August 8, 2010

Novel HCV Drug Can Double Response Rate

By Michael Smith, North American Correspondent, MedPage Today
Published: August 08, 2010

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston.

An investigational protease inhibitor aimed at blocking hepatitis C replication can double the response rate compared with standard care, researchers said.

In an open-label randomized phase II trial, adding the compound -- boceprevir -- to standard therapy in various combinations increased the so-called sustained virological response compared with a control group who got only standard care, according to Paul Kwo, MD, of the Indiana University School of Medicine in Indianapolis, and colleagues.

But the response rate was doubled when patients were first treated with four weeks of standard therapy -- peginterferon alfa-2b and ribavirin -- before boceprevir was added for another 44 weeks, they reported online in The Lancet.

The current standard therapy for hepatitis C aims to stimulate the immune system in general without specific interference in viral replication. For patients with the difficult-to-treat genotype 1 of the virus, the therapy yields a sustained virological response in between 40% and 50% of patients.

In contrast, boceprevir (and a second drug, telaprevir, being investigated separately) blocks the action of the NS3 protease enzyme of hepatitis C, directly preventing viral replication. Early results of this trial were reported last year. (See Sustained Response Seen with New Hepatitis C Drug)

The researchers tested various drug combinations and treatment schedules in 520 treatment-naive patients with genotype 1 virus. They were randomly assigned to get:

•A control standard therapy of peginterferon alfa-2b plus ribavirin for 48 weeks
•Standard care for four weeks, then standard care plus boceprevir (at 800 milligrams three times a day) for 24 weeks
•Standard care for four weeks, then standard care plus boceprevir (at the same dosage) for 44 weeks
•Standard care and boceprevir for 28 weeks
•Standard care and boceprevir for 48 weeks

In a second part of the study, 75 patients were randomly assigned to get 48 weeks of the triple combination or a 48-week variant in which the ribavirin dose was reduced from 800 to 1,400 milligrams daily to 400 to 1,000 milligrams.

All of the combinations that included boceprevir did better than standard therapy, the researchers reported, with sustained virological response rates ranging from 54% to 75%, compared with 39% for patients in the control arm.

The 75% response rate occurred in the patients who got standard care for four weeks, followed by peginterferon alfa-2b, ribavirin, and boceprevir for 44 weeks. The difference from the control arm was significant at P<0.0001.

Next best was a 67% response rate seen in patients who got all three drugs for 48 weeks. The difference from the control arm was also significant at P<0.0001.

In the second part of the trial, the low-dose ribavirin combination yielded a response rate of 36% and was associated with a high rate of both viral breakthrough (caused by resistance mutations) and relapse, the researchers wrote.

In both parts of the study, they reported, boceprevir-based groups had higher rates of anemia and dysgeusia (altered sense of taste) than did the control group -- 55% versus 34% and 27% versus 9%, respectively.

The new NS3 protease inhibitors are a step forward in the treatment of hepatitis C, according to Laura Milazzo, MD, and Spinello Antinori, MD, both of the University of Milan.

Writing in an accompanying editorial, they said the results of the study suggest that adding boceprevir to the standard treatment substantially improves outcomes, "although not to the desired proportion."

But, they added, the emergence of resistance is an issue that needs to be addressed. "Such resistance will be the biggest challenge in the future," they wrote.

Lessons from the HIV pandemic, they commented, demonstrate that only complete suppression of viral replication can prevent drug resistance, so that new strategies are needed to explore combinations of drugs, improve adherence, improve the pharmacokinetics of the drugs, and develop resistance testing.

Limitations of the study included its open-label design (although the authors noted that the endpoints were hepatitis C RNA levels which were blinded laboratory measurements) and classification of patients as with or without cirrhosis based on liver biopsy, which could have been as much as five years old.

The study was supported by Merck.

Kwo reported financial links with Schering-Plough/Merck, Vertex, Tibotec, Roche, Abbott, Bristol-Myers Squibb, Gilead, Idenix, Valeant, Novartis, Anadys, GlaxoSmithKline, and Human Genome Sciences. Several other authors reported financial links with Schering-Plough/Merck, as well as with a range of other pharmaceutical companies.

The editorialists declared they had no competing interests.

