The Importance Of Monitoring Vitamin D Levels In All Patients With Cirrhosis
March 16
Vitamin D deficiency is a well reported complication in chronic cholestatic liver disease such as primary biliary cirrhosis. While the prevalence and treatment of this deficiency has been addressed in many articles over the last decades, little is known of the vitamin D status in alcoholic liver cirrhosis.

A research article published in the World Journal of Gastroenterology addresses this question. The authors described the serum vitamin D status in a retrospective case series of patients with alcoholic liver cirrhosis compared to those with primary biliary cirrhosis.

The study showed that vitamin D deficiency is more frequent and severe in patients with alcoholic liver cirrhosis than in patients with primary biliary cirrhosis. Furthermore, it indicated that the degree of liver dysfunction, rather than the aetiology of cirrhosis, dictates the risk of vitamin D deficiency.

This study emphasizes the importance of monitoring vitamin D levels in all patients with cirrhosis. However, further studies are needed to find the most favourable form of vitamin D supplementation for these patients.

Reference:
Malham M, Jørgensen SP, Ott P, Agnholt J, Vilstrup H, Borre M, Dahlerup JF. Vitamin D deficiency in cirrhosis relates to liver dysfunction rather than aetiology. World J Gastroenterol 2011; 17(7): 922-925

Source:
Ye-Ru Wang
World Journal of Gastroenterology

Factors associated with hepatocellular carcinoma in Hep C

March's issue of Gut investigates maintenance peginterferon therapy and other factors associated with hepatocellular carcinoma in Hep C.

Interferon reportedly decreases the incidence of hepatocellular carcinoma in patients with chronic hepatitis C.

The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial showed that 4 years of maintenance therapy with pegylated interferon (peginterferon) does not reduce liver disease progression.

Dr Anna Lok and colleagues investigated whether peginterferon decreases the incidence of hepatocellular carcinoma in the HALT-C cohort over a longer posttreatment follow-up period.

The research team evaluated 1048 patients with chronic hepatitis C who did not have a sustained virologic response to therapy.
In treated patients, incidences were 8%
Gastroenterology

The patients were randomly assigned to groups given a half-dose of peginterferon or no treatment for about 4 years, and followed up for a median of 6 years.

The researchers found 88 patients who developed hepatocellular carcinoma.

The team reported that these patients included 37 of 515 who were given peginterferon, and 51 of 533 controls.

There was a significantly lower incidence of hepatocellular carcinoma among patients given peginterferon therapy who had cirrhosis, but not fibrosis, based on analysis of baseline biopsy samples.

The team found that after 7 years, the cumulative incidences of hepatocellular carcinoma in treated and control patients with cirrhosis were 8% and 24%, respectively.

In treated and control patients with fibrosis, incidences were 8% and 7%, respectively.

Treated patients with a 2 or more point decrease in the histologic activity index, based on a follow-up biopsy, had a lower incidence of HCC than those with unchanged or increased scores.

Dr Lok's team concludes, "Extended analysis of the HALT-C cohort showed that long-term peginterferon therapy does not reduce the incidence of hepatocellular carcinoma among patients with advanced hepatitis C who did not achieve sustained virological response."

"Patients with cirrhosis who received peginterferon treatment had a lower risk of hepatocellular carcinoma than controls."
Gastroenterol 2011: 140(3): 840-84914 March 2011

Second phase HCV RNA decline during telaprevir based therapy increases with drug effectiveness: Implications for treatment duration

Hepatology. 2011 Mar 7. doi: 10.1002/hep.24272.
Guedj J, Perelson AS.

Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos 87545, USA.

Abstract

Hepatitis C virus (HCV) RNA decay during antiviral therapy is characterized by a rapid first phase followed by a slower second phase. The current understanding of viral kinetics attributes the magnitude of the first phase decay to the treatment effectiveness, whereas the second phase decay is attributed to the progressive loss of infected cells. Here we analyzed data from 44 patients treated with telaprevir, a potent HCV protease inhibitor. Using a viral kinetic model that accounts for the pharmacokinetics of telaprevir, we found that the second phase slope of viral decline to be strongly correlated with the treatment effectiveness and to be roughly four-fold more rapid than has been reported with interferon-based therapies. Since telaprevir is not known to increase the death rate of infected cells, our results suggest the second phase slope of viral decline is driven not only by the death of infected cells but may also involve other mechanisms, such as a treatment effectiveness-dependent degradation of intracellular viral RNA. As a consequence of the enhanced viral decay caused by the high antiviral effectiveness of telaprevir, we predict that if drug resistance could be avoided by using an appropriate combination of antiviral agents, treatment duration needed to clear HCV might be dramatically shortened. Indeed, we predict that in 95% of fully compliant patients, the last virus particle should be eliminated by week 7 of therapy. If the remaining infected hepatocytes act as a potential reservoir for the renewal of infection, no more than 10 weeks of treatment should be sufficient to clear the infection in 95% of fully compliant patients. However, if patients miss doses, treatment duration would need to be extended.

