Richard Manch

Hepatitis C virus as a systemic disease: reaching beyond the liver

Chronic hepatitis C (CHC) is associated with multiple extrahepatic manifestations that may impact infected patients. The mechanisms through which these develop include those which are immunological, in which the chronic persistence of virus leads to the circulation of immune complexes (mixed cryoglobulinemia) and other autoimmune phenomena, and those which are virological and related to the extrahepatic tropism of the virus to other tissues. It is estimated that 40–74xa0% of patients with CHC may develop at least one extrahepatic manifestation during the course of the disease. Extrahepatic syndromes may represent the first signal of hepatitis C infection in some patients. CHC is associated with a four-fold increased risk of insulin resistance and type 2 diabetes mellitus; with cardiovascular disease in 17–37xa0% of patients; and with increased risk for cerebrovascular deaths, with a biological gradient of cerebrovascular mortality correlating with an increasing serum viral load. CHC is also associated with lymphoproliferative disorders, particularly non-Hodgkin B-cell lymphoma. The kidney is involved in 35–60xa0% of patients with CHC-associated mixed cryoglobulinemia. The prevalent type of glomerulonephritis associated with mixed cryoglobulinemia is membranoproliferative glomerulonephritis. In 30xa0% of cases, renal involvement begins with a nephritis syndrome and acute renal failure, while in 55xa0% there is only mild hematuria, microalbuminuria, proteinuria and renal insufficiency. CHC is also associated with cognitive impairment, especially in memory and concentration. Thus, extrahepatic CHC manifestations involve multiple organ systems outside the liver linked to a variety of comorbidities which may lead to significantly increased mortality from non-liver-related events.

Alcoholic Liver Disease : High Risk or Low Risk for Developing Hepatocellular Carcinoma?

In this review we critically assess the literature to evaluate the level of risk posed by alcohol as both a primary etiology of hepatocellular carcinoma (HCC) and as a cofactor in its development. Although there have been conflicting findings, based on the body of evidence to date, it appears that the linkage between compensated alcoholic liver disease-associated cirrhosis and HCC is best characterized as medium-high risk, with the risk increasing with age and with quantity and duration of alcohol consumption and is more pronounced in females. While abstinence is the most effective way to reduce HCC risk, its effect seems largely dependent on the severity of liver damage at the point of cessation. Alcohol clearly interacts with other etiologies and conditions including viral hepatitis B and C, hereditary hemochromatosis, diabetes, and obesity to increase the risk for developing HCC, either synergistically or additively. Continued progress in genetics, especially through mechanistic-based and genome-wide association studies may ultimately identify which single nucleotide polymorphisms are risk factors for the onset of alcoholic liver disease and its progression to HCC and lead to the development of targeted therapeutics which may help providers better manage at-risk patients.

Direct-acting antivirals for the treatment of chronic hepatitis C in patients with chronic kidney disease.

All-oral, direct-acting antivirals (DAAs) have significantly improved the efficacy and safety of chronic hepatitis C (CHC) treatment but their effectiveness and safety among patients with chronic kidney disease (CKD) remains poorly understood. Our aim was to assess the efficacy and safety of DAAs for treatment of CKD patients. The National Library of Medicine through PubMed was searched for studies evaluating the efficacy of DAAs for the treatment of patients with CKD stages 4 or 5, as defined by the Kidney Disease Outcomes Quality Initiative guidelines [i.e. glomerular filtration rate (GFR) 15–29 ml/min per 1.73 m2 and GFR <15 ml/min per 1.73 m2, respectively, or hemodialysis or peritoneal dialysis]. Randomized clinical trials (RCTs) and relevant cohort studies were included if they were published in English and included sustained viral response after 12 weeks (SVR12) as a primary or secondary endpoint. After applying inclusion and exclusion criteria, eight studies (one RCT and seven cohort studies) following 350 patients were selected. For patients with CKD stage 4 or 5, ± hemodialysis, the overwhelming majority of DAA regimens were well-tolerated and resulted in SVR12 rates of 90–100%. Most studies were small, with the exception of one RCT evaluating elbasvir and grazoprevir. Overall, treatment of CHC in patients with CKD is highly effective with SVR12 rates similar to those seen in patients without CKD and with acceptable adverse event profiles. In patients with hepatitis C virus (HCV) genotype (GT) 1a, 1b or 4 and Stage 4 or 5 CKD, the best evidence available is for the use of elbasvir and grazoprevir. This combination as well as the combination of paritaprevir/ritonavir/ombitasvir/dasabuvir for HCV GT-1b are recommended. More studies are needed to assess efficacy and adverse effects of DAAs and their impact on CKD patients and to fully elucidate the effect of curing CHC on the natural history and sequelae of renal disease in CHC patients with CKD.

