September 25, 2010

Prevalence of Vitamin D Deficiency in Chronic Liver Disease

Authors: Arteh, J.1; Narra, S.2; Nair, S.3

Source: Digestive Diseases and Sciences, Volume 55, Number 9, September 2010 , pp. 2624-2628(5)

Publisher: Springer

Abstract:
 
Vitamin D deficiency has been associated with cholestatic liver disease such as primary biliary cirrhosis. Some studies have suggested that cirrhosis can predispose patients to development of osteoporosis because of altered calcium and vitamin D homeostasis. The aim of this study was to determine the prevalence of vitamin D deficiency in patients with chronic liver disease.

One hundred and eighteen consecutive patients (43 with hepatitis C cirrhosis, 57 with hepatitis C but no cirrhosis, 18 with nonhepatitis C-related cirrhosis) attending the University of Tennessee Hepatology Clinic had their 25-hydroxyvitamin D level measured. Severity of vitamin D deficiency was graded as mild (20-32 ng/ml), moderate (7-19 ng/ml) or severe (<7 ng/ml), normal being >32 ng/ml.

Of patients, 109/118 (92.4%) had some degree of vitamin D deficiency. In the hepatitis C cirrhosis group, 16.3% (7/43) had mild, 48.8% (21/43) had moderate, and 30.2% (13/43) had severe vitamin D deficiency. In the hepatitis C noncirrhotic group, 22.8% (19/57) had mild, 52.6% (30/57) had moderate, and 14% (8/57) had severe vitamin D deficiency. In the nonhepatitis C-related cirrhosis group, 38.9% (7/18) had mild, 27.8% (5/18) had moderate, and 27.8% (5/18) had severe vitamin D deficiency. Severe vitamin D deficiency (<7 ng/ml) was more common among patients with cirrhosis compared with noncirrhotics (29.5% versus 14.1%, P value = 0.05). Female gender, African American race, and cirrhosis were independent predictors of severe vitamin D deficiency in chronic liver disease.

Vitamin D deficiency is universal (92%) among patients with chronic liver disease, and at least one-third of them suffer from severe vitamin D deficiency. African American females are at highest risk of vitamin D deficiency.

Keywords: Vitamin D deficiency; Chronic liver disease; Cirrhosis

Document Type: Research article

DOI: 10.1007/s10620-009-1069-9

Affiliations: 1: Department of Internal Medicine, University of Tennessee Health Science Center, Memphis, TN, USA 2: Division of Gastroenterology and Hepatology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA 3: Division of Gastroenterology and Hepatology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA, Email: snair@utmem.edu

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Types of medications that put you at risk for liver disease

by Dawn Hawkins

Liver damage can occur for many different reasons but one that we may overlook is the fact that the medications we put in our body can cause liver damage. Though many cases can be reversed when liver damage has occurred, there are cases that drugs can cause permanent liver damage. It is important to know the dangers that medications can do to your liver so that you don't end up with liver disease that you can't reverse.

Drugs that can Cause Liver Damage

Acetaminophen- Acetaminophen is found in medications such as Tylenol. These are over the counter drugs for headaches. Although occasional use probably will not cause long-term damage, taking these drugs everyday or overdosing on them can cause long-term damage to your liver.

Statins- Drugs with Statins in them can cause liver damage in patients it is prescribed to. Statins are used to lower bad cholesterol in patients who are at risk for heart disease and stroke. Though the risk is low, it is still possible that patients taking Statins can develop liver problems due to using the drug.

Niacin- This is also used to lower cholesterol levels in patients who are at risk for heart disease. It can also cause liver problems. In some cases, it could even cause liver failure. That doesn’t mean that you shouldn't take them if the doctor says to, but you should discuss this possibility with your doctor to make sure you aren't at a higher risk for liver damage because of taking them.

Cordarone- This drug is used to treat patients with irregular heartbeats. It can also cause liver damage. The damage can vary from very mild to very serious. It is important that you discuss options with your doctor if you are at a higher risk for developing irreversible signs of liver damage.

N-Saids- N-Saids are pain relievers for such conditions as arthritis. Although when you take N-Said pain relievers as prescribed by the doctor won't give you liver disease, if you have liver disease prior to taking N-Saids can raise your risk. Liver disease in patients that take N-Saids for pain relief can be worsened by using the drug.

Vitamin A- High doses of Vitamin A over an extended period can cause liver damage. People who are taking high doses of Vitamin A on a regular basis are putting themselves at high risk for liver disease. If you are one of those people, consider lowering your dosage and intake of Vitamin A so that you lower your risk of getting liver disease.

Liver disease can be very dangerous. Those who get liver disease due to their medication can often reverse the effects that have already occurred so that there is no long-term damage to the liver. It can be as simple as discontinuing the use of these medications. Talk to your doctor to see if there are other alternatives that won't put you at risk for liver damage. There are other medications that can cause possible liver damage so be aware of that fact and make yourself aware of any drugs that you are putting into your body no matter how innocent the drug may seem.

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Novel method for detection of fatty liver disease receives international recognition

2010/9/23

A novel method for the early diagnosis of non-alcoholic fatty liver disease (NAFLD) was published this August in the Journal of Proteome Research. The new analysis test, based on metabolomics technology, was devised by a consortium of research centres, universities and business companies, and led by CIC bioGUNE and Owl Genomics. From this method a new efficacious tool will be developed and which will be shortly available, when OWL Genomics begins marketing the product in Spain.

Apart from CIC bioGUNE and Owl Genomics, the development of this novel project also involved the participación of INSERM and a number of university hospitals (Hospital APHP Pitié Salpêtrière, the Pierre y Marie Curie University in Paris, the University Hospital Centre in Nice and the Sophia-Antipolis University in the same French city, the Vanderbilt University in Nashville, USA, the University of South California (Los Angeles, USA), el Hospital Clínico and IDIBAPS (Barcelona) and the University of Alcalá de Henares in Spain). Likewise, HEPADIP (www.hepadip.org) and CIBERehd (www.ciberehd.es) form part of the projects and have the support of the European Commission and the Carlos III Institute of Health (Spain).

Obesity is a serious risk factor in NAFLD, a progressive disease that goes from the simple accumulation of fat in the liver (steatosis) to more severe necroinflammatory complications such as non-alcoholic steatohepatitis (NASH), affecting 24% of the US and European population. While only a small number of patients suffering from NAFLD develop cirrhosis and hepatocellular carcinoma (HCC), the increasing tendency to obesity could give rise to an increase in the rate of these, more serious, diseases, which represent a greater risk to health. This is why early diagnosis is crucial for identifying patients with NAFLD, in order to evaluate the risk of the disease progressing and to monitor the response to treatment.

The most commonly employed methods for diagnosing NAFLD today are those involving ultrasounds and magnetic resonance imaging techniques, and the histological examination of a liver biopsy sample. Nevertheless, imaging techniques are expensive and not very precise (not being able to differentiate between a NASH and a simple steatosis), while the liver biopsy is an expensive and invasive technique with a subjective procedure associated with potential complications and prone to sampling errors.

The metabolomics-based blood analysis devised by OWL Genomics and CIC bioGUNE does detect the difference between a simple steatosis and NASH. «The results of these blood analyses can help health care professionals to diagnose NAFLD and tell how the patient is responding to treatment», stated José Mato, Director of CIC bioGUNE and researcher at CIBERehd. «We believe that this is the first application of a new experimental approach to determine a metabolomic profile of the blood, thus providing identification of possible biomarkers for any liver disease and constituting a magnificent example of translational research », added Mr Mato.

