May 26, 2013

Impact of sustained virologic response on all-cause mortality†‡


Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Hepatology Elsewhere

Lisa I. Backus MD PHD1,*, Pamela S. Belperio PharmD2

DOI: 10.1002/hep.26504

Copyright © 2013 American Association for the Study of Liver Diseases

Publication History: Accepted manuscript online: 23 MAY 2013 03:32PM EST Manuscript Accepted: 23 APR 2013 Manuscript Revised: 8 APR 2013 Manuscript Received: 27 FEB 2013

Chronic hepatitis C virus (HCV) infection outcomes include liver failure, hepatocellular carcinoma (HCC), and liver-related death.


To assess the association between sustained virological response (SVR) and all-cause mortality in patients with chronic HCV infection and advanced hepatic fibrosis.


An international, multicenter, long-term follow-up study from 5 large tertiary care hospitals in Europe and Canada of 530 patients with chronic HCV infection who started an interferon-based treatment regimen between 1990 and 2003, following histological proof of advanced hepatic fibrosis or cirrhosis (Ishak score 4-6). Complete follow-up ranged between January 2010 and October 2011.


All-cause mortality. Secondary outcomes were liver failure, HCC, and liver-related mortality or liver transplantation.


The 530 study patients were followed up for a median (interquartile range [IQR]) of 8.4 (6.4-11.4) years. The baseline median (IQR) age was 48 (42-56) years and 369 patients (70%) were men. The Ishak fibrosis score was 4 in 143 patients (27%), 5 in 101 patients (19%), and 6 in 286 patients (54%). There were 192 patients (36%) who achieved SVR; 13 patients with SVR and 100 without SVR died (10-year cumulative all-cause mortality rate, 8.9% [95% CI, 3.3%-14.5%] with SVR and 26.0% [95% CI, 20.2%-28.4%] without SVR; P < .001). In time-dependent multivariate Cox regression analysis, SVR was associated with reduced risk of all-cause mortality (hazard ratio [HR], 0.26; 95% CI, 0.14-0.49; P < .001) and reduced risk of liver-related mortality or transplantation (HR, 0.06; 95% CI, 0.02-0.19; P < .001), the latter occurring in 3 patients with SVR and 103 without SVR. The 10-year cumulative incidence rate of liver-related mortality or transplantation was 1.9% (95% CI, 0.0%-4.1%) with SVR and 27.4% (95% CI, 22.0%-32.8%) without SVR (P < .001). There were 7 patients with SVR and 76 without SVR who developed HCC (10-year cumulative incidence rate, 5.1%; 95% CI, 1.3%-8.9%; vs 21.8%; 95% CI, 16.6%-27.0%; P < .001), and 4 patients with SVR and 111 without SVR experienced liver failure (10-year cumulative incidence rate, 2.1%; 95% CI, 0.0%-4.5%; vs 29.9%; 95% CI, 24.3%-35.5%; P < .001).


Among patients with chronic HCV infection and advanced hepatic fibrosis, sustained virological response to interferon-based treatment was associated with lower all-cause mortality. (HEPATOLOGY 2013.)


Patients reluctant to avail free hepatitis C treatment

Published in The Express Tribune, May 27th, 2013

By Umer Farooq Published: May 27, 2013


Dr Muhammad Zafar said his department has received reports of patients refusing the treatment from hospitals in Mardan, Abbottabad and a few other districts. PHOTO: FILE

PESHAWAR: The number of patients visiting government-run hospitals to avail free treatment for hepatitis C has decreased slightly after the procurement of substandard hepatitis C curing interferon injections became known to the public.

“People have been reading newspapers and are now reluctant to get free medication for hepatitis C virus (HCV) treatment,” said a doctor treating HCV patients at the Lady Reading Hospital (LRH).

He said patients are fearful they might die of the free treatment as the Anti-Corruption Establishment (ACE) team probing the incident had confirmed the death of seven people after the use of the spurious medication. “The patients prefer to get treatment at private hospitals rather than visiting state-run establishments,” he added.

