Strategies for assignment of HIV/HCV genotype 1-coinfected patients to either dual-therapy or direct-acting antiviral agent based triple therapy

Antivir Ther. 2013 Dec 17. doi: 10.3851/IMP2717. [Epub ahead of print]

Mandorfer M, Neukam K, Rivero A, Puoti M, Boesecke C, Baumgarten A, Grzeszczuk A, Zangerle R, Ernst D, Rockstroh JK, Trauner M, Pineda JA, Peck-Radosavljevic M, Reiberger T.

Abstract

BACKGROUND: The aim of this study was to evaluate strategies for assignment of HIV/hepatitis C virus genotype 1-coinfected patients (HIV/HCV-GT1) to either dual-therapy or direct-acting antiviral agent (DAA)-based triple-therapy.

METHODS: 148 treatment-naïve HIV/HCV-GT1 who received antiviral therapy with pegylated interferon/ribavirin were included in this multinational, retrospective analysis. Patients with rapid virologic response (RVR) were treated for 48weeks, while patients without RVR received either 48 or 72weeks of treatment. IL28B rs12979860 (IL28B) non-C/C, advanced liver fibrosis and high HCV-RNA were considered as established risk factors for treatment failure.

RESULTS: A trend toward higher SVR rates in patients with IL28B C/C (65%(37/57)vs.51%;(40/79); p=0.097) was observed. Higher SVR rates were observed in patients without advanced liver fibrosis (61%(47/77)vs.42%(22/52); p=0.036) and low HCV-RNA (73%(35/48)vs. 49%(49/100); p=0.006), as well as in patients with RVR (90%(35/39)vs.45%(49/109); p<0.001). SVR rates varied statistically significantly between the risk factors for treatment failure subgroups (0:86%(6/7)vs.1:69%(34/49)vs.2:48%(21/44)vs.3:(4/20); p<0.001). In patients without RVR, higher rates of SVR were observed in those treated for 72weeks (62%(23/37)), when compared to patients treated for 48weeks (36%(26/72); p=0.01).

CONCLUSIONS: RVR had an excellent PPV for the response to dual-therapy in HIV/HCV-GT1, emphasizing the utility of a lead-in phase for assigning these patients to dual-therapy or DAA-based triple-therapy. The use of an IL28B-guided approach was suboptimal, while a combination of established baseline predictors may provide guidance for individual treatment decisions prior to the initiation of antiviral therapy. However, the extension of treatment duration to W72 in HIV/HCV-GT1 without RVR should be strongly considered if triple-therapy is not available.

PMID: 24342953 [PubMed - as supplied by publisher]

Source

Characteristics and Impact of Methamphetamine Use in Patients With Chronic Hepatitis C

J Addict Med. 2013 Dec 13. [Epub ahead of print]

Riley DE, Liu L, Cohen B, Robinson S, Groessl EJ, Ho SB.

Abstract

OBJECTIVES:: Methamphetamine (MA) use has increased in the United States in the last 20 years and is a risk factor for hepatitis C virus(HCV) infection. The purpose of this study was to determine the characteristics and HCV infection outcomes of patients with a history of MA use.

METHODS:: Subjects consisted of newly entered patients in the Veterans Affairs (VA) HCV registry at a single VA medical center from January 1, 2004, to June 30, 2004, and from January 1, 2007, to June 30, 2007. Univariate and multivariate analyses related to HCV infection antiviral treatment outcomes through 2010 was performed.

RESULTS:: A total of 198 consecutive eligible HCV registry patients were analyzed, and 40% had a history of MA use. Of patients with MA use history, 46% (36/79) had active use (within 6 months) at initial contact. Active MA users were significantly younger (mean age, 45.5 years), with more concomitant drug use (86%), compared with patients without MA use (mean age, 53.5 years; 42% minority; 29% other drug use). Overall, 71% of the 198 patients reported a history of problematic alcohol use, and 47% of those reported active abuse. Logistic regression analyses indicated that MA use did not significantly adversely affect antiviral treatment initiation, completion, or sustained virological response rates compared with that in patients without MA use. Active alcohol users had lower treatment initiation than patients without alcohol use.

CONCLUSIONS:: MA use is common in recent US veterans with HCV infection and occurs in younger patients with polysubstance use. Prior history or active MA use does not seem to adversely affect HCV infection clinic treatment compared with that in HCV-infected patients without MA use.

PMID: 24343127 [PubMed - as supplied by publisher]

Source

Hepatitis C Drug War Heats Up

Provided by The Motley Fool

By Brian Orelli | More Articles
December 18, 2013 | Comments (0)

AbbVie (NYSE: ABBV ) may have been first to release phase 3 data for an all-oral hepatitis treatment for genotype 1 patients, but Gilead Sciences (NASDAQ: GILD ) now has the lead for the most phase 3 data. It might even have the best data. Maybe.

The biotech passed AbbVie in the data count, releasing results from three different phase 3 clinical trials today. The trials combined sofosbuvir, which was recently approved as Sovaldi, and a new drug ledipasvir, with and without a generic called ribavirin.

In one trial, dubbed ION-1, 97.7% of patients who had never been treated before were clear of virus 12 weeks after finishing a 12-week course of the two medications; essentially, they were cured. Adding ribavirin didn't help any -- the cure rate was actually slightly lower at 97.2% -- possibly due to patients dropping out because of unwanted side effects of ribavirin.

