virologic response with half‐standard dose sofosbuvir and standard‐dose simeprevir combination therapy in a hepatitis C virus genotype 1a‐infected liver transplant recipient on hemodialysis – uncharted territory for sofosbuvir‐based therapy. The patient was a non‐responder to prior treatment with pegylated interferon plus ribavirin. Sofosbuvir efficacy was maintained despite pill‐splitting and administration of half‐standard dose, 200 mg per day. No drug–drug interactions were noted with tacrolimus‐based immunosuppression. Laboratory tests remained stable or improved during therapy. Our observation, if reproduced in a larger study, may lead to significant improvement in clinical outcomes and cost savings in this patient population.

Real-world experience with interferon-free, direct acting antiviral therapies in Asian Americans with chronic hepatitis C and advanced liver disease.

Abstract Real-life data on interferon (IFN)-free direct acting antiviral (DAA) therapies for chronic hepatitis C (CHC) is limited for Asian Americans. To evaluate sustained virologic response (SVR) and adverse events (AE) in Asian Americans treated with sofosbuvir (SOF)-based, IFN-free DAA therapies. This is a retrospective study of 110 consecutive Asian Americans with HCV genotypes 1 to 3 or 6 treated with IFN-free SOF-based regimens for 8 to 24 weeks between February 2014 and March 2016 at a university center in Northern California. Mean age was 63 ± 12 years, mean BMI was 25 ± 6 (kg/m2), and about half (52%) were male. Most patients were infected with HCV genotype 1 (HCV-1, 64%), followed by HCV-2 (14%), HCV-6 (13%), and HCV-3 (8%). Half had cirrhosis, and the majority of these (67%) had decompensation. Overall SVR12 was 93% (102/110), and highest among patients without cirrhosis, liver transplant, or HCC (100%, 37/37). SVR12 was lower among patients with HCC (82%, 14/17), decompensated cirrhosis (84%, 31/37), or liver transplant (89%, 17/19), regardless of treatment and genotype. Most common AEs were anemia (25%), fatigue (20%), and headache (12%). Anemia was highest in patients receiving SOF/RBV (67%). There was 1 treatment-unrelated serious adverse effect (SAE). There were 7 dose reductions due to anemia or fatigue from RBV and 2 treatment discontinuations due to fatigue or loss of insurance authorization. This real-life cohort of Asian American CHC patients treated with IFN-free SOF-based therapies showed high overall treatment response and good tolerability, despite very high rates of advanced disease and prior treatment failure.

Effectiveness and tolerability of simeprevir and sofosbuvir in nontransplant and post-liver transplant patients with hepatitis C genotype 1.

Hepatitis C virus genotype 1a (HCV‐1a), prior treatment, cirrhosis and post‐transplant status are historically associated with poor treatment responses. The new oral direct‐acting agents appear to be effective and safe in these patients.

Fixed-dose combination of sofosbuvir and ledipasvir for the treatment of chronic hepatitis C genotype 1.

Introduction: The recent October 2014 approval of the fixed dose combination (FDC) of the NS5B polymerase inhibitor sofosbuvir (SOF) and the NS5A inhibitor ledipasvir (LDV) for the treatment of treatment-naive and -experienced HCV genotype 1a/1b (HCV-1) has marked a new era of IFN and ribavirin free treatment for chronic hepatitis C. SOF/LDV combination is approved for 12 weeks in treatment-naive patients with and without cirrhosis. For treatment-experienced patients, it is approved for 12 weeks in patients without cirrhosis but for 24 weeks in patients with cirrhosis. A shorter 8-week course of treatment can be considered for treatment-naive patients who have pretreatment HCV RNA of < 6 million IU/ml and do not have cirrhosis. Areas covered: The purpose of this synopsis is to review the pharmacotherapy and results of pivotal clinical trials for SOF/LDV as the current standard-of-care for HCV-1 patients. We also briefly discuss emerging data with SOF/LDV for certain special populations. Preliminary data is also emerging for HCV genotypes non-1, but their discussion is beyond the scope of this synopsis. The review was done based on data from Phase I, II and III published studies as well as data presented at major national and international meetings. Expert opinion: The FDC of LDV (90 mg) and SOF (400 mg) has a sustained virologic response of approximately 96% when given as a once-a-day pill for 3 months to both treatment-naive and -experienced HCV-1 patients with the exception of prior null responders with cirrhosis. The latter group of patients also achieves high sustained virologic response of 95% but with therapy for 24 weeks. In addition, emerging data suggest that this FDC regimen may be effective in the treatment of HCV-1 co-infected patients with HIV, HCV-1 and -4, patients with cirrhosis and hepatic decompensation and those with post-liver transplant HCV recurrence.