Primary source: The Lancet
Source reference:
Kwo PY, et al "Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial" Lancet 2010; DOI: 10.1016/S0140-6736(10)60934-8.

Additional source: The Lancet
Source reference:
Milazzo L, Antinori S "STAT-C: a full revolution or just a step forward?" Lancet 2010; DOI: 10.1016/S0140-6736(10)61056-2.

Source

Milk Thistle Is Good For More Than Just The Liver

August 8 2010 by Admin in Liver Cancer

Milk thistle has been used in Europe for over 2000 years for the treatment of liver problems. It is native to the Mediterranean regions of Europe, North Africa, the Middle East and has been naturalized to Australia and California. Milk thistle has been used for the treatment of liver disease such as alcoholic hepatitis, cirrhosis, liver poisoning, and viral hepatitis. It helps regulate blood sugar, fat metabolism and helps with the excretion of certain hormones. It’s been known to help with acne, constipation, crohn’s disease, and irritable bowel syndrome. The liver produces bile and milk thistle helps in the production of bile which metabolizes fats in the small intestines.

Milk thistle can help with atherosclerosis, gallstones, high cholesterol, iron overload, and some forms of cancer. Milk thistle helps the liver convert LDL cholesterol (Bad cholesterol) into HDL cholesterol (Good cholesterol), and milk thistle helps the liver reduce the amount of cholesterol in the bile which is dumped directly into the intestines where it can be reabsorb. Reducing the cholesterol in bile will help lower the chances of forming gallstones.

Milk thistle can help with some forms of cancer related to the hormone estrogen. Laboratory experiments demonstrated silybin, the active ingredient in milk thistle, will fight for estrogen receptor sites and block the estrogen that is in the body from landing on cancer cells. Milk thistle would be a good preventative herb for those at risk for breast cancer and cancers stimulated by estrogen.

Milk thistle in large doses has shown to protect the kidneys from damage during chemotherapy. A study done with mice given milk thistle in very large doses equivalent to 30grams per 110 pounds in adults completely shielded the kidneys from damage during chemotherapy. The two drugs used were doxorubicin and cisplatin; milk thistle actually increased the effectiveness of these two drugs. With liver cancer, milk thistle will protect a special immune system cell called kuppfer cells which destroys bacteria, toxins, and other foreign matter that enters the liver. Milk thistle has also shown to help fight prostate cancer.

Milk thistle can help the liver become less insulin resistant which would be a benefit for diabetics. The liver helps remove insulin from the blood stream with type 2 diabetes and can help with diabetes caused by liver damage from excess alcohol drinking. When there is excess insulin in the blood stream weight gain can occur, milk thistle can help fight weight gain by helping the liver remove insulin from the blood.

Milk thistle is best used with phosphatidylcholine, when taken together can boost the absorption by 95% that means more of the milk thistle makes it into the blood stream then with out phosphatidylcholine. Phosphatidylcholine is also known as soy lecithin which can be picked up at any health food store. If you are currently a diabetic, you should monitor your blood sugar carefully while you on milk thistle. Women who are using the birth control pill should not take milk thistle because it helps the liver remove hormones from the blood stream and may render the birth control pill ineffective. Anybody who starts taking milk thistle might experience loose bowels because gallbladder activity will increase, but after a few days this will subside.

The statements in this article are not intended to diagnose, treat and cure or prevent disease please consult your health care physician before discontinuing medication or introducing herbs into your diet if you are currently on medication of any kind.

Source
Curr Hepat Rep. 2010 August; 9(3): 147–154.

Published online 2010 June 19. doi: 10.1007/s11901-010-0047-1.
PMCID: PMC2895868
Copyright © The Author(s) 2010

Eric Chak 1 and Sammy Saab 2,3

1 Department of Medicine, UCLA-Oliver View Medical Center, Sylmar, CA USA
2 Departments of Medicine and Surgery, at the David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA USA
3 Pfleger Liver Institute, UCLA Medical Center, 200 Medical Plaza, Suite 214, Los Angeles, CA 90095 USA

Sammy Saab, Phone: +1-310-2066705, Fax: +1-310-2064197, Email: SSaab@mednet.ucla.edu.
Corresponding author
 