Type of genetically modified mouse

In order to carry out the work published in the Journal of Proteome Research, the scientists used a type of genetically modified mouse that developed a fatty liver spontaneously, and so parallel studies could be undertaken and the metabolic profile of both human and mouse blood could be determined. Making use of this approach, a series of metabolite biomarkers in NAFLD common to humans and mice was identified. This metabolic footprint of NAFLD in the blood includes free fatty acids, phospholipids and biliary acids.

After establishing the metabolic footprint of NAFLD in the blood, the scientists focused on the identification of biomarkers that distinguish human steatosis and NASH. Using blood samples taken from biopsies of patients with steatosis and NASH, the scientists identified various biomarkers that distinguish these two different conditions of the liver. This list of biomarkers of NASH in the blood includes other subtypes of phospholipids (diacylglycerol phospholipids and ether glycerophospholipids) and arachidonic acid. «This is the first global serological study determining metabolites that establishes a link between steatosis demonstrated through biopsy and NASH histology for a non-diabetic human population with a similar body mass index», stated Mr Jonathan Barr, head of the OWL Genomics research team.

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Liver Disease Reported in Three Nitrofurantoin Patients

Date Published: Friday, September 24th, 2010

A new study has linked the use of the antibiotic nitrofurantoin with autoimmune hepatitis, a type of liver injury. Nitrofurantoin, which is primarily used in the treatment and prevention of urinary tract infections, is sold under the brand names Furadantin, Macrobid, Macrodantin, Nitrofur Mac, Nitro Macro, Nifty-SR, Martifur-MR and Urantoin.

According to a case study in the Journal of Medical Case Reports, three women (aged 65, 42 and 74 years old) developed autoimmune hepatitis after treatment with nitrofurantoin. All were receiving long-term nitrofurantoin to prevent recurrent urinary tract infections.

Two of the patients presented with jaundice, and one required a prolonged hospital admission for liver failure. In all three patients nitrofurantoin was withdrawn, and long-term immunosuppressive therapy with prednisolone and azathioprine or mycophenolate was given. Fortunately, the patients responded well, with liver biochemistry returning to normal within a few months.

The authors of the report pointed out that although nitrofurantoin rarely causes autoimmune hepatitis, this antimicrobial is increasingly used as long-term prophylaxis against recurrent urinary tract infection. They cautioned general practitioners and urologists who prescribe long-term nitrofurantoin therapy to be aware of this adverse effect.

Autoimmune hepatitis is a disease in which the body’s immune system attacks liver cells. This immune response causes inflammation of the liver, also called hepatitis. Autoimmune hepatitis is usually quite serious and, if not treated, gets worse over time. Autoimmune hepatitis is typically chronic, meaning it can last for years, and can lead to cirrhosis—scarring and hardening—of the liver. Eventually, liver failure can result. About 70 percent of those with autoimmune hepatitis are female.

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Hong Kong: Alert on sealing defect in PegIntron Redipen single dose delivery system

Submitted by editor on September 25, 2010 - 20:30

The Department of Health (DH) was yesterday (September 24) informed by Schering-Plough SOL Limited (Schering-Plough), the registration holder of a drug delivery system PegIntron Redipen, of a sealing defect involving glass cartridges in the system.

PegIntron Redipen is a single-dose delivery system to deliver peginterferon alfa-2b, a prescription drug used for the treatment of hepatitis C.There are 5 registered preparations in Hong Kong: PegIntron Redipen 50mcg per 0.5ml (HK-55115), PegIntron Redipen 80mcg per 0.5ml (HK-55119), PegIntron Redipen 100mcg per 0.5ml (HK-55118), PegIntron Redipen 120mcg per 0.5ml (HK-55117) and PegIntron Redipen 150mcg per 0.5ml (HK-55116).

According to Schering-Plough, the defect is related to individual Redipen device and it may affect the product quality, with possible safety consequence.Based on available information in hand, it is estimated that the defect occurred with a frequency of about 3 in 20,000.

Records in Schering-Plough showed that the products have been supplied to 10 medical practitioners and three local hospitals.Due to the low prevalence of the defect and no readily available stock replacement, Schering-Plough proposed to send medical representatives to visit all involved doctors and hospitals to inspect their stock before being utilised.Healthcare professionals should only administer the products to patients after Schering-Plough has confirmed that their products are satisfactory.

After risk assessment, DH endorsed the above proposal.Meanwhile, DH is also liaising with leading overseas authorities about the issue and will continue to monitor the wholesaler¦s inspection.

Schering-Plough has set up a hotline, 3791 2987, for public enquiries.

Patients should consult healthcare professionals if in doubt, he said.

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Prevalence and factors associated with significant liver fibrosis assessed by transient elastometry in HIV/hepatitis C virus-coinfected patients

Authors: Pineda, J. A.1; González, J.2; Ortega, E.3; Tural, C.4; Macías, J.1; Griffa, L.5; Burgos, A.5
Source: Journal of Viral Hepatitis, Volume 17, Number 10, October 2010 , pp. 714-719(6)
Publisher: Wiley-Blackwell

Abstract:
 
Summary. 

Transient elastometry (TE) could provide a more accurate evaluation of the frequency and risk factors of liver fibrosis in hepatitis C virus (HCV) infection than that based on biopsy. The aim of this study was to assess the prevalence of and factors associated with significant liver fibrosis in a large population of HIV/HCV-coinfected patients. HIV/HCV-coinfected patients, who had participated in a cross-sectional, multicenter, retrospective study of liver fibrosis using noninvasive markers and in whom a determination of liver stiffness (LS) by TE was available, were included in this analysis. Factors potentially associated with significant fibrosis (LS ≥ 9 kPa) were analyzed. One thousand three hundred and ten patients fulfilled the inclusion criteria, 526 (40%) of them showed LS ≥ 9 kPa and 316 (24%) cirrhosis (LS ≥ 14 kPa). The factors independently associated with significant fibrosis [adjusted odds ratio (95% confidence interval, P value) were the following: older age [1.04 (1.01-1.07), 0.002], daily alcohol intake > 50 g/day [1.58 (1.10-2.27), 0.013] and the length of HCV infection [1.03 (1.00-1.06), 0.023]]. A CD4 cell count lower than < 200 per mm3 [1.67 (0.99-2.81), 0.053] and HCV genotype 4 [0.66 (0.42-1.02), 0.066] were marginally associated with LS ≥ 9 kPa. In conclusion, the prevalence of cirrhosis in HIV/HCV-coinfected patients seems to be higher than previously reported in studies based on liver biopsy. Older age, alcohol consumption and lower CD4 cell counts are related with significant fibrosis. The latter association supports an earlier starting of antiretroviral therapy in this setting.

Keywords: hepatitis C; HIV; liver fibrosis; transient elastometry

Document Type: Research article

DOI: 10.1111/j.1365-2893.2009.01229.x

Affiliations: 1: Unit of Infectious Diseases, Hospital Universitario de Valme, Seville 2: Hospital Universitario La Paz, Madrid 3: Hospital Clínico, Valencia 4: Hospital Germans Trias i Pujol, Badalona 5: Abbott Laboratories, Madrid, Spain

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S-adenosyl methionine (SAMe) improves early viral responses and interferon-stimulated gene induction in hepatitis C nonresponders

Gastroenterology. 2010 Sep 17. [Epub ahead of print]

Feld JJ, Modi AA, El-Diwany R, Rotman Y, Thomas E, Koh C, Cherepanov V, Heller T, Ghany MG, Park Y, Hoofnagle JH, Liang TJ.

Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD; Toronto Western Hospital Liver Center, University Health Network, University of Toronto, Toronto, Canada.

Abstract

BACKGROUND & AIMS: Fewer than half of patients infected with Hepatitis C virus (HCV) achieve sustained viral clearance after peginterferon and ribavirin therapy. S-adenosyl methionine (SAMe) increases interferon signaling in cell culture. We assessed the effect of SAMe on the kinetics of the early anti-viral response and interferon signaling in patients that did not respond to previous therapy (nonresponders) and investigated its mechanisms.

METHODS: Nonresponders with HCV genotype-1 were given 2 weeks of peginterferon alfa-2a and ribavirin (Course A, baseline/control). After a 1-month period, patients received SAMe (1600 mg daily) for 2 weeks and then peginterferon and ribavirin for 48 weeks (Course B; completed by 21 of 24 patients). Viral kinetics and interferon-stimulated gene (ISG) expression in peripheral blood mononuclear cells (PBMCs) were compared between courses.

RESULTS: The decrease in HCV RNA from 0 to 48 hours (phase 1) was similar before and after administration of SAMe. However, the slope increased for the second-phase decrease in HCV between courses A and B (Course A=0.11±0.04 log(10)IU/mL/week, Course B=0.27±0.06; P=0.009); 11 patients (53%) achieved an early virological response and 10 (48%) had undetectable HCV RNA by week 24. Induction of ISGs in PBMCs was significantly greater after Course B. In cultured cells, SAMe increased induction of ISGs, compared with only peginterferon and ribavirin, and the antiviral effects of interferon by increasing STAT1 methylation, which might promote binding of STAT1 to DNA.

CONCLUSIONS: The addition of SAMe to peginterferon and ribavirin improves the kinetics of the early anti-viral response and induces ISGs in patients with HCV genotype 1 that do not respond to interferon therapy. SAMe might be used with peginterferon-based therapies in patients with chronic HCV infections.

PMID: 20854821 [PubMed - as supplied by publisher]

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Hepatitis C virus: Prevention, screening, and interpretation of assays

doi: 10.3949/ccjm.77a.09162
Cleveland Clinic Journal of Medicine September 2010 vol. 77 9 616-626

MAZEN ALBELDAWI, MD
Department of Internal Medicine, Cleveland Clinic

ERNESTO RUIZ-RODRIGUEZ, MD
Department of Internal Medicine, Cleveland Clinic

WILLIAM D. CAREY, MD
Transplant Center and Digestive Disease Institute, Cleveland Clinic; Director, Center for Continuing Education; Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

ADDRESS: William D. Carey, MD, Department of Gastroenterology and Hepatology, A51, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail careyw@ccf.org
 
Abstract
 
Patients at risk of hepatitis C virus (HCV) infection should be screened for it so that they can be treated and potentially cured, or can at least avoid transmitting the disease to others. The authors describe why and how to screen for HCV and how to interpret the test results.
 
Key points
 
Patients who should be screened include intravenous drug abusers, people infected with human immunodeficiency virus, patients with unexplained elevated alanine aminotransferase levels, infants born to infected mothers, and people with infected sexual partners.
 
Patients at risk of HCV infection should be tested for anti-HCV antibody using an enzyme immunoassay (EIA).
 
Positive results on anti-HCV EIA testing should be confirmed with an assay for HCV RNA.
 
HCV genotyping can help predict the response to therapy. Genotypes 2 or 3 are more likely to respond to therapy than genotype 1

Screening for hepatitis c virus (HCV) infection in high-risk populations can identify, early on, people at risk of progressive liver disease who may benefit from antiviral therapy and counseling. The US Centers for Disease Control and Prevention (CDC) recommends that all people be assessed for HCV risk factors and that those with risk factors be screened for HCV antibodies (anti-HCV),1 and members of the national societies of gastroenterology and hepatology have endorsed this recommendation.2

Unfortunately, rates at which primary care patients are assessed for risk factors and the rates at which patients at higher risk are screened remain below the goals set by the CDC.3–6 All health care practitioners need to understand how to establish or exclude a diagnosis of HCV infection and to interpret the tests correctly.

WHY SCREEN FOR HCV?
 
HCV infection is a major public health problem and a leading cause of chronic liver disease. In the United States, an estimated 3.2 million persons (1.3% of the population) have been infected.7 However, in the inner-city primary care setting the rate of HCV infection is as high as 8%, and in Veterans Administration populations it is 17%.8,9 The worldwide prevalence of HCV infection is 2.0%, corresponding to 140 million persons.

Screening of blood products has led to a decline in the incidence of acute hepatitis C since the late 1980s, although rates have reached a plateau in recent years (FIGURE 1).10

Approximately 20% of patients infected with HCV develop a serious sequela, such as severe fibrosis, cirrhosis, end-stage liver disease, or hepatocellular carcinoma. Currently, HCV infection causes an estimated 8,000 to 10,000 deaths annually in the United States, and that number is predicted to triple in the next 10 to 20 years. Furthermore, HCV-related disease is the leading indication for liver transplantation in the United States, and it is estimated to cost $600 million to $1 billion annually in medical expenses and loss of work.8

Screening can reduce adverse outcomes

HCV screening has several potential benefits. By detecting HCV infection early, screening facilitates virologic suppression, as treatment earlier in the course of the disease is more effective than later.11,12 Further, early diagnosis together with patient education and subsequent lifestyle modifications may reduce the risk of transmission of HCV infection to other people.13,14

Antiviral therapy with pegylated interferons and ribavirin can cure hepatitis C in up to 90% of cases, depending on the viral genotype15–17 (see discussion of HCV genotypes below). In addition, treatment slows the progression of fibrosis.18 The incidence of hepatocellular carcinoma is lower in patients who achieve a sustained virologic response to antiviral therapy.19 Finally, antiviral therapy prolongs survival.20

New drug therapies are being developed and may, we hope, be even more effective than current drugs. Inhibitors of HCV-specific enzymes such as NS3/4 protease, combined with pegylated interferons and ribavirin, are in phase III clinical trials. These drugs are expected to be available for clinical practice within the next 2 years.21–23 Additionally, nitazoxanide (Alinia), an inducer of eIF2a and PKR phosphorylation, has been shown to increase the treatment response to HCV genotype 4. Studies24 are currently under way in patients infected with HCV genotype 1.

Screening is cost-effective

The National Hepatitis Surveillance Program25 calculated the cost of screening for HCV to be $1,246 per case detected. However, a more vigorous analysis of the same data using several different models to incorporate risk factors based on history revealed costs between $357 and $1,047 per case detected. This compares favorably with the cost of screening for other diseases that physicians routinely screen for.


FIGURE 1 Incidence of acute hepatitis C, by year—United States, 1992–2007*
DANIELS D, GRYTDAL S, WASLEY A; US CENTERS FOR DISEASE CONTROL AND PREVENTION. SURVEILANCE FOR ACUTE VIRAL HEPATITIS—UNITED STATES, 2007. MMWR SURVEILL SUMM 2009; 58:SS-3.

Antiviral combination therapy for chronic hepatitis C has been shown to be effective in terms of quality-adjusted life-years gained and cost-effectiveness in several studies.26–28

HOW TO SCREEN

The optimal approach to screening for HCV is to look for a history of risk of exposure to the virus and then to test those who have risk factors (TABLE 1).

To test everyone in the general population would be neither cost-effective nor practical, which is why the CDC recommends that serologic screening for HCV infection be done only in people who have well-established risk factors for it.1,5

Therefore, screening should begin by obtaining a relevant medical history as part of a routine health evaluation. But how should this be done?