On the other hand, Dr Amir Ghaffur, another doctor treating HCV patients at the LRH, begs to differ.

“We continue to run this programme. Patients visit the out-patient department and I don’t think their numbers have reduced,” he claimed.

However, Director General Health Khyber-Pakhtunkhwa (K-P) Dr Muhammad Zafar said his department has received reports of patients refusing the treatment from hospitals in Mardan, Abbottabad and a few other districts.

The managements of these hospitals have complained that the patients are afraid of getting free HCV treatment.

Zafar further added the health department had bought a new stock of HCV curing injections from another company and 95,000 vials, tested by the Central Drug Laboratory Islamabad, were available with it.

“Patients should not refuse the medication anymore. I have talked to the health secretary and will convene a meeting on Monday (today) to discuss the issue further,” Zafar informed. “We will request the media to highlight the current situation in the same manner as it did when the scam surfaced,” he added.

The issue of procurement of substandard interferon injections by the K-P Health Department came to light on February 6 when the Peshawar High Court (PHC) took notice of the supply of bogus medicines to public hospitals and directed the ACE to probe the issue and arrest all those involved.

“You are playing with the lives of underprivileged people. Those involved need to be hanged publically,” PHC Chief Justice Dost (CJ) Muhammad Khan was quoted as telling health department officials during a case hearing of the Rs250 million scam.

The ACE’s probe led to the arrest of four K-P health officials including the then DG Health Dr Shareef Ahmad, former hepatitis C control programme project director Ghulam Subhani and a storekeeper identified as Mubarak Shah.

Another suspect, former DG Health Dr Muhammad Ali Chohan managed to obtain pre-arrest bail and tried to confirm his bail. However, his pre-arrest bail was not extended by Justice Khan and Chohan was arrested from the court room on May 24.

Published in The Express Tribune, May 27th, 2013.


IL28B minor allele is associated with a younger age of onset of hepatocellular carcinoma in patients with chronic hepatitis C virus infection

Sato M,et al. Show all

Sato M, Kato N, Tateishi R, Muroyama R, Kowatari N, Li W, Goto K, Otsuka M, Shiina S, Yoshida H, Omata M, Koike K.


J Gastroenterol. 2013 May 22. [Epub ahead of print]


Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.


BACKGROUND: IL28B polymorphisms were shown to be associated with a response to peg-interferon-based treatment in chronic hepatitis C (CHC) and spontaneous clearance. However, little is known about how this polymorphism affects the course of CHC, including the development of hepatocellular carcinoma (HCC). We evaluated the influence of IL28B polymorphisms on hepatocarcinogenesis in CHC patients.

METHODS: We genotyped the rs8099917 single-nucleotide polymorphism in 351 hepatitis C-associated HCC patients without history of IFN-based treatment, and correlated the age at onset of HCC in patients with each genotype.

RESULTS: Frequencies of TT, TG, and GG genotypes were 74.3 % (261/351), 24.8 % (87/351), and 0.9 % (3/351), respectively. The mean ages at onset of HCC for TT, TG, and GG genotypes were 69.9, 67.5 and 66.8, respectively. In multivariate analysis, IL28B minor allele (TG and GG genotypes) was an independent risk factor for younger age at onset of HCC (P = 0.02) in males (P < 0.001) with higher body mass index (BMI; P = 0.009). The IL28B minor allele was also associated with a lower probability of having aspartate aminotransferase-to-platelet ratio index (APRI) >1.5 (minor vs. major, 46.7 vs. 58.6 %; P = 0.01), lower AST (69.1 vs. 77.7 IU/L, P = 0.02), lower ALT (67.8 vs. 80.9 IU/L, P = 0.002), higher platelet count (12.8 vs. 11.2 × 10(4)/μL, P = 0.002), and higher prothrombin time (79.3 vs. 75.4 %, P = 0.002).