(HEPATOLOGY 2011.).

Copyright © 2011 American Association for the Study of Liver Diseases.

PMID: 21384401 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/21384401



Antiviral activity, safety, and pharmacokinetics of danoprevir/ritonavir plus PEG-IFN α-2a/RBV in hepatitis C patients

J Hepatol. 2011 Feb 24

Gane EJ, Rouzier R, Stedman C, Wiercinska-Drapalo A, Horban A, Chang L, Zhang Y, Sampeur P, Nájera I, Smith P, Shulman NS, Tran JQ.

Auckland Clinical Studies, New Zealand.

Abstract

BACKGROUND AND AIMS:
Danoprevir (RG7227; ITMN-191) is a potent inhibitor of the HCV NS3/4A serine protease. The aims of this double-blind, placebo-controlled, multiple-ascending dose phase Ib study were to evaluate safety, tolerability, antiviral activity, resistance and pharmacokinetics of once- and twice-daily danoprevir in the presence of low-dose ritonavir (danoprevir/r) and in combination with peginterferon alfa-2a (40KD)/ribavirin in treatment-naive HCV genotype 1 patients.

METHODS:
Thirty eligible patients were enrolled into 3 cohorts and treated with danoprevir/r or placebo/r all in combination with peginterferon alfa-2a (40KD)/ribavirin for 15 days. Cohort 1 received danoprevir/r at 100/100mg twice daily; Cohort 2 200/100mg once daily; and Cohort 3 200/100mg twice daily.

RESULTS:
The median reductions in HCV RNA from baseline after 14 days of treatment (day 15) were -5.1, -4.8 and -4.6 log(10) IU/mL in Cohorts 1, 2 and 3, respectively, and -2.7 log(10) in placebo/r and peginterferon alfa-2a (40KD)/ribavirin recipients. Viral breakthrough was not observed in any patient. On day 15 HCV RNA was undetectable (<15 IU/mL) in 6/9 (67%), 4/8 (50%) and 8/8 (100%) patients in Cohorts 1, 2 and 3 respectively. When co-administered with low dose ritonavir, danoprevir concentrations reached steady state between 6 to 10 days of dosing. Danoprevir exposures increased more than dose proportionally between 100/100 mg and 200/100 mg. Danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin was well-tolerated with no safety-related discontinuations.

CONCLUSIONS: Danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin provides profound and robust reductions in serum HCV RNA, at substantially lower systemic exposures compared to those observed with higher doses of danoprevir in the absence of ritonavir. These results support further studies of danoprevir/r.

http://www.ncbi.nlm.nih.gov/pubmed/21354234
. What Is Danoprevir (ITMN-191) ? .Danoprevir (ITMN-191) = (RG7227 formerly R7227 also known as ITMN-191) is a investigational protease inhibitor, which targets the hepatitis C virus, used in combination with the standard of care for HCV infection; peg-interferon alpha-2a and ribavirin. It has demonstrated rapid and profound reductions in HCV RNA. Data has shown Direct-acting Drugs Danoprevir plus RG7128 Suppress HCV without Interferon. ..

Related; Hepatitis C:Update and Background On Danoprevir (RG7227/ITMN-191) .

What Is Ritonavir? Ritonavir is in a class of antiviral medications called protease inhibitors. Ritonavir as a (boosting agent). Ritonavir boosting is an option to enhance and improve pharmacokinetic profiles of protease inhibitors. It is well established in the treatment of HIV where it leads to more convenient dosing, reduced resistance development and high efficacy. .

Norvir (ritonavir); Full US Prescribing Information

Early menopause is associated with lack of response to antiviral therapy in women with chronic hepatitis, finds March's publication of Gastroenterology.

Chronic hepatitis C and liver fibrosis progress more rapidly in men and menopausal women than in women of reproductive age.

Professor Erica Villa and colleagues from Italy investigated the associations among menopause, sustained virologic response, and liver damage in patients with chronic hepatitis C.

The research team performed a prospective study of 1000 consecutive, treatment-naïve patients 18 years of age and older with compensated liver disease from chronic hepatitis C.

Liver biopsy samples were analyzed before patients received standard antiviral therapy.
Baseline levels of liver inflammation were higher among postmenopausal women
Gastroenterology

The research team collected data from 442 women on the presence, type, and timing of menopause, associated hormone and metabolic features, serum levels of interleukin-6, and hepatic tumor necrosis factor-α.

Postmenopausal women achieved sustained virological response less frequently than women of reproductive age, but as frequently as men.

By multivariate regression analysis, an independent significant predictor for women to not achieve a sustained virological response was early menopause.