McGinn et al29 asked 1,000 patients attending an inner-city clinic to fill out a 27-item questionnaire assessing five “domains” of risk factors for HCV: work, medical, exposure, personal care, and social history. Afterward, they tested all 1,000 patients. They found that the risk factors that best predicted positive results on testing were in three domains: medical (eg, blood transfusions, dialysis, other medical procedures, and elevated liver enzymes), exposure (past contact with another person’s blood), and social history (eg, illicit drug use, incarceration, and sexual activity).

The National Hepatitis Surveillance Program25 explored the cost and yield of several screening strategies for hepatitis C, ie, testing only in patients who had a greater than 7% likelihood of infection based on an empirically derived mathematical model; testing only if significant risk factors were revealed in a simple questionnaire; or testing only if the alanine aminotransferase (ALT) level was elevated. The predictive mathematical model was the most effective and efficient means of deciding who should be tested.

Unfortunately, such a model is too cumbersome to be clinically applicable, and clinical prediction tools for HCV screening have been underused.

GROUPS AT HIGH RISK OF HCV

Groups at risk of HCV infection can be classified as being at high, intermediate, or low risk. The American Association for the Study of Liver Diseases2 rates the level of evidence for screening in all of the following risk groups as class I (ie, there is evidence or general agreement that it is beneficial, useful, and effective) and level B (ie, the data are derived from non-randomized studies).

Intravenous drug abusers

Intravenous drug abuse is the strongest independent risk factor for HCV infection.30–33 It has been the main route of HCV infection over the past decades and currently accounts for 60% of HCV transmission in the United States.7,10,34–37

Hemophilia patients treated with clotting factor concentrates produced before 1987

HCV seroprevalence is very high in patients with hemophilia who received infusions of plasma-derived clotting factor concentrates before 1987.38 In these patients, the HCV genotypes are predominantly 1 and 3, and to a lesser extent genotype 2.39,40 These genotypes likely reflect the prior exposures of the plasma donors.41 (See discussion of HCV genotypes below.) Individuals receiving clotting factor concentrates prepared from plasma pools were at high risk of HCV infection until effective procedures to inactivate viruses were introduced in 1985 (factor VIII) and 1987 (factor IX).42

People infected with HIV

About 25% of people infected with human immunodeficiency virus (HIV) in the Western world also have chronic HCV infection.43 Progression of liver disease is accelerated in HIV-HCV coinfection, and the risk of cirrhosis is twice as high.44

However, about 6% of HIV-positive patients fail to develop HCV antibodies when infected. Thus, HCV RNA should be assessed in HIV patients with unexplained liver disease who are negative for anti-HCV.45

The distribution of HCV genotypes in HIV-infected patients reflects the route of transmission. Genotype 1b accounts for 66% of posttransfusion HCV infections, while genotypes 1a and 3a are more common in intravenous drug users.

GROUPS AT INTERMEDIATE RISK OF HCV

Recipients of blood transfusions before 1992

Before 1992, blood transfusions carried a risk of HCV infection of up to 7% with each unit transfused. Prospective studies of transfusion recipients in the United States found that rates of posttransfusion hepatitis in the 1960s exceeded 20%,36 since most patients received multiple units of blood.

In the mid-1970s, before HCV had been identified, available diagnostic tests indicated that 90% of cases of posttransfusion hepatitis were not caused by hepatitis A or hepatitis B viruses. By this time, the move to all-volunteer blood donors instead of paid donors had reduced the risk of posttransfusion hepatitis to 10%.22,37,46

Although non-A, non-B hepatitis was first recognized because of its association with blood transfusion, population-based sentinel surveillance showed that it accounted for 15% to 20% of cases of community-acquired viral hepatitis in the United States.35 The advent of molecular cloning in 1988 indicated that non-A, non-B hepatitis was primarily caused by HCV.47–52

Screening of blood has reduced the rate of posttransfusion hepatitis C by a factor of about 10,000, to a current rate of 1 per million transfusions.53 The few cases that still occur are due to newly infected people donating blood before they have developed antibodies to the virus, which can take up to 8 weeks.54

Recipients of solid-organ transplants before 1992

Before organ donors were screened for HCV, recipients of solid-organ transplants from infected donors had a high risk of acquiring HCV infection. Transmission rates in different cohorts ranged from 30% to 80%.55 In an attempt to improve the safety of organ transplantation, many transplant centers now screen donors for anti-HCV and test for HCV RNA for verification.

A related problem is pre-existing HCV infection in transplant recipients. Izopet et al56 reported that, in renal transplant recipients with preexisting HCV infection, the HCV RNA titer rose about 10 times (1 log) higher after transplantation, owing to the immunosuppressive drugs that transplant recipients must take. Although this higher viral load does not affect the progression of fibrosis in all patients, the effect of immunosuppressive therapy on liver disease results in a worse outcome for some, and it reduces survival beginning in the second decade after kidney transplantation.56

Additionally, treatment of HCV infection in transplant recipients may pose a challenge, as those receiving immunosuppressive therapy with tacrolimus (Prograf) or cyclosporine (Sandimmune) may develop some degree of renal insufficiency, complicating the use of ribavirin (Rebetol) and subjecting patients to a higher risk of severe anemia. Furthermore, interferon therapy increases the risk of renal allograft rejection and, accordingly, is not often used in renal transplant recipients.

Patients with unexplained elevated aminotransferase levels

HCV infection affects an estimated 1.8% of the general population, but the rate is much higher in people with ALT levels over 40 U/L. Most patients with chronic hepatitis C have no symptoms or only mild symptoms and minimally elevated levels of ALT and aspartate aminotransferase (AST)—ie, two to five times higher than the upper limit of normal.

The first step in the workup of aminotransferase elevations is to confirm the abnormality by repeating the blood test. If an elevation is confirmed, further investigation is warranted. A directed history and physical examination is important and may disclose risk factors, raising clinical suspicion of a particular disease.

Some caveats: The proportion of patients with HCV viremia who have abnormally high aminotransferase levels ranges between only 54% and 66%.57–59 In patients with risk factors for HCV infection and abnormal liver enzyme levels, HCV infection is probable but not certain. Also, liver enzyme tests do not reveal the extent of hepatic injury or reflect the true status of hepatic function.60

Infants born to infected mothers

Children born to HCV-positive women should be tested for anti-HCV no sooner than age 12 months, when passively transferred maternal anti-HCV declines below detectable levels. If earlier diagnosis of HCV infection is desired, a real-time polymerase chain reaction (PCR) test for HCV RNA can be done at or after the infant's first “well-child” visit at age 1 to 2 months.

If positive for either anti-HCV or HCV RNA, children should be evaluated for liver disease, and those with persistently elevated ALT levels should be referred to a specialist for medical management.2,5

GROUPS AT LOW RISK OF HCV

People who have had sexual relations with multiple or infected partners

Sexual activity is associated with a low but measurable risk of transmission of HCV. Large population-based studies, including the National Hepatitis Surveillance Program,25 found an independent association between HCV infection and having sexual relations with multiple partners or with a partner who is infected with HCV.

The CDC reported that 15% to 20% of patients with acute hepatitis C had a history of sexual exposure but no other risk factors. Two-thirds of them had an anti-HCV-positive sexual partner, and one-third reported having had more than two partners in the 6 months before illness.5

More data are needed to determine the risk of and the factors related to transmission of HCV between long-term steady partners as well as in persons with high-risk sexual practices, including whether other sexually transmitted diseases promote transmission of HCV by influencing viral load or modifying mucosal barriers.