Advances in cirrhosis: Optimizing the management of hepatic encephalopathy.

Hepatic encephalopathy (HE) is a major complication of cirrhosis resulting in significant socioeconomic burden, morbidity, and mortality. HE can be further subdivided into covert HE (CHE) and overt HE (OHE). CHE is a subclinical, less severe manifestation of HE and requires psychometric testing for diagnosis. Due to the time consuming screening process and lack of standardized diagnostic criteria, CHE is frequently underdiagnosed despite its recognized role as a precursor to OHE. Screening for CHE with the availability of the Stroop test has provided a pragmatic method to promptly diagnose CHE. Management of acute OHE involves institution of lactulose, the preferred first-line therapy. In addition, prompt recognition and treatment of precipitating factors is critical as it may result in complete resolution of acute episodes of OHE. Treatment goals include improvement of daily functioning, evaluation for liver transplantation, and prevention of OHE recurrence. For secondary prophylaxis, intolerance to indefinite lactulose therapy may lead to non-adherence and has been identified as a precipitating factor for recurrent OHE. Rifaximin is an effective add-on therapy to lactulose for treatment and prevention of recurrent OHE. Recent studies have demonstrated comparable efficacy of probiotic therapy to lactulose use in both primary prophylaxis and secondary prophylaxis.

Coffee: A Panacea or Snake Oil for the Liver?