Abstract

Hepatitis C virus (HCV) affects about 170 million people worldwide and is the most common chronic blood borne infection in the United States. Since the advent of blood screening protocols in the early 1990s, injection drug use has become the leading cause of infection. Hepatitis C can have both hepatic and nonhepatic manifestations of infection. Hepatic manifestations include hepatic fibrosis, cirrhosis, liver cancer, and liver failure. The standard treatment for chronic HCV is combination therapy with pegylated interferon-α and ribavirin. Although pegylated interferon and ribavirin has been used against HCV for close to a decade, advances in therapy have centered on doses and treatment durations. There has been increasing interest in applying on-treatment response or viral kinetics to predict antiviral response rates and shape therapeutic intervention. Protease inhibitors are a promising adjuvant to combination therapy, but their efficacy and safety are still under investigation.

Keywords: Hepatitis C virus, Chronic hepatitis C, Pegylated interferon-α, Ribavirin, Viral kinetics, Protease inhibitors

Introduction

Hepatitis C virus (HCV) infection is a worldwide public health and medical concern. About 170 million persons are infected worldwide, with an estimated 3 to 4 million Americans infected [1]. Since the advent of blood screening measures, injectable drug use has supplanted transfusion-related HCV transmission as the leading cause of new infections [1]. Many individuals with chronic hepatitis C (CHC) are unaware of their infection and are diagnosed incidentally. Indeed, the cohort of individuals infected two or three decades ago are now seeking medical care, and presenting with advanced liver disease [2].

CHC can lead to hepatic fibrosis, cirrhosis, hepatocellular carcinoma, and hepatic failure. Hepatitis C is currently the most common indication for liver transplantation in the United States [3]. Current treatment strategies for CHC involve an immune modulator, pegylated interferon (peginterferon)-α and the antiviral drug, ribavirin. The mechanism of interferon’s antiviral activity is thought to interact directly to interferon-stimulated response elements on DNA leading to translation of proteins that interfere with HCV replication and have immunomodulatory actions on the innate and adaptive immune systems [4]. Similarly, ribavirin is believed to work via RNA viral mutagenesis [5].

Treatment using interferon-based therapy improves patient outcomes and natural history [6, 7]. The survival in one study was related to duration of antiviral therapy [8]. The predictors of antiviral response are stratified according to host, viral, and on-treatment factors [9]. Unfortunately, most of these factors are nonmodifiable. The genetic polymorphism in the interleukin (IL) 28b gene can predict the likelihood of achieving a sustained virologic response (SVR). This finding highlights the important role of the human host in dealing with the viral infection. Indeed, IL-28B genotype is an important predictor in achieving a sustained viral response in patients with hepatitis C genotype 1.

Although some guidelines have been established, duration of treatment and dosing strategies of the aforementioned drugs are still being optimized in an effort to improve the SVR. Recent studies have demonstrated increasing efficacy in extended therapy beyond 48 weeks in slow interferon responders, and the use of weight-based ribavirin. Furthermore, select patients may not require standard treatment durations.

Epidemiology

There are six HCV genotypes, which appear to vary by region of the world. In the United States and Western Europe, genotype 1 is the most common, followed by genotypes 2 and 3. Genotypes 4, 5, and 6 are generally found in Egypt, South Africa, and Southeast Asia, respectively. According to the most recent National Health and Nutrition Examination survey, the prevalence of anti-HCV antibodies in the United States is about 1.6%. The peak prevalence was seen in those ages 40 to 49 years with the strongest risk factor being injection drug use. However, the survey did not include incarcerated or homeless persons, so the true prevalence of HCV infection may actually be much higher than reported [10].

Natural History of Infection

Although HCV accounts for about 20% of acute hepatitis in the United States [11], it is generally not diagnosed in the acute phase because most patients are asymptomatic. Recent data has suggested that genetic polymorphisms upstream of the IL28B gene may be related to the ability to spontaneously clear the virus. Of note, patients with the C/C genotype have been shown to have spontaneous clearance rates of 50% to 55%, but those with the T/T genotype only had clearance rates of 16% to 20% [12••]. The authors of this study note that the C allele is more common in people of European than African ancestry. Preliminary data suggest the genetic polymorphism may also predict treatment response in patients infected with CHC virus genotype 1 [13••].