Is response guided therapy dead? Low cure rates in patients with detectable hepatitis C virus at week 4 of treatment

BackgroundHistorically, chronic hepatitis C virus (HCV) treatment was response-guided. Clinical trials with sofosbuvir indicated on-treatment virologic response was not predictive of sustained virologic response (SVR) and hence response-guided therapy (RGT) was abandoned. The purpose of this study is to examine the association between on-treatment 4-week HCV RNA and SVR in patients treated in real-world practice.MethodsThe study is a retrospective analysis of consecutive patients started on treatment with a sofosbuvir-containing regimen, January 1, 2014 through August 20, 2014, for HCV genotype 1–6 infection. Patients were treated by HCV specialists at 6 centers in the Project ECHO (Extension for Community Healthcare Outcomes) HCV Collaborative or in the community by primary care clinicians mentored by HCV specialists through Project ECHO. Patients were included if they were over 18xa0years, had evidence of chronic HCV, and were started on a sofosbuvir-containing regimen. The aspartate aminotransferase:platelet ratio index (APRI) was used to estimate fibrosis. The main outcome measures were 4-week HCV RNA and SVR.ResultsOverall SVR was 82.5xa0%. At week 4, HCV RNA was detected in 27.4xa0% of patients. Stepwise multivariable logistic-regression analyses identified APRIxa0>xa01.0, male sex, genotype 3, and detectable on treatment 4-week HCV RNA as independent predictors of failure to achieve SVR.ConclusionsIn a real-world setting, a significant proportion of sofosbuvir treated patients have detectable on-treatment 4-week HCV RNA. Detectable on-treatment 4-week HCV RNA is associated with virologic failure. More data are needed to formulate guidance for RGT with newly available HCV therapies.

Defining the possibilities: is short duration treatment of chronic hepatitis C genotype 1 with sofosbuvir-containing regimens likely to be as effective as current regimens?

This review summarizes published data on sofosbuvir-based regimens for patients infected with HCV GT1 with a focus on evaluating the optimal and possible durations of treatment. Methods: PubMed and conference abstract books published between 2011–2015 were searched. Results: HCV treatment has decreased from 24 week regimens to studies done as short as 4 weeks. History of prior treatment or cirrhosis have consistently shown lower SVR12 rates with shorter duration therapies. Low cure rates have been seen in patients within 4 week trials, however, select patients with low fibrosis scores, low HCV VL and HCV GT-1b have moderate cure rates. Conclusion: Most patients will require 12–24 weeks of therapy. Further studies are needed to elucidate the predictors of treatment response to short duration therapies and optimal combination of DAAs.

Real-World Effectiveness of Simeprevir-containing Regimens Among Patients With Chronic Hepatitis C Virus: The SONET Study

Abstract Background The Simeprevir ObservatioNal Effectiveness across practice seTtings (SONET) study evaluated the real-world effectiveness of simeprevir-based treatment for hepatitis C virus (HCV) infection. Methods The SONET study was a phase 4, prospective, observational, United States–based study enrolling patients ≥18 years of age with chronic genotype 1 HCV infection. The primary endpoint was the proportion of patients who achieved sustained virologic response 12 weeks after the end of treatment (SVR12), defined as HCV ribonucleic acid undetectable ≥12 weeks after the end of all HCV treatments. Results Of 315 patients (intent-to-treat [ITT] population), 275 (87.3%) completed the study. Overall, 291 were treated with simeprevir + sofosbuvir, 17 with simeprevir + sofosbuvir + ribavirin, and 7 with simeprevir + peginterferon + ribavirin. The majority of patients were male (63.2%) and white (60.6%); median age was 58 years, 71.7% had genotype/subtype 1a, and 39.4% had cirrhosis. The SVR12 was achieved by 81.2% (255 of 314) of ITT patients (analysis excluded 1 patient who completed the study but was missing SVR12 data); 2 had viral breakthrough and 18 had viral relapse. The SVR12 was achieved by 92.4% (255 of 276) of patients in the modified ITT (mITT) population, which excluded patients who discontinued treatment for nonvirologic reasons before the SVR12 time point or were missing SVR12 assessment data. Among mITT patients, higher SVR12 rates were associated with factors including age ≥65 years, non-Hispanic/Latino ethnicity, and employment status, but not genotype/subtype nor presence of cirrhosis. Simeprevir-based treatment was well tolerated; no serious adverse events were considered related to simeprevir. Conclusions In the real-world setting, simeprevir + sofosbuvir treatment was common and 92% of mITT patients achieved SVR12. Simeprevir-based treatment was effective and well tolerated in this cohort, including patients with cirrhosis.