Health care workers exposed to HCV, eg, by needlestick

The prevalence of HCV infection in health care workers is no greater than that in the general population, averaging 1% to 2%, and is actually 10 times lower than that of hepatitis B virus infection.47,48,61,62

However, within the disciplines, some groups have a higher prevalence of HCV infection, suggesting that some occupations carry a higher risk. In two US studies, the prevalence of HCV infection was higher in oral surgeons (2.0% and 9.3%) than in other dentists (0.7% and 0.97%).63,64

In a single study that evaluated risk factors for infection, a history of needlestick injury was the only occupational risk factor that was independently associated with HCV infection.65 The average incidence of anti-HCV seroconversion after a needlestick or after an injury with a sharp object contaminated by an HCV-positive source is 1.8% (range 0%–7%).66–69

Although no studies of incidence have documented transmission via mucous membrane or nonintact skin exposures, transmission of HCV from blood splashes to the conjunctiva have been described.70,71

Refer to TABLE 2 for postexposure follow-up recommendations.

It is worth noting that exposure to blood from unclean needles used in tattooing or body piercing also confers a risk of HCV infection.

SEROLOGIC SCREENING TESTS FOR HCV

FIGURE 2 is an algorithm for laboratory investigation of suspected HCV infection,72 TABLE 3 summarizes how to interpret the test results, and TABLE 4 lists how the various tests are used in diagnosing HCV infection, estimating the prognosis, and treating HCV infection.73

Two classes of assays are used to diagnose HCV infection:

■ Serologic assays that detect specific antibody to HCV (anti-HCV)

■ Molecular assays that detect viral RNA.

Initial serologic screening tests for anti-HCV

Enzyme immunoassays (EIAs) are reproducible, inexpensive, and approved by the US Food and Drug Administration for diagnosing HCV infection. They are suitable for screening populations at risk and are recommended as the initial serologic test for patients with clinical liver disease.

Two EIAs are approved for clinical use:

■ Abbott HCV EIA 2.0 (Abbott Laboratories, Abbott Park, IL)

■ Ortho HCV Version 3.0 enzyme-linked immunosorbent assay (ELISA) (Ortho-Clinical Diagnostics, Rochester, NY).

One enhanced chemiluminescence immunoassay is also approved:

■ Vitros Anti-HCV assay (Ortho-Clinical Diagnostics). In practical terms, this test is equivalent to the two EIAs, and the discussion below about EIAs applies to this test as well.

These third-generation tests are highly sensitive (> 99%) and specific (99%) in immunocompetent patients, and eliminate the need for a confirmatory immunoblot assay in patients with clinical liver disease, particularly those with risk factors for HCV infection.

False-positive results are rare now, but they were common with earlier generations of these assays. Most false-positive results occur in patients with autoimmune liver disease or hypergammaglobulinemia who have normal liver enzyme levels and no risk factors for HCV infection. In fact, all positive anti-HCV results should be followed up with an HCV RNA test.

False-negative results are also uncommon, usually occurring only in immunosuppressed patients (eg, organ transplant recipients and HIV-positive patients) and in patients on long-term hemodialysis. Therefore, patients with a history of hemodialysis should be considered for an HCV RNA assay rather than an EIA. Measurement of ALT will not be useful because ALT levels are lower in patients with end-stage renal disease. In most other clinical situations, the HCV EIA is an outstanding screening test for HCV infection because of its high sensitivity and relatively low cost (< $50).

Although the specificity of these tests is good, the predictive value of a positive result varies substantially by the pretest probability of HCV infection. For example, in a group of injection-drug users who are very likely to have ongoing or remote infection, all positive HCV EIA results are likely truly positive.74 On the other hand, in healthy blood donors, up to half of all positive third-generation EIA tests are falsely positive.75

Important points

■ A positive anti-HCV antibody test does not distinguish acute from chronic disease or active from past infection, nor is it a sign of immunity or protection.

■ A positive anti-HCV EIA requires HCV RNA measurement to discriminate between current infection on the one hand, and either resolved HCV infection or a false-positive result on the other.

■ A positive EIA anti-HCV test is a marker that hepatitis C may be present, and it must be followed by confirmatory HCV RNA testing.

■ Physicians should be mindful of the potential tribulations associated with false-positive tests. A false-positive test may result in harm to patients that is difficult to measure, such as anxiety, labeling in the medical record, and detrimental effects on close relationships.

CONFIRMATORY TESTING WITH ASSAYS FOR HCV RNA

As stated above, a positive result on an anti-HCV EIA needs to be confirmed with an assay for HCV RNA, of which there are two types, ie, qualitative and quantitative.

Each involves trade-offs. Qualitative assays are more sensitive and detect more cases, but they provide no information about the amount of virus (viral load). Quantitative assays are less sensitive, so a negative result does not completely exclude hepatitis C, although they can still can detect 95% of cases. They do, however, measure the viral load.

Therefore, the type of test to use depends on the patient’s risk profile, the goals of testing, and the setting in which future care will be provided. The primary objective when a patient has a positive EIA test is to determine whether he or she has ongoing infection, a goal most expeditiously achieved using a qualitative assay. However, since a quantitative assay can detect the vast majority of cases of active HCV infection, many clinicians select this as the test of first choice when the probability of HCV is high (eg, in a patient with risk factors and abnormal liver tests). If the pretest probability is low, a qualitative assay is the better choice.

Many commercial assays are available for detecting (qualitative assays) or measuring (quantitative assays) HCV RNA.

Qualitative HCV RNA assays

The approved qualitative assays are:

■ Amplicor HCV Test, version 2.0 (Roche Molecular Diagnostics, Pleasanton, CA)

■ Cobas Amplicor HCV Test, version 2.0 (Roche Molecular Diagnostics)

■ Ampliscreen (Roche Molecular Diagnostics)

■ Versant HCV RNA Qualitative Assay (Siemens Healthcare Diagnostics, Deerfield, IL)

■ Procleix HIV-1/HCV Assay (Chiron, Emeryville, CA).

Quantitative HCV RNA assays

The approved quantitative assays are:

■ Amplicor HCV Monitor (Roche Molecular Diagnostics)

■ Cobas Amplicor HCV Monitor, version 2.0 (Roche Molecular Diagnostics)

■ Versant HCV RNA 3.0 Assay (bDNA) (Siemens Healthcare Diagnostics)

■ Cobas Taqman HCV Test (Roche Molecular Diagnostics).

Quantitative tests use target amplification with PCR, transcription-mediated amplification (TMA), or a signal amplification technique such as a branched DNA (bDNA) assay. The sensitivity varies for different types of amplification. TMA assays appear to be the most sensitive for detecting HCV RNA.

The latest innovation is real-time PCR, which shortens the typical time for PCR processing from 1.5 hours to 35 minutes. It may also detect relapsed HCV infection earlier than regular PCR. With the recent availability of real-time PCR assays, which have sensitivities of 10 to 50 IU/mL, many experts feel there is no longer a need for qualitative assays.74 In fact, many laboratories no longer offer qualitative testing. The Cleveland Clinic laboratory has recently stopped offering this test.

Because RNA testing is widely available, the recombinant immunoblot assay (RIBA) has become obsolete in diagnosing HCV infection, except in special circumstances. Currently, the primary purpose of RIBA testing is to distinguish between resolved HCV infection (EIA-positive, HCV RNA-negative, RIBA-positive) and a false-positive EIA (EIA-positive, HCV RNA-negative, RIBA-negative).