In AbbVie's first phase 3 trial, 96% of genotype 1 patients were cured with its five-drug cocktail. While lower than Gilead's 97.7%, it's not clear how comparable the number is. AbbVie released the breakdown of genotype 1a, which is harder to treat, and genotype 1b patients with cure rates of 95% and 98%, respectively. If Gilead enrolled a lot of genotype 1b patients, it's 97.7% cure rate could be artificially inflated.

In a second trial, Gilead enrolled patients whohad failed a previous treatment, producing a 93.6% cure rate for the two-drug combination, and a 96.4% cure rate when ribavirin was added for the 12 weeks. That's close to AbbVie's second phase 3 trial where 96% of treatment-experienced patients were cured, although it's even more dangerous to compare those two.

Not only do we still have the issue of the breakdown for genotype 1a/1b, but how the patients responded to the previous treatment -- null responders versus partial responders -- and this should predict how hard they are to treat. AbbVie said about 49% of the patients in the trial were prior null responders, while Gilead didn't release the breakdown. Complicating matters more, Gilead's patients previously failed the best regimen currently available, which includes a protease inhibitor -- either Vertex Pharmaceuticals' (NASDAQ: VRTX ) Incivek orMerck's (NYSE: MRK ) Victrelis -- while AbbVie's trial doesn't mention that the patients had to fail the first-generation oral medications from Vertex or Merck.

Unlike AbbVie, Gilead also tested its drug combo for 24 weeks, which appears to have paid off. A solid 99.1% of treatment-experienced patients were cured regardless of whether ribavirin was added to the treatment. Gilead is also testing the combo for 24 weeks in treatment-naive patients, but the results aren't available yet.

In a third trial, Gilead gambled in the other direction, testing the drug combination for just eight weeks. With cure rates dropping to 93.1% to 94% with and without ribavirin respectively, it doesn't look like the shorter course of treatment will get adopted widely. Of course, we could just be looking at a tough-to-treat population, because the control group that was treated for 12 weeks had a cure rate of 95.4%, lower than the 97.7% seen in the first trial mentioned above.

Based on what we know now, it appears Gilead's combination has better efficacy than AbbVie's, but probably not enough to make that much of a difference in which drug is prescribed. Doctors' choice will likely come down to convenience, pricing, and side effects. With fewer pills required, Gilead appears to have AbbVie beat on convenience, but the latter two are still undecided. What we can say for certain is the all-oral combinations are so much better than Vertex's and Merck's drugs, that their use will disappear during the coming year.

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Source

Non-invasive prediction of hepatocellular carcinoma development using serum fibrosis marker in chronic hepatitis C patients

J Gastroenterol. 2013 Dec 15. [Epub ahead of print]

Tamaki N, Kurosaki M, Matsuda S, Muraoka M, Yasui Y, Suzuki S, Hosokawa T, Ueda K, Tsuchiya K, Nakanishi H, Itakura J, Takahashi Y, Asahina Y, Izumi N.

Abstract

BACKGROUND: The FIB-4 index is a simple formula to predict liver fibrosis. This study aimed to evaluate the utility of the FIB-4 index and associated time-course changes as a predictor of hepatocellular carcinoma (HCC) development.

METHODS: A total of 171 chronic hepatitis C patients who underwent paired liver biopsies and 875 patients who underwent a single liver biopsy (validation group) were investigated during mean follow-up periods of 6.4 and 5.9 years, respectively. All patients had received interferon therapy and had not achieved a sustained virological response. Factors associated with HCC development were analyzed in these patients.

RESULTS: HCC developed in 30 patients in the paired biopsy group and 89 patients in the validation group. Univariate analysis demonstrated that the FIB-4 index >3.25 and change in the FIB-4 index per year (ΔFIB-4/year) ≥0.3 were predictive factors for HCC development in both groups. Multivariate analysis in the combined population revealed that these two factors were independent. The hazard ratio (HR) for the FIB-4 index >3.25 was 2.7 (p < 0.001) and ΔFIB-4/year ≥0.3 was 1.8 (p = 0.003). Patients with a FIB-4 index >3.25 and a ΔFIB-4/year ≥0.3 were defined as high risk, and those with a FIB-4 index ≤3.25 and a ΔFIB-4/year <0.3 were defined as low risk. The HR of HCC development in patients at high risk was 7.3 (95 % confidence interval 4.3-12.5, p < 0.001).

CONCLUSIONS: It was possible to define a group at high risk of developing HCC by intermittently measuring the FIB-4 index and considering time-course changes in this index.

PMID: 24337828 [PubMed - as supplied by publisher]

Source

Raising public awareness of hepatitis B and C through a testing road show

Br J Nurs. 2013 Dec 12;22(22):1308-12.

Perrett S¹, Hams P².

Abstract

Over the past decade, as the profile of hepatitis B and C has been raised, a range of nurse-led services has been developed among substance misuse services, prisons and homeless services to reach those at the highest risk of infection. In the UK, it is estimated that up to two-thirds of people with hepatitis C are unaware of their infection (Cornberg et al, 2011). These patients represent those at the highest risk of developing cirrhosis and liver cancer, and many are unlikely to be in contact with services that offer routine testing. To help address this, the Welsh Hepatitis Nurse Forum (WHNF) carried out two road shows aimed at raising awareness of hepatitis B and C among the general public and offering testing. This paper describes the process, results and evaluation of the road shows that took place in 2011 and 2012. The road show is a unique way in which nurses can reach those who may not have regular contact with health services, and has proved useful for generally raising awareness. Further work is needed to evaluate the cost-effectiveness of the road shows.