In addition, levels of γ-glutamyl transpeptidase, infection with hepatitis C virus genotype 1 or 4, and cholesterol levels were independent significant predictor for women to not achieve a sustained virological response.

Early menopause was the only independent factor that predicted lack of a sustained virological response among women with genotype 1 hepatitis C virus infection.

The team observed that baseline levels of liver inflammation, fibrosis, steatosis, serum interleukin-6, and hepatic tumor necrosis factor-α were significantly higher among postmenopausal women than women of reproductive age.

Professor Villa and colleagues conclude, "Among women with chronic hepatitis C, early menopause was associated with a low likelihood of sustained virological response, probably because of inflammatory factors that change at menopause."

Gastroenterol 2011: 140(3): 818-82911 March 2011

Prevention of hepatitis infections in patients with inflammatory bowel disease
The latest issue of Alimentary Pharmacology & Therapeutics investigates the prevention and management of hepatitis B and C infections in patients with inflammatory bowel disease

Viral hepatitis is a very common infection.
The prevalence of both hepatitis B virus and hepatitis C virus infection in IBD patients is now similar to that of the general population.
All IBD patients should be screened for HBV markers at diagnosis.

Dr Gisbert and colleagues from Spain reviewed the prevention and management of hepatitis B virus and hepatitis C virus infection in inflammatory bowel disease (IBD).
The team performed bibliographical searches in MEDLINE up to 2010.

The research team found that liver dysfunction in IBD patients treated with immunosuppressants is more frequent and severe in hepatitis B than in hepatitis C carriers, and is associated with combined immunosuppression.

In patients receiving anti-TNF drugs, hepatitis B virus reactivation is common unless anti-viral prophylaxis is administered.

Hepatitis B surface antigen-positive patients should receive anti-viral prophylaxis before starting immunosuppressants.

The research team found that, as interferon might worsen underlying IBD, nucleoside/nucleotide analogues are preferred for anti-viral prophylaxis in patients with hepatitis B.

IBD patients should be vaccinated against hepatitis B virus at diagnosis.
The researchers noted that the response rate to hepatitis B virus vaccination is low, mainly in those receiving anti-tumor necrosis factor therapy.

The serological response to hepatitis B virus vaccine should be confirmed, and patients with an inadequate response should receive a second full series of vaccine.

Peginterferon for hepatitis C virus infection is as effective and safe as in non-IBD patients.
Dr Gisbert's team concudes, "The present manuscript poses a series of questions on the prevention and management of HBV/HCV infection in IBD, and attempts to answer them using scientific evidence in order to provide
practical conclusions for the clinician."

Aliment Pharmacol Ther 2011; 33: 619–633

18 February 2011

Incidence and Transmission Patterns of Acute Hepatitis C in the United States, 1982-2006 Ian T. Williams, PhD; Beth P. Bell, MD; Wendi Kuhnert, PhD; Miriam J. Alter, PhD
Arch Intern Med. 2011;171(3):242-248. doi:10.1001/archinternmed.2010.511

Background  Monitoring disease incidence and transmissionpatterns is important to characterize groups at risk for hepatitisC virus (HCV) infection. Clinical cases generally representabout 20% to 30% of all newly acquired infections.

Methods  We used sentinel surveillance to determine incidenceand transmission patterns for acute hepatitis C in the UnitedStates using data from 25 years of population-based surveillancein the general community. Acute cases of hepatitis C were identifiedfrom 1982 through 2006 by a stimulated passive surveillancesystem in 4 to 6 US counties. Cases were defined by a discreteonset of symptoms, alanine aminotransferase (ALT) levels greaterthan 2.5 times the upper limit of normal (xULN), negative findingsfor serologic markers for acute hepatitis A and B, and positivefindings for antibody to HCV or HCV RNA. Incidence and frequencyof reported risk factors were the main outcome measures.

Results  Of 2075 patients identified, the median age was31 years, 91.5% had ALT values greater than 7 x ULN,77.3% were jaundiced, 22.5% were hospitalized, and 1.2% died.Incidence averaged 7.4 per 100 000 individuals (95% confidenceinterval [CI], 6.4-8.5 per 100 000) during 1982 to 1989then declined averaging 0.7 per 100 000 (95% CI, 0.5-1.0per 100 000) during 1994 to 2006. Among 1748 patients interviewed(84.2%), injection drug use (IDU) was the most commonly reportedrisk factor. The average number of IDU-related cases declinedparalleling the decline in incidence, but the proportion ofIDU-related cases rose from 31.8% (402 of 1266) during 1982to 1989 to 45.6% (103 of 226) during 1994 to 2006. Among IDU-relatedcases reported during 1994 to 2006, 56 of 61 individuals (91.8%)had been in a drug treatment program and/or incarcerated.

Conclusions  The incidence of acute HCV declined substantiallyover the 25 years of population-based surveillance. Despitedeclines, IDU is the most common risk factor for new HCV infection.

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