In summary, patients suspected of having acute or chronic HCV infection should first be tested for anti-HCV. Subsequently, HCV RNA testing should be performed in:

■ Patients with a positive anti-HCV test

■ Patients for whom antiviral treatment is being considered (using a sensitive quantitative assay)

■ Patients with unexplained liver disease whose anti-HCV test is negative and who are immunocompromised or suspected of having acute HCV infection.

Significance of the HCV viral load

The significance of the HCV viral load is widely misunderstood. The amount of virus in the blood does not correlate with symptoms, histologic liver injury, or the stage or aggressiveness of disease. Its sole importance is in relation to therapy.

The HCV viral load, measured before treatment, helps predict the likelihood of a treatment response: the lower the pretreatment viral load, the more likely that the patient will respond to current HCV therapies.

Additionally, the pretreatment viral load serves as a baseline for comparison with subsequent measurements during treatment. Patients with HCV genotype 1 who do not achieve more than a 2-log (99%) reduction in viral load by the 12th week of treatment (an early virologic response) have a low response rate, and treatment should generally be stopped, given its cost and side effects.76 However, measuring the viral load to detect an early virologic response is less helpful in patients with HCV genotype 2 or 3 infection, since these patients require only 24 weeks of therapy and most of them clear the virus by week 12 and respond to therapy.

Additionally, patients with genotype 2 or 3 and those with a viral load of less than 600,000 IU/mL have been found to achieve higher rates of sustained virologic response.15 A sustained virologic response is defined as the absence of HCV RNA 24 weeks after stopping treatment and is now considered to be the best predictor of long-term treatment response. A sustained virologic response is generally regarded as a “virologic cure.”

HCV GENOTYPE AFFECTS SUCCESS AND DURATION OF TREATMENT

HCV has at least six major genotypes.1,3–6 Several genotypes are subclassified as “a” or “b” (ie, genotype 1a or 1b); however, these distinctions are of little clinical use.

In the laboratory, HCV genotypes are identified by restriction fragment length polymorphism, by direct sequence analysis, or by reverse hybridization. Once the HCV genotype has been identified, there is no need to repeat the test.

Different genotypes are more common in some areas of the world than in others. Genotype 1 is the one most common in the United States (accounting for 70% to 75% of cases), followed by genotypes 2 and 3 (25%–30%). Genotype 4 is most common in Egypt and the Arabian peninsula.

HCV genotyping is important because it can help predict the likelihood of a response to treatment and in planning the dose and duration of therapy.77 For example, treatment with pegylated interferon plus ribavirin is predicted to work approximately 50% of the time for people with genotype 1, but 80% to 90% of the time for people with genotypes 2 or 3.15–17,78 Additionally, patients with genotype 1 need 12 months of therapy to achieve maximum benefit, whereas those with genotypes 2 and 3 require treatment for only 6 months to achieve maximum benefit.

■ Copyright© 2010 The Cleveland Clinic Foundation

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Source

Estimating the likelihood of sustained virological response in chronic hepatitis C therapy

Journal of Viral Hepatitis
doi: 10.1111/j.1365-2893.2010.01372.x

Mauss, S., Hueppe, D., John, C., Goelz, J., Heyne, R., Moeller, B., Link, R., Teuber, G., Herrmann, A., Spelter, M., Wollschlaeger, S., Baumgarten, A., Simon, K.-G., Dikopoulos, N. and Witthoeft, T.

*Correspondence: Dr. Stefan Mauss, Center for HIV and Hepatogastroenterology, Grafenberger Allee 128a, 40237 Duesseldorf, Germany. E-mail: stefan.mauss@center-duesseldorf.de

Article first published online: 16 SEP 2010
Received March 2010; accepted for publication July 2010

Abstract

Summary. The likelihood of a sustained virological response (SVR) is the most important factor for physicians and patients in the decision to initiate and continue therapy for chronic hepatitis C (CHC) infection. This study identified predictive factors for SVR with peginterferon plus ribavirin (RBV) in patients with CHC treated under ‘real-life’ conditions. The study cohort consisted of patients from a large, retrospective German multicentre, observational study who had been treated with peginterferon alfa-2a plus RBV or peginterferon alfa-2b plus RBV between the years 2000 and 2007. To ensure comparability regarding peginterferon therapies, patients were analysed in pairs matched by several baseline variables. Univariate and multivariate logistic regression analyses were used to determine the effect of nonmatched baseline variables and treatment modality on SVR. Among 2378 patients (1189 matched pairs), SVR rates were 57.9% overall, 46.5% in HCV genotype 1/4-infected patients and 77.3% in genotype 2/3-infected patients. In multivariate logistic regression analysis, positive predictors of SVR were HCV genotype 2 infection, HCV genotype 3 infection, low baseline viral load and treatment with peginterferon alfa-2a. Negative predictors of SVR were higher age (≥40 years), elevated baseline gamma-glutamyl transpeptidase (GGT) and low baseline platelet count (<150 000/μL). Among patients treated with peginterferon plus RBV in routine clinical practice, genotype, baseline viral load, age, GGT level and platelet levels all predict the likelihood of treatment success. In patients matched by baseline characteristics, treatment with peginterferon alfa-2a may be a positive predictor of SVR when compared to peginterferon alfa-2b.

Keywords: chronic hepatitis C; clinical practice; peginterferon; predictors; sustained virological response

Source

Antiviral therapy in HCV-infected decompensated cirrhotics

Saudi J Gastroenterol Year : 2010 Volume : 16 Issue : 4 Page : 310-314

Fazal A Danish 1, Salman S Koul 2, Fazal R Subhani 3, Ahmed E Rabbani 4, Saeeda Yasmin 5

1 St Mary's Hospital, Isle of Wight, PO30 5TG, United Kingdom
2 Department of Medicine, Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan
3 Department of Pediatrics, Holy Family Hospital, Rawalpindi, Pakistan
4 Foundation University Medical College (FUMC), Rawalpindi, Pakistan
5 Department of Surgery, Shifa International Hospital, Islamabad, Pakistan

Click here for correspondence address and email

Date of Submission 01-Sep-2009
Date of Acceptance 05-Mar-2010
Date of Web Publication 24-Sep-2010

Abstract

Decompensated cirrhosis has traditionally been considered a contraindication to interferon and ribavirin therapy. Whereas, the same may be true for advanced cirrhosis, which is only successfully amenable to liver transplantation (LT), there are reports in the literature in which antiviral therapy was given successfully in selected cases of early hepatic decompensation with an aim to attain sustained viral clearance, halt disease progression, and expect potential (though, often, partial) recovery of hepatic metabolic activity. Antiviral therapy may also be instituted to prevent hepatitis C recurrence after LT (it has even caused removal of some patients from the waiting list for LT). Thus, decompensation per se is no more an absolute contraindication to antiviral therapy. Nonetheless, considering that a large proportion of such patients have pre-existing hematological cytopenias, modifications in antiviral dose regimens and close monitoring is required in order to prevent worsening of the same. Although the final sustained virological response rates attained in these patients are relatively low, successful antiviral therapy is potentially lifesaving which explains the need to go for it. In this article, the pros and cons of antiviral therapy in decompensated liver cirrhosis are reviewed with special emphasis on how to avoid antiviral dose reductions/withdrawals secondary to the development of hematologic side effects by using hematopoietic growth factors.