Of patients who are acutely infected with HCV, the viral load can be detected as early as 1 to 3 weeks and antibodies detected between 2 and 3 months after exposure [14], and more than 90% will have anti-HCV antibodies 3 months after first exposure. Further, 54% to 86% of patients fail to clear the virus by 6 months and develop a chronic hepatitis [15]. Over time, fibrosis and then cirrhosis may develop. Hepatocellular carcinoma (HCC) develops in about 1% to 5% of patients with CHC infection after 2 decades of infection [14].

Indications for Treatment

According to recent guidelines from the American Association for the Study of Liver Diseases (AASLD), any patient who is infected with HCV should be considered a candidate for treatment [16]. Specifically, the AASLD recommends treating patients with compensated liver disease (total serum bilirubin <1.5 g/dL, International Normalized Ratio 1.5, serum albumin >3.4, platelet count 75,000 mm, and no evidence of encephalopathy or ascites). The risk and benefits of antiviral therapy need to be considered, and patients must be healthy enough to endure the treatment regimen. Patients being treated should have a liver biopsy showing evidence of chronic liver injury. Because of the high SVR rate and the short duration of treatment, the liver biopsy may be considered optional in patients with genotypes 2 and 3. Contraindications to treatment include uncontrolled major depressive illness, history of solid organ transplant (other than liver), autoimmune hepatitis, and severe concurrent medical diseases like heart failure, coronary artery disease, and chronic obstructive pulmonary disease.

Treatment Strategies

Antiviral therapy is associated with several adverse effects, and a varied likelihood of achieving long-term viral suppression. Thus, patients on therapy are assessed on a regular basis to determine treatment continuation. Therapy is discontinued in patients who do not achieve viral milestones, because antiviral therapy is no longer considered efficacious. The goal of therapy is to achieve a SVR, defined as an undetectable viral load 6 months after completing antiviral therapy.

Currently, two major milestones help predict SVR and determine continual use of antiviral therapy. First, patients must achieve an early virologic response (EVR), defined as at least a 2-log drop in the viral load 12 weeks after starting therapy [17]. If treated patients do not achieve this milestone, SVR is unlikely to be realized, and therapy should be discontinued. In the last several years, the clinical impact of an EVR has been further refined. The predictability of achieving SVR in those patients who develop complete viral suppression (complete EVR [cEVR]) is different from those who achieve a 2-log drop but detectable virus (partial EVR [pEVR]). Higher SVR are realized with cEVR in comparison with pEVR [18••, 19••]. The second milestone is the viral load at week 24 of therapy. Treatment is continued only if the viral level is undetectable. Other definitions used to characterize patients’ response to antiviral therapy include end-of-treatment response (EOT), defined as an undetectable viral level at the end of therapy. Figure 1 demonstrates viral milestones and definitions used during HCV antiviral treatment.

Fig. 1
Terms used to describe different responses to treatment for chronic hepatitis C virus. Rapid viral response (RVR)—undetectable viral level 4 weeks after starting antiviral therapy. Partial early viral response (pEVR), the “slow (more ...)
 
There has been increasing interest in another milestone, the viral load 4 weeks after starting antiviral therapy (rapid virologic response [RVR]). Patients who have an undetectable viral level at this time have an increased likelihood of achieving a SVR. In fact, the likelihood of achieving a SVR is similar: high regardless of genotype [20].Other terms used in describing patients’ response to antiviral therapy include null response (lack of 2-log drop with antiviral therapy), and partial response (2-log drop in viral load, but viral load still detectable 24 weeks after starting therapy).

Currently Approved Doses for HCV Genotypes 1, 2, and 3

The approved doses and duration of antiviral therapy are shown in Table 1. Patients infected with genotypes 1 and 4 require 48 weeks of treatment, whereas for those infected with genotypes 2 and 3, 24 weeks of treatment are believed sufficient. No large prospective study for the treatment for genotypes 5 and 6 exists, but it seems reasonable to treat these patients like genotypes 1 and 4 because they would be receiving the maximum length of combination therapy under those regimens.
 