PMID: 24335868 [PubMed - in process]

Source

The Impact of Hepatitis C Infection on Ischemic Heart Disease Via Ischemic Electrocardiogram: A Cross-sectional Observational Study

Am J Med Sci. 2013 Dec 12. [Epub ahead of print]

Lin MS, Guo SE, Chen MY, Huang TJ, Huang JC, Hu JH, Lin YS.

Abstract

BACKGROUND:: Hepatitis C virus (HCV) infection is a serious disease worldwide and it leads to several serious hepatic sequels. Some studies find possible correlation between HCV and ischemic heart disease in retrospective observations. Based on lacked community-based evidence, the study aims to assess correlation between ischemic heart disease and chronic HCV infection via electrocardiogram (ECG) because its abnormalities is strongly associating with cardiovascular disease mortality.

METHODS:: The population was from one community health examination in December 2010 in a southern village of Taiwan. A total of 9856 participants were evaluated and finally 5015 eligible residents with age older than 40 years were included. The baseline characteristics and laboratory data in nonischemic ECG and ischemic ECG groups were compared, and multivariate-adjusted analysis was used to evaluate the risks to ischemic ECG.

RESULTS:: The higher prevalence of hypertension, metabolic syndrome and even HCV infection (25.3% versus 11.6%; P < 0.001) in ischemic ECG group than those in nonischemic ECG group. In the multivariate adjusted analysis, HCV infection would lead to a 1.759-fold risk to ischemic ECG when compared with non-HCV subjects.

CONCLUSIONS:: HCV was strongly associated with ischemic ECG findings in this community study, and it could be a nonconventional risk factor for coronary artery disease.

PMID: 24335568 [PubMed - as supplied by publisher]

Source

Clinical Characteristics of Patients who Developed Hepatocellular Carcinoma after Hepatitis C Virus Eradication with Interferon Therapy: Current Status in Japan

Intern Med. 2013;52(24):2701-6.

Sato A, Sata M, Ikeda K, Kumada T, Izumi N, Asahina Y, Osaki Y, Chayama K, Kaneko S, Sakai A, Onji M, Hiasa Y, Omura T, Ozeki I, Yokosuka O, Shiina S,Itsubo M, Nishiguchi S, Hirano K, Ide T, Sakisaka S, Yamasaki T, Hidaka I, Tanaka M, Kim SR, Ichida T.

Abstract

Objective We attempted to elucidate the clinical features of chronic hepatitis C patients who develop hepatocellular carcinoma (HCC) after achieving a sustained viral response (SVR) to interferon (IFN) therapy. Methods The clinical features of 130 patients at 19 hospitals who developed HCC after obtaining an SVR were retrospectively reviewed. Results Overall, 107 (82%) of the 130 patients were men, with 92 (71%) being ≥60 years of age and 76, 38 and 16 developing HCC within 5, 5-10 and 10-16.9 years after IFN therapy, respectively. Before receiving IFN therapy, 92 (71%) patients had cirrhosis and/or a low platelet count (<15×10(4) cells/μL). Lower albumin (<3.9 g/dL) and higher alpha fetoprotein (AFP) (≥10 ng/mL) levels were identified in a multivariate analysis to be independent variables of the development of HCC within five years after IFN therapy. Among 4,542 SVR patients, HCC occurred in 109 (2.4%) during a 5.5-year follow-up period, thus resulting in an occurrence rate of 4.6% for men and 0.6% for women. Conclusion SVR patients with lower albumin or higher AFP levels require careful assessments to prevent early HCC development after IFN therapy. HCC occurrence within >10 years of IFN therapy is not uncommon, and the risk factors remain uncertain, thus suggesting that all SVR patients should undergo long-term follow-up examinations for HCC development.

PMID: 24334571 [PubMed - in process]

Source

Beyond phase 3 registration trials: defining safety for triple therapy with protease inhibitors in cirrhosis

Gut doi:10.1136/gutjnl-2013-306480

Editorial

P Ferenci1, G Dusheiko2

+ Author Affiliations

Correspondence toDr Peter Ferenci, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Wien A 1090, Austria;peter.ferenci@meduniwien.ac.at

Received 22 November 2013
Accepted 26 November 2013
Published Online First 13 December 2013

Clinical trials are the standard method for evaluating a new drug for treatment of disease in humans. The phase 3 trial is designed to evaluate a new agent's clinical benefit and possible side effects; as such, it is considered to be the definitive test of the agent's usefulness. While there is no substitute for well-designed phase 3 trials, one should be aware of their limitations.1 Usually, the protocols use very strict selection criteria, creating ‘ideal’ patients, not necessarily reflecting the patient population seen by treating physicians. Good examples were the phase 3 studies for treatment of chronic hepatitis C by triple therapy with peginterferon/ribavirin (PEGIFN/RBV) and a first-generation protease inhibitor (telaprevir or boceprevir). All studies2–5 showed that this treatment augments cure rates substantially but failed to include sufficient patients with the highest need for an effective antiviral therapy, namely patients with advanced cirrhosis.6 In all studies, histologic grades F3 and F4 (according to the METAVIR classification) were grouped as ‘advanced fibrosis’. It should be stressed that F3 is not yet cirrhosis, and F4 is not the same as clinically symptomatic cirrhosis with portal hypertension. …

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High-Fat Diet Linked to Fewer Gallstones

Published: Dec 17, 2013 | Updated: Dec 17, 2013

By Cole Petrochko, Staff Writer, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points

• In a meta-analysis of randomized controlled trials of participants undergoing weight loss, ursodeoxycholic acid use was associated with a reduced risk of gallstones.
• Diets high in fat content also were associated with fewer gallstones, compared with those with low fat content.