Keywords: Antiviral therapy, chronic hepatitis C, decompensated cirrhosis, hematopoietic growth factors
 
Whereas, decompensated cirrhosis of liver has traditionally been considered a contraindication to antiviral therapy, the same is not true anymore. Ribavirin-induced hemolytic anemia and interferon-induced neutropenia are one of the most common causes of antiviral dose reductions/withdrawal, particularly in decompensated cirrhotics. Although, no consensus still exists, there are some recent reports in the literature that suggest the use of hematopoietic growth factors (HGF's) in selected cases of hemolytic anemia and neutropenia. Whereas, the addition of growth factors substantially increases the overall cost of the treatment, the same have provided an opportunity to institute antiviral therapy in some of the conditions previously included in the list of contraindications to antiviral therapy (like decompensated cirrhosis). Although more studies are needed to truly define the indications, dose regimen, side effects, and therapeutic efficacy of these factors, the initial results are encouraging and hematopoietic growth factors appear to be a useful adjunct to the antiviral therapy.
 
Fibrosis is the histopathological hallmark of chronic hepatitis causing progressive derangement of normal liver architecture with consequent reduction in hepatic synthetic function. Chronic liver disease is said to be decompensated when one or the other complication of chronic liver disease has developed - ascites, variceal bleeding (secondary to portal hypertension), impaired hepatic synthetic function (hypoalbuminemia), jaundice, or hepatic encephalopathy. Five year survival rate in decompensated cirrhotics is estimated to be 50%. [1] Liver transplantation (LT) is the treatment of choice in all such cases. If hepatitis C virus (HCV) is not eradicated before going for LT, reinfection with HCV occurs in all transplant recipients as a rule. This in turn leads to cirrhosis in around 30% patients in 5 years. [2] It is thus very common to see progressive post-transplantation disease of the allograft in HCV-infected cases. Pre-transplantation HCV eradication is associated with less likelihood of reinfection and this forms the rationale for treating decompensated cirrhotics waiting LT with antiviral therapy; [3] initiating pre-emptive post-transplantation antiviral therapy, and treating established post-transplant chronic hepatitis being other therapeutic options in cirrhotics.

LT per se is not a practical option for a great majority of the cirrhotic patients. This is not only because of limited number of organ donors available at a given time, but also because of the age-related cardiovascular, renal and/or pulmonary derangements that practically make going for LT infeasible and at times rather irrational. Additionally, old age (≥65 years) is generally considered an exclusion criterion for LT. In a nutshell, exploring and offering some potentially successful treatment option (like antiviral therapy) is the need of the hour in cirrhotics.

The aim of instituting pre-transplantation antiviral therapy is either to attain a SVR at transplantation, or an on-treatment HCV RNA clearance at transplantation. Importantly, mere reduction of viral load should not be the aim because, unlike HBV cirrhotics, this has not been shown to decrease the rate and/or severity of recurrence in HCV cases.

Traditionally, despite the known theoretical benefits of antiviral therapy (improvement in liver histology, partial reversal of established cirrhosis, and prevention of life-threatening complications), many cirrhotic patients have not been offered antiviral therapy. Peginterferon-ribavirin combination therapy has limited efficacy in patients with decompensated cirrhosis. [4],[5] Also, antiviral therapy is not safe from potentially serious adverse effects in this population group. As decompensated cirrhotics are more prone to develop hematologic side effects (neutropenia, thrombocytopenia and anemia) with antiviral therapy as compared to non-cirrhotics, [6] patients who already have neutropenia or thrombocytopenia below the permissible limits (neutrophil count >1500/mm 3 ; thrombocyte count >75,000/mm 3 ) are highly prone to develop life-threatening infections after starting antiviral therapy, particularly if they have Child-Pugh class C disease. [7],[8] Also, it is generally thought that age-related derangements in cardiovascular and pulmonary functions make the cirrhotic patients less tolerant to ribavirin-induced hemolytic anemia. Finally, there are concerns regarding decompensation actually made worse by antiviral therapy as is the case with decompensated chronic hepatitis B cases [9] (if you can't do any good to the patient, at least don't harm him, policy!).

The current literature review, however, shows that because of the unstandardized dosage schedules being administered over variable periods of time in the past studies, we have under- and overestimated the potential benefits and risks of antiviral therapy respectively in decompensated cirrhotic patients. There are now several reports in the literature in which antiviral therapy was relatively well tolerated in decompensated cirrhotic patients with reasonable attainment of ETR and SVR rates. [4],[7],[10],[11] In one study, [7] 39% of the patients receiving low, accelerating regimen of non-pegylated interferon plus ribavirin experienced clearance of HCV-RNA, and 21% attained an SVR. Results with pegylated interferon are even better. In the first study [12] proving the benefits of antiviral therapy in cirrhotics with signs of portal hypertension, 51 cirrhotics received 1 mg/kg/week of pegylated-interferon a-2b plus oral ribavirin at a fixed dose of 800 mg/day for 52 weeks. By intention-to-treat analysis, SVR was achieved in 21.6% patients. As otherwise, patients with genotypes 2 and 3 showed better results (83.3%) than genotype 1 cases (13.3%). Although antiviral therapy was stopped in five of the patients because of neutrophil counts falling below 0.75Χ10 3 /dL, none of them developed superadded infections. The disease deteriorated in only 6% of those who attained SVR compared to 38% of the non-responders. In another study, [10] Peg-IFN α-2b (1.0 mg/kg) plus standard dose of ribavirin were administered to all patients for 24 weeks regardless of the genotype. The overall SVR rate attained even with this suboptimal dose regimen was 19.7%. Except patients with very advanced liver disease (CTP score >10), none experienced life-threatening complications. Peg-IFN and ribavirin in the standard dosage (Peg-IFN α-2b 1.5 mg/kg and ribavirin 800-1000 mg for genotypes 2 and 3, and 1000-1200 mg for genotypes 1 and 4) for the standard duration of time (48 and 24 weeks for genotype 1 and non-1, respectively) have also been tried. In one study, [13] 35% of end-staged cirrhotics cleared the HCV infection (16% genotype 1 and 4, and 59% genotype 2 and 3 cases). 60% of all patients tolerated this 'standard' treatment without any major untoward effect; treatment was discontinued in 19.1% of the patients with 4 among those ending up having severe superadded infections. In yet another study, [14] a 48 week course was planned for patients who demonstrate EVR with a standard regimen of PEG-IFN alfa-2a (135μg, once a week) plus ribavirin (1000-1200 mg/day). Results showed 60% patients completing the course, with ETR and SVR achieved in 45% and 35% cases respectively. In a recent study, [15] aimed to evaluate both the prevention of post-transplantation HCV recurrence and the risk of bacterial infections during therapy, 47% patients achieved HCV RNA negativity during treatment, 29% were HCV RNA negative at the time of transplantation (drop outs n=3, deaths n=4, viral relapse n=2), and 20% achieved an SVR post-transplantation. Importantly, none of the patients who achieved SVR pre-transplantation developed a recurrence post-transplantation.

Based on the current literature review it is suggested that all cirrhotic patients with a CTP score ≤9 and history of a decompensated event that abated with routine therapy be offered antiviral therapy. A suggested protocol could be Peg-IFN α-2b in a dose of 1.5 mg/kg and ribavirin in a dose of 800-1000 mg for genotypes 2 and 3, and 1000-1200 mg for genotypes 1 and 4 for 48 and 24 weeks for genotype 1 and non-1, respectively. As otherwise, attainment of a rapid / early virological response and genotypes 2 and 3 are the most robust predictors of viral clearance with antiviral therapy. [10],[12] Child-Pugh score class A (in genotype 1 cases only) and lower pre-transplantation viral loads are other positive predictors. A reduction in the viral load of ≤2 log­ 10 between baseline and week 4, and baseline Child-Pugh score of C or MELD >18 have a strong negative predictive value. In the absence of a ≥2 log 10 reduction in HCV RNA at week 4, probably the best approach to reduce the risk of complications is to stop antiviral therapy at this point.