United States is the worlds biggest consumer of coffee. About 83% of adults drink coffee in the U.S., according to the National Coffee Associations 2013 survey. There has been much interest in the potential health benefits both in scientific journals and lay media. One such example is a study by Freedman which showed a significant, dose-dependent, inverse relationship between coffee and mortality.(1) The benefits spanned a broad range of health conditions: consumption of coffee was associated with reduced mortality not only from heart disease, stroke and diabetes but also infections, respiratory diseases and even accidents.( 2) Other studies have shown less impressive results, where in a large prospective European study showed no association between caffeinated, decaffeinated coffee and pancreatic cancer.(4) With regard to liver health, coffee has been shown to benefit patients with liver disease due to hepatitis C, non- alcoholic steatohepatitis (NASH) and hepatitis B. For example, in a large cross-sectional US study, subjects who consumed more than two cups of coffee a day were much less likely to have chronic liver disease than those who had less than 1 cup a day (hazard ratio (HR)= 0.43).(3) In another population-based study, serum ALT activities were on average 10% lower in subjects who drank three or more cups of coffee daily (5). Regular consumption of three or more cups of coffee daily reduced progression of liver fibrosis in patients with hepatitis C, alcoholic liver diseases and non-alcoholic fatty liver disease.(6,7) Similarly, patients with liver disease consuming more than 3 cups of coffee had less risk of developing hepatocellular carcinoma (HCC), regardless of the etiology of liver disease.(8) These results have been subjected to a systemic review(9), which affirmed that coffee consumption was associated with reduced progression of fibrosis, decreased incidence of hepatocellular carcinoma in cirrhosis and ultimately, lowered mortality. It remains to be defined whether the type of coffee influences its benefits for the liver. In the study by Freedman, reduced mortality was seen with both caffeinated and decaffeinated coffee.(1) In patients with NASH, regular filtered coffee may be associated with less fibrosis than unfiltered coffee or espresso.(10,11) The filtered coffee has fewer amounts of cafestol and kahweol, compounds associated with increased low-density lipoprotein levels and worsening of steatosis in the liver. (11) The content of anti-angiogenic and anti-oxidant compounds may vary depending upon the preparation methods of the coffee, which might influence the incidence of HCC . (12) The exact protective mechanisms of coffees hepatoprotective effects remain unclear. Out of thousands chemical compounds found in coffee, the chlorogenic acid (belonging to a family of polyphenols which have antioxidant activity), xanthine, and caffeine have been shown to increase the levels of super oxidase dismutase, catalase and glutathione peroxidase. These antioxidant enzymes reduce the levels of oxygen radicals, hydrogen peroxide and peroxide anions which in turn reduces the formation of reactive oxygen species. Recent data suggest that coffee protects against fatty liver disease by stimulating autophagy and increasing mitochondrial beta oxidation, leading to removal of lipids in hepatocytes. (13) Caffeine has also been shown to increase cyclic monophosphate levels in the hepatocytes by inhibiting phosphodiesterase, which leads to inhibition of TGF-alpha-mediated proliferation of connective tissue. (14) Finally, caffeine has direct inhibitory effects on hepatic stellate cells by downregulating FAK and actin synthesis.(15) These effects result in decreased deposition of collagenous matrix and reduced progression of fibrosis. With the backdrop of multitudes of publications indicating favorable impact of coffee in patients with liver disease, the report by Lammert in the current issue of Clinical Gastroenterology and Hepatology investigates the association of coffee consumption with primary biliary cirrhosis and primary sclerosing cholangitis. The study found that in comparison to healthy controls, patients with PSC, but not those with PBC, consumed less coffee. In the multivariable logistic regression analysis, current coffee consumption was associated with PSC with an odds ratio (OR) of 0.68 (p<0.05) in comparison no present or prior consumption. There was no apparent benefits from prior coffee drinking (OR=1.05). Three quarters of PSC patients had concomitant inflammatory bowel disease (IBD). The protective effects of coffee in PSC patients were most pronounced in patients with IBD. For example, among PSC patients with concurrent ulcerative colitis, coffee was associated with less likelihood of proctocolectomy (HR=0.34, p<0.01). In contrast to the abundant data in parenchymal liver disease, there is paucity of studies about the effects of coffee in cholestatic and autoimmune disorders. It may be useful to note that the genetic influence is higher with these disorders than with common liver diseases such as hepatitis C or alcoholic liver disease. For example, in PSC, there is a 9 to 39 fold increased risk in first degree relatives. Besides IBD which obviously increases the risk of PSC, appendectomy and smoking have been shown to have protective effect in PSC . In a Norwegian cohort study, coffee consumption at 18 years of age was associated with a lower risk of development of PSC (HR=? p<0.05). (16) Based on these data, should one conclude that coffee consumption is protective against PSC? For example, are these sufficient data to support encouraging patients with IBD to consume a certain amount coffee in order to prevent PSC? Well, ideally such a recommendation should be derived from data from randomized trial data. In addition, we would submit that the data by Lammert et al are no where conclusive enough to make any changes in our practice. The most important potential flaw of the study is that it did not specifically take into account the impact of IBD on coffee consumption. A quick survey of information on the Internet directed towards patients shows that IBD patients are discouraged from drinking coffee because it may irritate the gastrointestinal tract and worsen the IBD symptoms. Although we did not find firm data to establish negative impact of coffee consumption on mucosal inflammation, bowel symptoms, or outcome of IBD, it is not difficult to postulate that IBD patients may avoid coffee because some may have experienced negative consequences from it themselves while others may try to eliminate non-essential food or beverage items from their diet.(17) Regardless, the point here is that if IBD patients are systematically less likely to consume coffee, PSC will have an apparent negative association with coffee consumtion. Obviously, in such a scenario, the association merely indicates the result of the disease (IBD) not the cause of PSC. This suspicion is compounded by a couple of aspects of the data. The effect of coffee was limited to current consumption and did not appear to be cumulative, which would be expected if it is causally related. The strong association between coffee consumption and proctocolectomy corroborates the postulate that patients with more severe IBD drink less coffee. One lesson to be learned from this study for scholars of epidemiological studies is the importance of selecting the right controls in a case control study. Unlike a cohort study in which individuals with and without the exposure event in question (coffee drinking) are derived from the same population and followed to determine who develops disease (e.g., PSC), a case control study may select patients and controls from completely different populations and thus disparate exposure history. For example, the Lammert study recruited from their specialy referral practice, whereas the controls were taken from individuals seeking preventive medical evaluation at Mayo Clinic. The latter group is likely enriched with individuals who are well-educated, affluent, and health-conscious, and thus have a significantly different life style than patients with PSC, for which Mayo is known as a major referral center. This mismatch may not have introduced a huge bias; however, since data that would be needed to take into account in the analysis were not included or reported in the analysis. Based on the large number of cross-sectional and cohort studies reported to date, there is strong evidence that coffee has hepatoprotective effect in a wide range of chronic liver diseases such as NASH, hepatitis C, cirrhosis, and HCC. However, data to date on cholestatic liver disease are far less certain. It may be that coffee may not be protective of cholangiocytes, the primary locus of damage in PBC and PSC, as it is of hepatocytes. Liver parenchymal damage in those patients may be too removed from the primary events that coffees benefit is reduced. It may be still possible that coffee is beneficial in cholestatic disease; yet, the studies to date may be underpowered or not designed properly to demonstrate the benefits. Regardless, for clinicians, the data are too premature to suggest any changes in our recommendation about coffee consumption in patients with PBC and PSC. For researchers, it will be helpful to understand the mechanisms of the benefits of coffee in hepatocytes versus cholangiocytes, which may lead to randomized trials to evaluate the compounds that drive those benefits.