Patients undergoing rapid weight loss who either received ursodeoxycholic acid (Ursodiol) or ate a high-fat diet had a reduced risk of gallstones, researchers found.

Compared with control treatments, risk for gallstones was significantly reduced among patients who received daily supplements of ursodeoxycholic acid (RR 0.33, 95% CI 0.18-0.60), according to Frank Lammert, MD, of Saarland University Hospital in Homburg, Germany, and colleagues.

There was also a significant reduction in gallstone formation in patients who consumed a high-fat diet versus a low-fat diet (RR 0.09, 95% CI 0.01-0.61), they wrote online in the journal Clinical Gastroenterology and Hepatology.

A study printed in the journal Hepatologyin July 2013 showed a causal relationship between high body mass index (BMI) and gallstones, particularly among women.

Similar findings were reported in the Journal of Pediatric Gastroenterology and Nutrition in August 2012 among overweight or obese children and teens; those who were moderately obese had more than four-fold risks for gallbladder disease compared with normal-weight pediatric patients.

The authors noted that these risks were also present in patients who underwent rapid weight loss or who underwent weight cycling.

The authors reviewed randomized controlled trials of nonsurgical gallbladder stone preventive interventions in adult patients who underwent rapid weight loss through bariatric surgery or with diet alone, an analysis that included 13 studies and 1,837 obese participants combined.

Outcomes included in the analysis were formation of ultrasonically-verified gallstones, mortality, and adverse events. Secondary outcomes included quality of life, cholecystectomy, bile lithogenicity, and weight loss.

Control interventions included placebo treatment, no intervention, or pharmacological and nonpharmacological interventions.

Low- versus high-fat diets were examined in two studies, which included groups receiving 3 g versus 12.2 g of fat, and 2 g versus 30 g of fat, each in daily quantities. Participants in the remaining 11 studies received 300 to 1,200 mg daily of ursodeoxycholic acid at a median 750 mg per day.

Participants were treated from 6 weeks to 18 months and were followed up with for 6 weeks to 24 months.

In the studies of ursodeoxycholic acid, 5% of those in a treatment arm developed gallstones versus 23% of those in the control arm. No deaths occurred in either arms of the studies. Treatment with ursodeoxycholic acid was associated with a reduced risk of cholecystectomy (RR 0.20, 95% CI 0.07-0.53).

Weight loss was equal among groups in all of the ursodeoxycholic acid trials. Among those who received bariatric surgery as their weight-loss intervention, type of surgery did not affect ursodeoxycholic acid-related outcomes, nor did dosage of ursodeoxycholic acid. Quality of life was not assessed in these studies.

In studies comparing high- versus low-fat diets, no patients in the high-fat groups developed gallstones, compared with 45% of control patients. There was no significant difference in weight lost. Quality of life was not assessed. Bile lithogenicity did not differ significantly between the two studies.

There were no adverse events reported with the high- versus low-fat diet studies.

Few serious events were reported related to ursodeoxycholic acid consumption; gastrointestinal-related complaints were the most common adverse events.

The authors noted that the small number of identified trials and low sample sizes in each trial limited their study. In addition, high risk of attrition bias may have also limited outcomes. The research was limited by an inability to perform a meta-analysis of other interventions that reduce cholesterol precipitation in bile.

The authors received support from the Falk Foundation and Merck.

Primary source: Clinical Gastroenterology and Hepatology
Source reference: Lammert F, et al "Ursodeoxycholic acid and high-fat diets prevent gallbladder stones during weight loss: a meta-analysis of randomized controlled trials" Clin Gastroenterol Hepatol 2013; DOI: 10.1016/j.cgh.2013.11.031.

Source

Development and Validation of a Comorbidity Scoring System for Patients With Cirrhosis

Gastroenterology
Volume 146, Issue 1 , Pages 147-156, January 2014

Peter Jepsen, Hendrik Vilstrup, Timothy L. Lash

Received 28 February 2013; accepted 12 September 2013. published online 19 September 2013.

Abstract

Background & Aims

At least 40% of patients with cirrhosis have comorbidities that increase mortality. We developed a cirrhosis-specific comorbidity scoring system (CirCom) to help determine how these comorbidities affect mortality and compared it with the generic Charlson Comorbidity Index.

Methods

We used data from nationwide health care registries to identify Danish citizens diagnosed with cirrhosis in 1999−2008 (n = 12,976). They were followed through 2010 and characterized by 34 comorbidities. We used Cox regression to assign severity weights to comorbidities with an adjusted mortality hazard ratio (HR) ≥1.20. Each patient's CirCom score was based on, at most, 2 of these comorbidities. Performance was measured with Harrell's C statistic and the Net Reclassification Index (NRI) and results were compared with those obtained using the Charlson Index (based on 17 comorbidities). Findings were validated in 2 separate cohorts of patients with alcohol-related cirrhosis or chronic hepatitis C.