As a general rule, decompensated cirrhotics are more prone to develop drug-induced side-effects compared to patients with compensated disease. Drug-induced neutropenia, thrombocytopenia, anemia, superadded infections (SBP etc), and liver decompensation during therapy are reported to occur in 50-60%, 30-50%, 30-60%, 4-13%, and 11-20% of decompensated cirrhotic cases respectively. [4],[10],[12] In one study, [16] the relative frequencies of clinical decompensation (22% vs. 18%, p0 =0.62), death before LT (8% vs. 2% p0 =0.06) or 24 weeks after LT (8% vs. 12%; p0 =0.67) were similar in treated and control subjects. However, a significantly higher incidence of superadded infections (spontaneous bacterial peritonitis and spontaneous bacteremia due to Gram-negative bacilli) was noted in the treated subjects (25%) compared to the controls (6%) ( p0 =0.01). Septic shock developed in 10% of the treated subjects compared to none in the control arm ( p0 =0.05). Studies have demonstrated that, besides antiviral therapy, variables independently associated with higher incidence of infective episodes include Child-Pugh class C (score of 12 (±1.2) and a neutrophil count <900 μL during treatment. [1],[7] Norfloxacin prophylaxis has been shown to reduce the incidence of superadded infections. [15],[16] In cases of established nosocomial SBP, multiresistant bacteria resistant to third-generation cephalosporins or amoxicillin-clavulanic acid are frequently found and should be treated with broad-spectrum antibiotics like carbapenems or glycopeptides.

The minimum effective doses of pegylated interferon and ribavirin appear to be 1 μg/kg/week and 10.6 mg/kg/day, respectively. In case a hematologic side effect develops, it is recommended to first reduce the dose of the antiviral therapy to the minimum effective. If no or little improvement occurs in blood counts, use of hematopoietic growth factors (HGF's) should be considered. HGF's that include erythropoietin (EPO) [17],[18] for ribavirin-induced hemolytic anemia, and granulocyte colony-stimulating-factor (G-CSF)/granulocyte monocyte-colony stimulating-factor (GM-CSF) [19],[20] for interferon-induced leucopenia may be used with an aim to avoid dose reductions, something that compromises drug efficacy and possibly final SVR rates attained.

Possible indications of EPO include a fall in Hb level by >4 g/dL, Hb levels of <8 g/dL, and patients developing symptoms and signs of anemia (palpitations, dyspnea, easy fatigability, pallor). [21],[22]

A suggested dose regimen for EPO is 20,000-40,000IU SQ weekly in three divided doses (max. 60,000IU/week) with an aim to maintain Hb level of >11 g/dL (return to the pretreatment level is not the aim). [23] Another study suggested starting EPO therapy at a lower dose of 4,000 IU SQ thrice weekly (12,000 IU/week) and then increasing the dose depending upon the response. [24] The first evidence of a response to the thrice weekly EPO administration is an increase in the reticulocyte count within 10 days. [25] Since erythroid progenitors take several days to mature, a clinically significant increase in hematocrit is usually not observed in less than 2 weeks and may require up to 6 weeks in some patients. [26] If the rate of rise of hemoglobin is greater than 1 g/dL over 2 weeks, it generally warrants decreasing EPO dose. This is because a greater than 1 g/dL rise in any 2 weeks during the course of the therapy has been associated with an increased risk of thromboembolic phenomenon, predisposing to myocardial infarction, stoke and even death. [27] Also, according to manufacturer's recommendations, a Hb level of greater than 12 g/dL should not be aimed, the reason being potentially increased risk of thromboembolic phenomenon. [28] Once adequate Hb level (≥10 g/dL) is achieved, ribavirin dose can be increased to the optimum level. [20] Once started, adjunct EPO therapy may be required till the very end of the treatment. In one study, [24] the median duration of EPO treatment was 24 weeks (range 6-39).

Regarding G-CSF, the current recommendation [21] is to reduce IFN dose if neutrophil count falls to <0.5 Χ 1 0 9 /L, and discontinue it if it falls to <0.3 Χ 10 9 /L. [17] Regarding platelet count, IFN dose should be reduced if platelet count falls to <30 Χ 10 9 /L, and discontinued if it falls to <20 Χ 10 9 /L. [17] The minimum effective dose of pegylated interferon appears to be 1 μg/kg/week. If despite of reducing the pegylated interferon dose to the minimum effective level, neutrophil counts of <0.5 Χ 10 9 /L and platelet counts of <30 Χ 10 9 /L persist, instituting G-CSF therapy may be considered. [21]

A suggested dose regimen is to start G-CSF therapy at a dose of 30 MU SQ once weekly and then to adjust it as per the response/requirement. Complete blood counts should be asked twice or thrice weekly and response to therapy monitored. Once adequate neutrophil count is achieved, IFN dose can be increased to the optimum level. [21] Once started, adjunct G-CSF therapy may be required till the end of the treatment. In one study, [24] the median duration of G-CSF therapy was 20 weeks (range 9-45).

Although it is not yet clear how much survival benefit antiviral therapy confers, a standardized mortality rate analysis in one study reported a lower liver-related mortality among cirrhotics with SVR (0.6: CI: 0.0-3.1) compared to untreated patients. [29] In post-liver transplant cases, avoidance of allograft failure due to recurrence of HCV infection has also been reported in the literature although it needs further study and validation. [30]

Conclusion
 
Although, decompensated cirrhosis of liver is no more considered an absolute contraindication to interferon therapy, because of the high risk of septic complications and low probability of attainment of an SVR, patients with Child-Pugh class C, CTP score ≥10 or MELD score 18 disease are not considered appropriate candidates for antiviral therapy. The ideal candidate for antiviral therapy remains a patient with Child-Pugh class A disease in whom the risk of drug-induced side effects is almost identical to that of the controls. Whether or not to institute antiviral therapy in Child-Pugh class B, patients should be individualized on case-to-case basis giving due consideration to factors like genotype and pre-treatment viral loads with antiviral therapy discontinued after 4 or 12 weeks if there is no virological response. Standard schedules of treatment may be considered in all patients with genotype 2 and 3 HCV infection; in genotype 1 cases, however, the risk-benefit ratio still needs to be defined. All cirrhotic patients on antiviral therapy need adjustment of the dosage schedule in accordance with the tolerability of the patient, especially in response to the development of hematologic side effects. HGF's, though not routinely recommended, appear to be a useful adjunct to antiviral therapy to reduce antiviral dose reductions/withdrawal. Since, addition of HGF's substantially increases the overall cost of the therapy, more studies are needed to establish the lower cut off limits for different blood counts below which HGF therapy may be considered. Additionally, norfloxacin prophylaxis has been shown to substantially reduce the risk of superadded infections. One thing that has increasingly become clear from the existing trial's data is that cirrhotic patients who achieve SVR are less likely to develop liver-related complications as compared to the non-responders. Despite the many encouraging studies in the recent past, however, data on the long-term disease progression, avoidance of transplantation, and most importantly, improvement of life expectancy are still sparse. Although liver functions have clearly been shown to improve with antiviral therapy (as indicated by significant reductions in CTP and MELD scores), the same are more likely to deteriorate within a few years in patients with advanced cirrhosis thus explaining the need to accumulate data on the survival benefit conferred by antiviral therapy in cirrhotic patients. Although not yet tried, novel therapeutic strategies like direct antiviral agents are likely to be most beneficial in patients with decompensated disease.
 
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