Table 1
Standard treatment for chronic hepatitis C
 
Weight-based Ribavirin Therapy

Recent data from a large, multicenter, prospective trial has suggested that weight-based ribavirin (800 mg for patients <65 kg; 1000 mg for patients 65–85 kg; 1200 mg for patients >85–100 kg; and 1400 mg for patients >105 but <125 kg) is more effective than flat-dose ribavirin in patients with genotype 1 (44.2% vs 40.5%), and safety profiles for each group were similar [21••]. Other studies have also suggested weight-based ribavirin dosing may be beneficial in patients infected with genotype 2 and 3. For instance, in patients with genotype 2 and 3, giving a lower dose of peginterferon-α-2a (135 µg/wk compared to the standard dose of 180 µg/wk) yielded high rates of SVR (85%–86%) when treated with weight-based ribavirin (11 mg/kg daily) [22••]. Other studies suggest the duration of therapy may be shortened in patients with genotype 2 and 3 infected patients treated with full-dose peginterferon-α when weight based ribavirin is used [23••, 24, 25••].
 
Duration of Therapy

Shortened Therapy for Genotypes 2 and 3

Research over the past several years has focused on tailoring therapy based on the patient’s virologic response to antiviral therapy. Currently, the standard duration and ribavirin dosing is 24 weeks and 800 mg ribavirin per day. However, several studies have demonstrated that similar sustained viral response rates may be obtained in patients treated for less than 24 weeks as long as certain criteria are met: rapid viral response (RVR), weight-based ribavirin dosing, low baseline viral load, and minimal fibrosis [23••, 24, 25••].
 
In one of the largest clinical trials assessing the duration of antiviral therapy in patients with genotype 2 and 3, Shiffman et al. [24] showed that there was a significant decrease in SVR when therapy was less than the approved 24 weeks as part of the multinational ACCELERATE trial. However, weight-based ribavirin dosing was not used. Recent data from the ACCELERATE investigators showed that patients with HCV viral load <400,000 who achieve RVR may be candidates for shortened therapy even while using flat-dose ribavirin [26]. Mangia et al. [23••] showed that patients treated with peginterferon-α-2a and weight-based ribavirin for 12 weeks had similar rates of SVR compared to those treated for the standard 24-week course (76% vs 77%, CI−13 to 10). Other trials found that treating patients with peginterferon and weight-based ribavirin showed similar rates of SVR for 14 weeks [25••] and 16 weeks [27••] of treatment compared to the standard duration of 24 weeks. Predictors of response weight-based ribavirin in these trials included the absence of bridging fibrosis or cirrhosis, lower pretreatment HCV RNA level, and lower body weight [24]. Thus, it would be reasonable to treat genotype 2 and 3 patients possessing these favorable characteristics for 12 to 16 weeks with peginterferon-α and weight-based ribavirin with the expectation of similar rates of SVR compared to 24 weeks of treatment.

Shortened Therapy for Genotype 1

Similarly, in genotype 1 patients whose viral loads are undetectable after only 4 weeks of treatment (RVR), Zeuzem et al. [28] showed that patients with baseline HCV RNA <600,000 IU/ml had an SVR rate similar to controls (89% vs 85%) when treated with only 24 weeks of combination therapy. However, these studies need to be confirmed in the United States because of different demographic and, potentially, IL28B allele distribution. Thus, shortened therapy in genotype 1 patients is not recommended at this time.
 
Indeed, patients who achieve a RVR have a high likelihood of achieving SVR regardless of genotype [20, 24, 29•, 30]. However, likelihood of achieving an RVR does vary by genotype. Patients with genotype 1 have a 16% likelihood of achieving a RVR, compared to 60% to 70% with genotypes 2 and 3 [20, 24, 29•, 30].
 
Extended Therapy for Genotype 1

Slow responders who achieve the milestone of a pEVR appear to benefit from extended therapy of 72 rather than 48 weeks. In the study by Berg et al. [19••], patients who had a pEVR had a SVR rate of 17% if they were treated for 48 weeks and 29% if treated for 72 weeks (P=0.04). In addition, patients who derived the most benefit from extended therapy were those whose absolute viral level at week 24 was less than 6,000 IU/mL. In a separate study by Pearlman et al. [18••], extending treatment duration from 48 weeks to 72 weeks in patients with pEVR was found to be beneficial (38% vs 18%, P=0.026). Support for extended therapy is supported by the results of a recent Spanish study (Table 2) [31].
 