Results

The CirCom score included chronic obstructive pulmonary disease, acute myocardial infarction, peripheral arterial disease, epilepsy, substance abuse, heart failure, nonmetastatic cancer, metastatic cancer, and chronic kidney disease; 24.2% of patients had 1 or more of these, and mortality correlated with the CirCom score. Patients' CirCom score correlated with their Charlson Comorbidity Index (Kendall's τ = 0.57; P < .0001). Compared with the Charlson Index, the CirCom score increased Harrell's C statistic by 0.6% (95% confidence interval: 0.3%−0.8%). The NRI for the CirCom score was 5.2% (95% confidence interval: 3.7%−6.9%), and the NRI for the Charlson Index was 3.6% (95% confidence interval: 2.3%−5.0%). Similar results were obtained from the validation cohorts.

Conclusions

We developed a scoring system to predict mortality among patients with cirrhosis based on 9 comorbidities. This system had higher C statistic and NRI values than the Charlson Comorbidity Index, and is easier to use. It could therefore be a preferred method to predict death or survival of patients and for use in epidemiologic studies.

Keywords: End-Stage Liver Disease, Prognostic Factors, Outcome, Prediction Model

Abbreviations used in this paper: CI, confidence interval, HR, hazard ratio, MELD, Model for End-Stage Liver Disease, NRI, Net Reclassification Index

Source

The treatment efficacy of pegylated interferon plus ribavirin therapy in chronic hepatitis C patients with mixed genotype 1/2 infection

J Gastroenterol Hepatol. 2013 Dec 10. doi: 10.1111/jgh.12467. [Epub ahead of print]

Huang CI, Huang CF, Huang JF, Dai CY, Yeh ML, Hsieh MY, Lin ZY, Chen SC, Wang LY, Yu ML, Chuang WL.

Abstract

BACKGROUND: The treatment efficacy of patients with mixed HCV genotype 1/genotype 2 (HCV-1/2) remains unknown.

AIM: We aimed to elucidate the sustained virological response (SVR) rate in patients with HCV-1/2 infection.

METHODS: 110 HCV-1/2 patients treated with response-guided peginterferon/ribavirin therapy (24 weeks for patients with a rapid virological response [RVR] and low viral loads; 48 weeks for patients without a RVR or high viral loads) were allocated. 200 HCV-1 patients were selected as a historical control. Interleukin-28B (IL-28B) rs8099917 genotype was tested for the association with an SVR.

RESULTS: The rates of RVR, SVR and relapse rate were 71.8%, 87.3% and 11.1%, respectively. The SVR rate was significantly higher in patients with an abbreviated regimen as compared with those with 48-week regimen (95.5% vs. 75.0 %, P=0.002), and both were similar to the HCV-1 historical control. Stepwise logistic regression analysis revealed that lower baseline viral loads was the single factor predictive of an RVR (odds ratio/95% confidence intervals [OR/CI] of 41.62/9.72-178.19, P<0.001). The achievement of an RVR was the single best factor predictive of an SVR (OR/CI: 7.5/1.33-42.27, P＝0.02). Nevertheless, an abbreviated regimen became the single factor associated with an SVR if treatment regimen was taken into consideration (OR/CI: 11.0/1.25-96.79, P=0.03). The SVR rate did not differ between patients with rs8099917 TT and TG/GG genotype (91.7% vs. 87.5%, P=0.63).

CONCLUSIONS: The treatment efficacy of patients with HCV-1/2 was satisfactory. The role of IL-28B genetic variants in the population with response guided therapy was limited.

This article is protected by copyright. All rights reserved.

KEYWORDS: HCV, IL-28B, RGT, mixed infection, treatment

PMID: 24325201 [PubMed - as supplied by publisher]

Source

Noncompliance with guidelines for the treatment of hepatitis C is frequent in daily practice

Eur J Gastroenterol Hepatol. 2014 Jan;26(1):65-73. doi: 10.1097/MEG.0b013e328362dd03.

Niederau C, Mauss S, Böker K, Lutz T, Heyne R, Moog G, John C, Witthöft T, Alshuth U, Hüppe D.

Abstract

PURPOSE: In trials of pegylated interferons (PEG-IFNs), the lack of an early virological response (EVR) was associated with sustained virological response (SVR) rates of only 0-3%. The rates were similarly low when hepatitis C virus (HCV)-RNA was positive at week 24. Treatment guidelines therefore recommend 'stop rules' on the basis of HCV-RNA levels at weeks 12 and 24 of treatment. We analyzed the use of these rules under 'real-life' conditions.

PATIENTS AND METHODS: This was a prospective, community-based cohort study involving 467 physicians from institutions throughout Germany, including 4727 treatment-naive genotype-1 patients who received a full course of treatment with PEG-IFN α-2a plus ribavirin between 2003 and 2009.

RESULTS: The overall SVR rate was 43.1%. Failure to determine EVR decreased from 20% in 2003-2004 to 10% in 2006-2007. Unexpectedly, treatment was continued in 86.1% of patients without an EVR and in those who had an EVR but were HCV-RNA positive at week 24 (67.5%), resulting in SVR rates of 15.7 and 40.9%, respectively. Between 77.5 and 95.3% of physicians did not follow prescribed recommendations to reduce PEG-IFN or ribavirin in cases of hematological abnormalities.

CONCLUSION: Although recommendations to assess EVR and HCV-RNA at week 24 were increasingly observed in daily practice, the corresponding 'stop rules' in nonresponders were neglected. The subsequent SVR was 5-10 times higher than that reported in controlled trials. This may partly be because of the fact that reductions in PEG-IFN or ribavirin dose were not performed despite recommendations. The issue of stop rules will gain even more interest since the first HCV protease inhibitors have been approved. Prolongation of treatment beyond the new stop rules is associated with risks of resistant HCV variants. Thus, the new stop rules are to be observed more strictly when compared with previous therapy with interferons and ribavirin.