CONCLUSIONS: The IL28B minor allele was associated with lower inflammatory activity and less progressed fibrosis of the liver; however, it constituted a risk factor for younger-age onset of HCC in CHC patients.

23689989 [PubMed - as supplied by publisher]

Full text: Springer


A novel program for treating patients with trimorbidity: hepatitis C, serious mental illness, and active substance use

Sockalingam S,et al. Show all

Sockalingam S, Blank D, Banga CA, Mason K, Dodd Z, Powis J.


Eur J Gastroenterol Hepatol. 2013 May 15. [Epub ahead of print]


aMedical Psychiatry Program, University Health Network, Toronto General Hospital Departments of bPsychiatry cPsychology dMedicine, University of Toronto eSouth Riverdale Community Health Centre fToronto East General Hospital, Toronto, Ontario, Canada.


BACKGROUND: Advances in hepatitis C virus (HCV) treatment have yielded improved virological response rates, and yet, many individuals with psychiatric illness still fail to receive HCV therapy. Concerns about safety, adherence, and efficacy of HCV treatment are compounded and treatment is further deferred when substance use is also present. This is especially problematic given the disproportionately high rates of both mental health issues and substance use among individuals living with HCV.

OBJECTIVE: This study sought to examine HCV treatment outcomes in clients with serious mental illness (SMI) and with high rates of active substance use who were participating in a community-based HCV treatment program.

PATIENTS AND METHODS: A retrospective chart review of 129 clients was carried out. Patients were classified as having an SMI if they had a history of bipolar disorder, psychotic disorder, past suicide attempt or mental health related hospitalization.

RESULTS: Fifty-one patients were defined as having an SMI. Among the 46 patients with SMI and a detectable HCV viral load, HCV antiviral therapy was initiated in nine (19.6%). A relapse or an increase in substance use was common (77.8% or n=7), as was the requirement for adjustment or initiation of psychotropic medications (66.7% or n=6) during HCV antiviral therapy. Despite these barriers, rates of adherence to antiviral therapy were high and overall sustained virological response rates were comparable with published trials.

CONCLUSION: This study is the first to report HCV treatment outcomes in a population in which SMI and active polysubstance use was prevalent and suggests that with appropriate models of care, clients with trimorbidity can be treated safely and effectively.

23680911 [PubMed - as supplied by publisher]

Full text: Lippincott Williams & Wilkins


Combination Therapy With Telaprevir for Chronic Hepatitis C Virus Genotype 1 Infection in Patients With HIV: A Randomized Trial

Sulkowski MS,et al. Show all

Sulkowski MS, Sherman KE, Dieterich DT, Bsharat M, Mahnke L, Rockstroh JK, Gharakhanian S, McCallister S, Henshaw J, Girard PM, Adiwijaya B, Garg V, Rubin RA, Adda N, Soriano V.


Ann Intern Med. 2013 May 17. doi: 10.7326/0003-4819-159-2-201307160-00654. [Epub ahead of print]


BACKGROUND: Telaprevir (TVR) plus peginterferon-α2a (PEG-IFN-α2a) and ribavirin substantially increases treatment efficacy for genotype 1 chronic hepatitis C virus (HCV) infection versus PEG-IFN-α2a-ribavirin alone. Its safety and efficacy in patients with HCV and HIV-1 are unknown.

OBJECTIVE: To assess the safety and efficacy of TVR plus PEG-IFN-α2a-ribavirin in patients with genotype 1 HCV and HIV-1 and evaluate pharmacokinetics of TVR and antiretrovirals during coadministration.

DESIGN: Phase 2a, randomized, double-blind, placebo-controlled study. ( NCT00983853) SETTING: 16 international multicenter sites.

PATIENTS: 62 patients with HCV genotype 1 and HIV-1 who were HCV treatment-naive and taking 0 or 1 of 2 antiretroviral regimens were randomly assigned to TVR plus PEG-IFN-α2a-ribavirin or placebo plus PEG-IFN-α2a-ribavirin for 12 weeks, plus 36 weeks of PEG-IFN-α2a-ribavirin.