Table 2
Extended therapy for slow responders to combination therapy

Treatment with High-dose Peginterferon

The use of higher than normal doses of peginterferon is currently under investigation and this may yield relevant treatment options for difficult to treat populations. One study by Buti et al. [32] randomly assigned 28 genotype 1 patients to receive three different once-weekly doses of peginterferon-α-2b (3 µg/kg for 1 week, 1.5 µg/kg for 3 weeks, and 1.0 µg/kg for 44 weeks). The control group of 27 patients would receive low-dose peginterferon (0.5 µg/kg for 48 weeks). Both groups also received ribavirin. The study found that in the high-dose interferon group, HCV RNA became undetectable faster and in more patients than the low interferon group [32]. In a more recent study by Roberts et al. [33], 896 genotype 1 patients were randomly assigned 1:1 to a 12-week induction therapy with high-dose peginterferon-α-2a (360 µg/week) and 36 weeks of standard peginterferon-α-2a (180 µg/week) or 48 weeks of standard peginterferon-α-2a. SVR rates were similar in the induction and control groups (53% vs 50%, P=0.29).

Similarly, in a large multicenter, randomized, open-label trial involving treatment naïve patients with genotypes 1 and 4 were either treated with induction peginterferon-α-2b (3.0 µg/kg/wk) for 12 weeks followed by standard dose of peginterferon-2b-α (1.5 µg/kg/wk) or standard dose of peginterferon-2b-α for 48 weeks. Both groups were treated with weight-based ribavirin. Overall, the SVR was 32% in the induction group versus 29% in the standard peginterferon dosing group, but the P-value was not significant [34]. Likewise, the PROGRESS trial was unable to find a difference between patients treated with induction doses of peginterferon-α-2a (360 µg/wk) for 12 weeks followed by standard dose peginterferon-α-2a (180 µg/wk) for 36 weeks compared to standard dose peginterferon-α-2a for 48 weeks (41% vs 43%, P-value not reported). Both arms were treated with weight-based ribavirin. The PROGRESS trial, however, found that patients weighing ≥95 kg and those with nonalcoholic fatty liver disease activity score ≥3 tended to have higher rates of SVR when treated with induction doses [35].

Treatment with High-dose Ribavirin

In a small prospective trial of 10 genotype 1 patients with high HCV viral loads (>800,000 IU/ml), the patients were treated with ribavirin doses to achieve a steady-state concentration of >15 µmol/L in addition to standard peginterferon-α-2a for 48 weeks. The mean dose of ribavirin was 2540 mg/d (range 1600–3600). The study found that 90% of patients achieved SVR, but two patients required blood transfusions and all patients in the study received erythropoietin for anemia (hemoglobin <8 g/dL), highlighting safety concerns associated with higher dosing of ribavirin [36]. In another trial by Shiffman et al. [37], 150 treatment-naïve genotype 1 patients treated with standard dose of peginterferon-α 2b, high-dose ribavirin (1000–1600 mg/d), and erythropoietin were found to have higher rates of SVR compared to patients treated with regimens containing lower doses of ribavirin (800–1400 mg/day) (49% vs 29%, P<0.05). Thus, it would appear that using higher doses of ribavirin than standard leads to higher rates of SVR when combined with standard dose peginterferon, but these patients will require regular screening for anemia and subsequent treatment via transfusion or erythropoiesis-stimulating agents [37].

Treatment of Nonresponders and Relapsers

About 30% of patients with CHC infection do not respond to peginterferon and ribavirin [29•, 38•]. In a recent study, only 10% of patients who were initially treated with peginterferon-α-2b (1.5 µg/kg) and standard dose ribavirin and did not respond to treatment, achieved SVR when retreated with peginterferon-α-2a (180 µg/wk) and ribavirin (1000 mg/d) [39]. Another study by Jensen et al. [40] found that by re-treating nonresponders with high-dose peginterferon-α-2a (360 µg/wk) for 12 weeks followed by standard dose peginterferon-α-2a to complete a 72-week course had similar SVR rates to re-treatment with peginterferon-α 2a (180 µg/wk) for 72 weeks (16% vs 14%), which was higher than groups treated for only 48 weeks (7% and 9%). All regimens included combination therapy with ribavirin. It appears then that switching the type of interferon has little effect on achieving SVR, but increasing re-treatment duration to 72 weeks may provide modest benefit. A more recent multinational study demonstrated the decision to re-treat requires consideration of degree of liver damage, genotype, and prior response to antiviral therapy [41].