PMID: 23751351 [PubMed - in process]

Source

Antiviral drug resistance increases hepatocellular carcinoma: A prospective decompensated cirrhosis cohort study

World J Gastroenterol. 2013 December 7; 19(45): 8373-8381.
Published online 2013 December 7. doi: 10.3748/wjg.v19.i45.8373.

Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.

Lei Li, Wei Liu, Yu-Han Chen, Chun-Lei Fan, Pei-Ling Dong, Fei-Li Wei, Bing Li, De-Xi Chen and Hui-Guo Ding.

Lei Li, Yu-Han Chen, Chun-Lei Fan, Pei-Ling Dong, Bing Li, Hui-Guo Ding, Department of Gastroenterology and Hepatology, Beijing You’an Hospital Affiliated with Capital Medical University, Beijing 100069, China
Wei Liu, Department of Internal Medicine, Beijing Ji Shui Tan Hospital Affiliated with Peking University, Beijing 100035, China
Fei-Li Wei, De-Xi Chen, Viral Laboratory of Liver Diseases Research Institute, Capital Medical University, Beijing 100069, China
Author contributions: Li L, Liu W and Chen YH equally contributed to the data collection and follow-up of patients in this study; Li L and Ding HG analysed the data and wrote the manuscript; Wei FL and Chen DX supervised the drug resistance mutation detection; Ding HG was responsible for this project and the final manuscript; the other authors contributed to the data acquisition and patient care.

Correspondence to: Hui-Guo Ding, MD, PhD, Director, Department of Gastroenterology and Hepatology, Beijing You’an Hospital Affiliated with Capital Medical University, Fengtai district, Beijing 100069, China. dinghuiguo@medmail.com.cn

Telephone: +86-10-83997155 Fax: +86-10-63295525

Received July 24, 2013; Revised September 22, 2013; Accepted September 29, 2013;

Abstract

AIM: To study the clinical outcome of antiviral therapy in hepatitis B-related decompensated cirrhotic patients.

METHODS: Three hundred and twelve patients with decompensated hepatitis B cirrhosis were evaluated in a prospective cohort. With two years of follow-up, 198 patients in the group receiving antiviral therapy with nucleos(t)ide analogues and 39 patients in the control group without antiviral treatment were analysed.

RESULTS: Among the antiviral treatment patients, 162 had a complete virological response (CVR), and 36 were drug-resistant (DR). The two-year cumulative incidence of hepatocellular carcinoma (HCC) in the DR patients (30.6%) was significantly higher than that in both the CVR patients (4.3%) and the control group (10.3%) (P < 0.001). Among the DR patients in particular, the incidence of HCC was 55.6% (5/9) in those who failed rescue therapy, which was extremely high. The rtA181T mutation was closely associated with rescue therapy failure (P = 0.006). The Child-Pugh scores of the CVR group were significantly decreased compared with the baseline (8.9 ± 2.3 vs 6.0 ± 1.3, P = 0.043).

CONCLUSION: This study showed that antiviral drug resistance increased the risk of HCC in decompensated hepatitis B-related cirrhotic patients, especially in those who failed rescue therapy.

Keywords: Hepatitis B, Decompensated cirrhosis, Nucleos(t)ide analogues, Hepatocellular carcinoma, Drug resistance

Core tip: This study was performed to analyse the clinical data of 312 patients with decompensated hepatitis B cirrhosis in a prospective cohort. These data showed that complete virological response could improve the clinical outcome in decompensated hepatitis B cirrhotic patients. However, clinicians should be aware of the high risk of hepatocellular carcinoma and liver failure in antiviral drug-resistant patients.

INTRODUCTION

Chronic hepatitis B virus (HBV) infection, the main aetiology of liver cirrhosis and hepatocellular carcinoma (HCC), remains a major public health problem worldwide, especially in China[^1-3]. Among these patients, the annual incidence of HCC is 2%-5%[^3-5]. The most effective method to prevent HCC is to control HBV infection through vaccination[^5,6]. In patients already infected with HBV, antiviral therapy remains the best strategy to prevent liver cirrhosis and HCC[^6-9]. Major progress in the treatment of chronic hepatitis B has recently been made during the last decade with the development of antiviral drugs, especially nucleos(t)ide analogues (NUCs)[^10-12]. Some data supporting the benefit of antiviral therapy on the prevention of HCC in chronic hepatitis B patients have been reported in several randomised controlled trials[^12-15]. Nonetheless, antiviral drug resistance is important in determining the success of long-term therapy for chronic hepatitis B patients[^16,17]. Based on recent clinical data, the development of resistance to NUCs is associated with an exacerbation of liver disease, including the development of cirrhosis and HCC[¹⁶]. In addition, the risk of HCC remains high in HBV-related cirrhosis patients who are treatment-naïve for NUCs[¹⁷]. Decompensated cirrhosis is the end stage of the disease and is characterised by high mortality and an extremely high risk of HCC. In HBV-related decompensated cirrhotic patients (DCPs), antiviral therapy using NUCs is recommended according to the 2005 global guidelines[^18-20]. However, clinical data regarding the incidence of HCC in HBV-related DCPs with NUC antiviral therapies are limited. Therefore, the aim of the current study was to evaluate the two year outcomes in HBV-related decompensated cirrhotic, treatment-naïve patients using NUCs in a real life practical prospective cohort.