Effectiveness of Simeprevir-Containing Regimens among Patients with Chronic Hepatitis C Virus in Various Us Practice Settings: The Sonet Study

EFFECTIVENESS OF SIMEPREVIR-CONTAINING REGIMENS AMONG PATIENTS WITH CHRONIC HEPATITIS C VIRUS IN VARIOUS US PRACTICE SETTINGS: THE SONET STUDY I. Alam, K. Brown, C. Donovan, J. Forlenza, K. Lauwers, M.A. Mah’moud, R. Manch, S.R. Mohanty, A. Prabhakar, R. Reindollar, G. Sawyerr, J. Slim, N. Tandon, S. Villadiego, S. Naggie. Austin Hepatitis Center, Austin, TX; Janssen Scientific Affairs, Titusville, NJ, United States; Janssen Research & Development, Beerse, Belgium; Duke University School of Medicine/Boice-Willis Clinic, Rocky Mount, NC; St. Joseph’s Hospital & Medical Center, Phoenix, AZ; New York Methodist Hospital, Brooklyn, NY; Piedmont Healthcare, Gastroenterology and Hepatology, Statesville, NC; Saint Michael’s Medical Center, Newark, NJ; DurhamVAMedical Center/Duke University School of Medicine, Durham, NC, United States E-mail: dralam@austin.rr.com

S1919 Coated Tips Does Not Improve Thrombocytopenia in Cirrhotic Patients (Preliminary Results From a Retrospective Analysis of Platelet Counts in Cirrhotic Patients After Tips Placement)

patients followed in an academic liver clinic. RESULTS. The study assessed 1,022 patients with a mean 20.0 (3-60) months of follow-up. The mean age was 45.6 (17-86) years; 29.8% (n=304) were elderly (age ≥ 60 years); 54.0% were males; 35.4% were Asians and 41.3%, Caucasians; 44.9% had chronic hepatitis C (CHC) and 19.0%, chronic hepatitis B (CHB). CHC was more common (77.8% vs. 67.4%), but CHB was less common (22.2% vs. 32.6%) in the elderly group than in the younger group, and the frequency of alcoholic liver diseases (ALD) was comparable in both groups (3.3 vs. 3.3%). Elderly patients had significantly higher incidence of history of hypertension (HTN, 50.0% vs. 23.5%), diabetes mellitus (DM, 28.5% vs. 13.6%), but lower incidence of obesity (22.4% vs. 29.0%). They also carried a significantly higher rate of cirrhosis (i.e., stage 3-4 fibrosis) and/or HD (i.e., presence of ascites and/or hepatic encephalopathy, 62.8% vs. 48.5%), and hepatocellular carcinoma (HCC, 8.3% vs. 1.9%). Laboratorially, elderly patients had significantly higher incidence of thrombocytopenia (28.8% vs. 16.4%), hypoalbuminemia (28.2% vs. 17.0%), and AST/ALT ratio ≥ 1 (57.2% vs. 38.3%). Multivariate analyses indicated that the significantly higher frequency of cirrhosis and/or HD in the elderly group was independently associated with age (p=0.003, OR=1.86) and obesity (p=0.0001, OR=2.11). CONCLUSIONS. In this large cohort of patients, elderly patients carried a higher frequency of CHC, history of DM, HTN, cirrhosis and/or HD, and HCC. Cirrhosis was independently associated with age and obesity.