The DIRECT (Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy) trial treated 487 patients who did not respond to treatment with standard peginterferon and ribavirin were re-treated with consensus interferon and ribavirin [42]. The SVR rate using 15 µg/d consensus interferon and ribavirin was 10.7%. Efficacy of re-treatment was associated with severity of liver damage and degree of viral response to prior therapy. For instance, the SVR in patients with at least a 2-log drop in viral levels with prior pegylated interferon and ribavirin and who did not have cirrhosis was greater than 30%.

Management of Adverse Reactions

Adverse effects can lead to dose reduction and even treatment discontinuation. According to the initial trials by Fried et al. [29•] and Manns et al. [38•], adverse reactions led to the discontinuation of therapy in 10% to 14% of patients. The most common adverse reactions reported in these studies were fatigue, headache, fevers, myalgias, and injection site reactions. Major reasons for discontinuation of treatment were severe anemia, neutropenia, thrombocytopenia, and psychiatric disturbances. In the study by Manns et al. [38•], dose reduction of combination therapy for neutropenia, anemia, and thrombocytopenia, occurred in 18%, 13%, and 3%, respectively. However, discontinuation of combination therapy for neutropenia was less than 1%, no patients discontinued therapy for thrombocytopenia, and discontinuation for anemia was rare. Although dose reduction appears to be the mainstay of adverse reaction management at this time, the use of growth factors is currently under investigation and is discussed here.

Hemolytic anemia is one of the limitations of using ribavirin. Anemia occurs between 15% to 20% of treated individuals and can lead to dose reduction or even discontinuation. Consequently, SVR can be decreased [43, 44]. Indeed, the minimal critical dose of ribavirin before SVR is compromised is likely between 60% and 80% of the expected dose [45]. In a study by Bronowicki et al. [46], 516 genotype 1 patients were treated with peginterferon-α-2a (180 µg/wk) plus ribavirin (800 mg/d). Those patients who achieved an undetectable HCV viral 2load at week 24 (70% of the original 516 patients) were randomized to either continuing ribavirin or receiving peginterferon monotherapy for the remaining 24 weeks. The study found that patients who stopped ribavirin had lower rates of SVR (52.8% vs 68.2%, P=0.004), but higher quality of life scores. Hence, ensuring the complete treatment course of ribavirin is critical to the achievement of SVR [46].

Efforts to maintain ribavirin without dose modification despite anemia have included the use of erythropoietin. However, small-scale studies have failed to demonstrate that the use of erythropoietin to maintain ribavirin dose translates to better SVR [37, 47, 48]. A concern with these trials is that they are underpowered to detect a difference, if one existed. Treatment of anemia with epoetin-α has been shown to increase patients’ quality of life [49, 50]. In addition, there has been increased scrutiny regarding the use of epoetin-α for ribavirin-induced anemia because of concerns of increased mortality, thrombosis, cardiovascular events (according to the Food and Drug Administration), and the rare observation of antibody-mediated pure red cell aplasia [51]. The Food and Drug Administration has recommended against the use of epoetin-α in patients with hemoglobin above 10 g/dL [52].

The role of granulocyte colony-stimulating factors (G-CSF) in the management of neutropenia induced by combination therapy has not been established. In a recent retrospective, cross-sectional study, Koskinas et al. [53] found that HCV patients who were given G-CSF while undergoing combination therapy had higher rates of SVR (32% vs 21%), but this result was not statistically significant. Interestingly, the authors of this study found that members of the G-CSF group had higher rates of treatment adherence (95% vs 73.1%, P<0.05). Infection was not listed as a major adverse reaction in the original trials [28, 33] despite not being treated with G-CSF; therefore, with the current evidence, routine use of G-CSF for the treatment of neutropenia induced by combination therapy is not recommended.