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California Stem Cell Announces Completion of Phase I Cancer Stem Cell Clinical Trial for Hepatocellular Carcinoma

December 18, 2013 09:00 AM Eastern Time

IRVINE, Calif.--(BUSINESS WIRE)--California Stem Cell, Inc. (CSC) announced today the successful completion of a Phase I clinical trial investigating the safety of a cancer stem cell-based therapy in patients with Stage IV hepatocellular carcinoma, a common form of advanced liver cancer. The trial, conducted in Shanghai, China in accordance with international standards, marks the second cancer type the Company has explored with its platform approach, the first being a Phase III treatment for melanoma in the United States.

“We were very encouraged by these early clinical and operational results”

Led by Global Medical Director Michael Bayer, M.D., Ph.D., the study called for 8 patients with Stage IV hepatocellular carcinoma to receive the Company’s patient-specific cancer immunotherapy, known as “DC-TC.” Study patients received weekly injections for three consecutive weeks and were evaluated over a two-month period.

CSC's "DC-TC" therapy begins with growing cancer stem cells that have been isolated from a patient's resected tumor sample, which are then enriched and inactivated. This newly created cancer stem cell line is then combined with dendritic cells, a type of antigen-presenting immune cell that is derived from the same patient's blood. The product is then introduced back into the patient via a series of subcutaneous injections.

This initial study sought to determine whether patients could safely receive the “DC-TC” product without experiencing adverse events, which could serve as an indication that the therapeutic product was safe for further research in human patients. The study also sought to explore whether the immune-activating process might create complications in trial patients who also had active hepatitis B.

“In China, a nation with the largest incidence rates for liver cancer in the world, many patients will co-present with hepatitis B,” said Dr. Bayer. “Initially there was some concern that these patients might experience flare-up of their hepatitis as the immune system was strengthened and directed to kill their cancer stem cells; however, those concerns proved to be unwarranted.”

In addition to demonstrating initial safety of the cell therapy product among the initial patient cohort, this trial demonstrated the successful transfer of CSC’s manufacturing technology to a remote manufacturing facility under its control, which the company considers a critical component in future trials using this approach. Manufacture of the patient-specific product for the trial was conducted by CSC under cGMP conditions.

“We were very encouraged by these early clinical and operational results,” said CEO Hans Keirstead, Ph.D. “Not only were the initial results promising, but the trial represented a successful first step in California Stem Cell’s goal of translating its platform cancer stem cell treatment to other cancer types. We expect this successful experience and the data collected will serve us well as we expand into other solid tumor cancers.”

About the DC-TC Treatment

CSC’s DC-TC treatment is based on recent clinical findings that the rapid proliferation and subsequent spreading of cancer throughout a patient’s body may be fueled by a small number of cancer stem cells. Through proprietary processes developed at CSC, researchers have refined isolation and expansion of these cancer stem cells to clinically useful numbers, which are then combined with autologous dendritic cells, and reintroduced into the patient with the intention of training and bolstering the patient’s immune system to target the cancer stem cells that have the ability to metastasize and create new tumors.

About California Stem Cell

California Stem Cell Inc. (CSC) is an Irvine, CA-based company focused on the development of stem cell-based therapies for metastatic cancers and neuromuscular disorders such as spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s Disease) and spinal cord injury.

CSC has proprietary methods to generate human stem cell lines, expand them to clinically and commercially useful numbers, and differentiate them at extremely high purity using fully-defined, proprietary media and cGMP processes.

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Contacts

California Stem Cell, Inc.
Matt Bayless, 949-725-1750
press@californiastemcell.com

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Gilead Announces SVR12 Rates From Three Phase 3 Studies Evaluating a Once-Daily Fixed-Dose Combination of Sofosbuvir and Ledipasvir for Genotype 1 Hepatitis C Patients

-- High Cure Rates Observed with Single Tablet Regimen May Eliminate Interferon and Ribavirin from HCV Therapy for Genotype 1 Patients --

-- U.S. NDA Submission Planned for Q1 2014--

FOSTER CITY, Calif.--(BUSINESS WIRE)--Dec. 18, 2013-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced topline results from three Phase 3 clinical trials (ION-1, ION-2 and ION-3) evaluating the investigational once-daily fixed-dose combination of the nucleotide analog polymerase inhibitor sofosbuvir (SOF) 400 mg and the NS5A inhibitor ledipasvir (LDV) 90 mg, with and without ribavirin (RBV), for the treatment of genotype 1 chronic hepatitis C virus (HCV) infection.

Across the three studies, 1,952 patients with genotype 1 HCV infection were randomized to receive SOF/LDV with or without RBV for eight, 12 or 24 weeks of therapy. Of these, 1,512 patients were treatment-naïve, 440 were treatment experienced and 224 had compensated cirrhosis.

The intent-to-treat SVR12 rates observed to date in the ION studies are summarized in the table below. Results of the 24-week arms from ION-1 will be available in the first quarter of 2014 and will be presented at a future scientific meeting.