MEASUREMENTS: HCV RNA concentrations.

RESULTS: Pruritus, headache, nausea, rash, and dizziness were higher with TVR plus PEG-IFN-α2a-ribavirin during the first 12 weeks. Serious adverse events occurred in 5% (2 in 38) of those receiving TVR plus PEG-IFN-α2a-ribavirin and 0% (0 in 22) of those receiving placebo plus PEG-IFN-α2a-ribavirin; the same number in both groups discontinued treatment due to adverse events. Sustained virologic response occurred in 74% (28 in 38) of patients receiving TVR plus PEG-IFN-α2a-ribavirin and 45% (10 in 22) of patients receiving placebo plus PEG-IFN-α2a-ribavirin. Rapid HCV suppression was seen with TVR plus PEG-IFN-α2a-ribavirin (68% [26 in 38 patients] vs. 0% [0 in 22 patients] undetectable HCV RNA levels by week 4). Two patients had on-treatment HCV breakthrough with TVR-resistant variants. Patients treated with antiretroviral drugs had no HIV breakthroughs; antiretroviral exposure was not substantially modified by TVR.

LIMITATION: Small sample size and appreciable dropout rate.

CONCLUSION: In patients with HCV and HIV-1, more adverse events occurred with TVR versus placebo plus PEG-IFN-α2a-ribavirin; these were similar in nature and severity to those in patients with HCV treated with TVR. With or without concomitant antiretrovirals, sustained virologic response rates were higher in patients treated with TVR versus placebo plus PEG-IFN-α2a-ribavirin.

PRIMARY FUNDING SOURCE: Vertex Pharmaceuticals and Janssen Pharmaceuticals.


23685940 [PubMed - as supplied by publisher]


Detection of hepatocellular carcinoma at advanced stages among patients in the HALT-C trial: where did surveillance fail?

Singal AG,et al. Show all

Singal AG, Nehra M, Adams-Huet B, Yopp AC, Tiro JA, Marrero JA, Lok AS, Lee WM.


Am J Gastroenterol. 2013 Mar;108(3):425-32. doi: 10.1038/ajg.2012.449. Epub 2013 Jan 22.


Department of Internal Medicine, UT Southwestern Medical Center, and Parkland Health and Hospital System, Dallas, Texas 75390-8887, USA.


OBJECTIVES: Only 40% of patients with hepatocellular carcinoma (HCC) are diagnosed at an early stage, suggesting breakdowns in the surveillance process. The aim of our study was to assess the reasons behind surveillance process failures among patients in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial (HALT-C), which prospectively collected HCC surveillance data on a large cohort of patients.

METHODS: Binary regression analysis was used to identify predictors of consistent surveillance, which was defined as having an ultrasound and alpha-fetoprotein every 12 months. Surveillance failures among patients who developed HCC were classified into one of three categories: absence of screening, absence of follow-up, or absence of detection.

RESULTS: Over a mean follow-up of 6.1 years, 692 (68.9%) of 1,005 patients had consistent surveillance. Study site was the strongest predictor of consistent surveillance (P<0.001). After adjusting for study site, patient-level predictors of consistent surveillance included platelet count >150,000/mm(3) (hazard ratio (HR) 1.28; 95% confidence interval (CI): 1.05-1.56) and complete clinic visit adherence (HR 1.72, 95% CI: 1.11-2.63). Of 83 patients with HCC, 23 (27.7%) were detected beyond Milan criteria. Three (13%) had late-stage HCC due to the absence of screening, 4 (17%) due to the absence of follow-up, and 16 (70%) due to the absence of detection.

CONCLUSIONS: Surveillance process failures, including absence of screening or follow-up, are common and potentially contribute to late-stage tumors in one-third of cases. However, the most common reason for finding HCC at a late stage was an absence of detection, suggesting better surveillance strategies are needed.

23337478 [PubMed - indexed for MEDLINE]

Full text: Nature Publishing Group