Optimizing the Nutritional Support of Adult Patients in the Setting of Cirrhosis

Aim: The aim of this work is to develop a pragmatic approach in the assessment and management strategies of patients with cirrhosis in order to optimize the outcomes in this patient population. Method: A systematic review of literature was conducted through 8 July 2017 on the PubMed Database looking for key terms, such as malnutrition, nutrition, assessment, treatment, and cirrhosis. Articles and studies looking at associations between nutrition and cirrhosis were reviewed. Results: An assessment of malnutrition should be conducted in two stages: the first, to identify patients at risk for malnutrition based on the severity of liver disease, and the second, to perform a complete multidisciplinary nutritional evaluation of these patients. Optimal management of malnutrition should focus on meeting recommended daily goals for caloric intake and inclusion of various nutrients in the diet. The nutritional goals should be pursued by encouraging and increasing oral intake or using other measures, such as oral supplementation, enteral nutrition, or parenteral nutrition. Conclusions: Although these strategies to improve nutritional support have been well established, current literature on the topic is limited in scope. Further research should be implemented to test if this enhanced approach is effective.

Increased Prevalence of Metabolic Risk Factors in Asian Americans With Hepatocellular Carcinoma.

Background: We used metabolic risk factors to estimate the prevalence and clinical significance of nonalcoholic fatty liver disease in Asian Americans with hepatocellular carcinoma (HCC). Methods: This is a retrospective cohort study of 824 consecutive Asian HCC patients at Stanford University Medical Center from 1998 to 2015. Patients were subdivided as: Chinese, other East Asian (Japanese and Korean), South East Asian (Vietnamese, Thai, and Laotian), Maritime South East Asian (MSEA: Malaysian, Indonesian, Filipino, and Singaporean), and South West Asian (Indian, Pakistani, and Middle Eastern). Metabolic risk factors studied were body mass index, hypertension, type II diabetes, and hyperlipidemia. Results: Most patients were male (76%) with mean age 63 years. Metabolic risk factors were highly prevalent on presentation and increased over time (P<0.001), as did the prevalence of cryptogenic HCC (P<0.004). Compared with other Asian subgroups, MSEAs had the highest body mass index (26.3) and higher rates of type II diabetes (44% vs. 23% to 35%, P=0.004), hypertension (59% vs. 38% to 55%, P=0.04), and cryptogenic HCC (15% vs. 4% to 10%, P=0.01). They were more likely to be symptomatic on presentation (44% vs. 32% to 58%, P=0.07), less likely to present within Milan criteria (34% vs. 35% to 63%, P<0.0001), and trended toward decreased 10-year survival rates compared with other ethnic subgroups (9% vs. 25% to 32%, P=0.07). Conclusions: Metabolic risk factors were increasingly prevalent among Asian Americans with HCC. MSEAs, who had the highest incidence of these risk factors, had more advanced tumor stage and trended toward worse survival.

Temporal trends in disease presentation and survival of patients with hepatocellular carcinoma: A real-world experience from 1998 to 2015: Long-Term Survival in Patients With HCC

Hepatocellular carcinoma (HCC) is one of the few cancers whose incidence continues to increase. The goal of the current study was to investigate the presentation and survival trends of patients with HCC presenting to a university hospital between 1998 and 2015.

Sofosbuvir Use in the Setting of End-stage Renal Disease: A Single Center Experience

Abstract Background and Aims: Patients with chronic hepatitis C (CHC) and end-stage renal disease (ESRD) who are dialysis-dependent form a unique group, in which safety, tolerability and efficacy of sofosbuvir (SOF)-based direct-acting antivirals (DAAs) need further evaluation. Methods: We performed a retrospective analysis of 14 patients with CHC and ESRD on dialysis who received 15 courses of SOF-based therapy. We evaluated dose escalation to standard-dose SOF in this proof-of-principle experience. Results: Sustained virological response (defined as undetectable viral load at 12 weeks, SVR-12) was achieved in 13 out of the 15 (86.7%) treatment courses. Seven (46.6%) patients received reduced half dose as conservative proof-of-principal to mitigate potential toxicity. In 13 out of 15 treatment courses, patients completed the designated treatment duration. One patient was treated twice and developed SVR-12 with the retreatment. One patient was lost to follow-up and counted as a non-responder. Premature discontinuations were not due to DAA-related adverse effects. There were no reports of severe adverse effects or drug interactions. Conclusion: We treated CHC patients with ESRD using dose escalation to standard-dose SOF in this proof-of-principle experience and achieved SVR rates comparable to general population.