Study		Population		Treatment		Duration		SVR12 Rates
ION-1		GT 1 treatment-naïve (including 15.7 percent (136/865) with cirrhosis)		SOF/LDV		12 weeks		97.7% (209/214)
				SOF/LDV + RBV		12 weeks		97.2% (211/217)
				SOF/LDV		24 weeks		NA (n=217)
				SOF/LDV + RBV		24 weeks		NA (n=217)
ION-2		GT 1 treatment-experienced (including 20.0 percent (88/440) with cirrhosis)		SOF/LDV		12 weeks		93.6% (102/109)
				SOF/LDV+RBV		12 weeks		96.4% (107/111)
				SOF/LDV		24 weeks		99.1% (108/109)
				SOF/LDV+RBV		24 weeks		99.1% (110/111)
ION-3		GT 1 treatment-naïve		SOF/LDV		8 weeks		94.0% (202/215)
				SOF/LDV + RBV		8 weeks		93.1% (201/216)
				SOF/LDV		12 weeks		95.4% (206/216)

Of the 1,518 patients randomized to the 12-week arms of ION-1 and to all arms of ION-2 and ION-3, 1,456 patients (95.9 percent) achieved the primary efficacy endpoint of SVR12. Of the 62 patients (4.1 percent) who failed to achieve SVR12, 36 patients (2.4 percent) experienced virologic failure: 35 due to relapse and only one patient due to on-treatment breakthrough (with documented non-compliance). Twenty-six patients (1.7 percent) were lost to follow-up or withdrew consent.

Fewer adverse events were observed in the RBV-free, fixed-dose combination arms compared to the RBV-containing arms in all ION studies. Adverse events observed in those taking the SOF/LDV tablet were generally mild and included fatigue and headache. In the RBV-containing arms of the ION studies, the most common adverse events were fatigue, headache, nausea and insomnia. Anemia, which is a common side effect associated with RBV, was reported in 0.5 percent of patients in the SOF/LDV arms versus 9.2 percent of patients in the RBV-containing arms. Less than 1 percent of patients in the studies discontinued treatment due to treatment-emergent adverse events.

“The results of the ION studies demonstrate that a simple, safe and short course of therapy with a single tablet regimen of sofosbuvir/ledipasvir can provide high cure rates among patients with genotype 1 HCV infection, while eliminating the need for both interferon and ribavirin,” said Norbert Bischofberger, PhD, Executive Vice President of Research and Development and Chief Scientific Officer. “With the availability of these results, Gilead is finalizing its regulatory filing for sofosbuvir/ledipasvir, with the goal of submitting a New Drug Application in the first quarter of 2014.”

The FDA has assigned the SOF/LDV fixed-dose combination a Breakthrough Therapy designation, which is granted to investigational medicines that may offer major advances in treatment over existing options. Sofosbuvir was approved as Sovaldi™ in the United States on December 6 and in Canada on December 13. Applications are pending in the European Union, Australia and New Zealand, Switzerland and Turkey.

About the ION Studies

The Phase 3 ION studies are randomized, open-label Phase 3 clinical trials evaluating the efficacy and safety of a once-daily fixed-dose combination of SOF/LDV for 8, 12 or 24 weeks, with and without RBV, among 1,952 genotype 1 HCV patients. The studies included patients who were treatment-naïve or who had failed previous treatment, including protease inhibitor-based regimens. The primary endpoint for each study was SVR12. Complete results from all three studies will be presented at a future scientific conference.

In ION-1, 865 treatment-naïve genotype 1 HCV patients, including those with cirrhosis, received SOF/LDV with or without RBV for 12 or 24 weeks. In March 2013, a planned review by the study’s Data and Safety Monitoring Board (DSMB) of interim safety and efficacy data from an initial enrollment of patients concluded that the trial should continue without modification. Enrollment of the remaining patients was completed in May 2013. Prior to the DSMB meeting, the statistical analysis plan was amended to allow for the analysis of the primary efficacy endpoint for the two 12-week arms, independent of the 24-week arms. Per the amendment, if SVR12 rates in the 12-week arms were >90 percent (including among those with cirrhosis), early regulatory filings could be pursued, given that longer treatment durations would not be able to show statistically significantly higher SVR12 rates.

The ION-2 study evaluated 440 treatment-experienced genotype 1 HCV patients who had failed past therapy with regimens containing Peg-IFN (including Peg-IFN plus a protease inhibitor). Patients received SOF/LDV with or without RBV for 12 or 24 weeks.

In ION-3, 647 non-cirrhotic treatment-naïve genotype 1 HCV patients received SOF/LDV with or without RBV for 8 weeks or without RBV for 12 weeks.

The SOF/LDV fixed-dose combination is an investigational product and its safety and efficacy has not yet been established.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that Gilead may be unable to file for U.S. regulatory approval of the SOF/LDV fixed-dose combination in the currently anticipated timelines. In addition, the FDA and other regulatory agencies may not approve the SOF/LDV fixed-dose combination, and any marketing approvals, if granted, may have significant limitations on its use. Additional clinical studies of sofosbuvir and the SOF/LDV fixed-dose combination, including results from the 24-week arms of ION-1, may not produce favorable results. As a result, Gilead may not be able to successfully commercialize the SOF/LDV fixed-dose combination, and may make a strategic decision to discontinue its development if, for example, the market for the product fails to materialize as expected. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2013, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full prescribing information for Sovaldi is available at www.Sovaldi.com.

Sovaldi is a trademark of Gilead Sciences, Inc., or its related companies.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Source: Gilead Sciences, Inc.

Gilead Sciences, Inc.
Patrick O’Brien, 650-522-1936 (Investors)
Cara Miller, 650-522-1616 (Media)

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