In a recent study by McHutchison et al. [54], 72 patients with HCV-related cirrhosis and thrombocytopenia (platelet counts 20,000 to 70,000/cm3) were randomly assigned to either receive eltrombopag, an orally active thrombopoietin-receptor agonist that stimulates thrombopoiesis, or placebo each day for 4 weeks. In this study, 95% of patients reached the goal of 100,000 platelets at the end of treatment and were able to initiate antiviral therapy for HCV [54]. The use of eltrombopag for the treatment of thrombocytopenia caused by peginterferon and ribavirin is yet to be studied, but may represent a novel approach to this adverse effect.

Major depression affects about one third of patients being treated for HCV, and is primarily caused or exacerbated by the interferon component of combination therapy. A recent systematic review analyzed interferon-α-induced major depressive disorder [55]. The study found that prophylactic treatment of patients with a history of depression using selective serotonin reuptake inhibitors (SSRIs) led to decreased rates of treatment discontinuation. For patients who become depressed while undergoing combination therapy, the SSRIs appear safe and efficacious, though evidence is limited at this time. Consultation with mental health professionals and use of a multidisciplinary team is advised for patients undergoing combination therapy who have a history of depression or have become depressed during treatment.

Investigative Therapies

Current response rates appear to be improved with the addition of protease inhibitors to pegylated interferon and ribavirin. For instance, in genotype 1 patients, the addition of telaprevir has been associated with an increase of SVR from 46% in patients treated with peginterferon and ribavirin for 48 weeks of treatment, to 69% in patients treated with telaprevir for 12 weeks then peginterferon and ribavirin for 24 additional weeks for 36 weeks of total treatment (P=0.004) [56]. However, this study also showed that these protease inhibitors have their own set of signature adverse effects, and are associated with greater rates of discontinuation (21% vs 11%). Use of a different protease inhibitor, boceprevir, with peginterferon and ribavirin was also associated with greater SVR than using peginterferon and ribavirin alone (74% vs 38%, respectively) [57]. The signature adverse effect associated with telaprevir appears to be a skin rash, and with boceprevir anemia. Treatment duration for both drugs is currently under investigation, but regimens containing boceprevir appear to range from 24 weeks to 48 weeks at present.

Conclusions

For now, the mainstay of treatment for CHC virus infection is peginterferon-α and ribavirin. Genotypes 2 and 3 are the most responsive to therapy and a 24-week course is sufficient, whereas a 48-week course is recommended for genotypes 1 and 4. Currently, too little evidence exists to recommend treatment regiments for genotypes 5 and 6. Evidence exists to support treatment with combination therapy using weight-based ribavirin for as short as 12 weeks for patients with genotypes 2 and 3, but may need to be extended to 72 weeks for genotype 1 patients who are slower to respond to therapy.

Disclosure

Sammy Saab's disclosure: a) consulting ~ Genentech, b) speaker ~ Merck, Genentech, Three Rivers, c) Stock ~ Vertex, Zymogenetics; Eric Chak's disclosure - none.

Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance


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35. Reddy KR, Shiffman ML, Rodriguez-Torres M, et al.: Standard versus higher induction doses of peginterferon alfa-2A (40KD) and/or higher ribavirin (RBV) in HCV G1 patients with high viral load and body weight ≥85 kg: final results of the PROGRESS study [abstract]. Presented at the American Association for the Study of Liver Disease. Boston, MA; October 2009.

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52. Federal Drug Agency. Information for Healthcare Professionals: Erythropoiesis Stimulating Agents (ESA) [Aranesp (darbepoetin), Epogen (epoetin alfa), and Procrit (epoetin alfa)]. www.fda.gov/Drugs/DrugSafety. Accessed February 8, 2009.

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58. Sánchez-Tapias JM, Diago M, Escartín P, et al. Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology. 2006;131(2):451–460. doi: 10.1053/j.gastro.2006.05.016.
 
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Management of acute variceal bleeding has greatly improved over recent years. Available data indicates that general management of the bleeding cirrhotic patient by an experienced multidisciplinary team plays a major role in the final outcome of this complication. It is currently recommended to combine pharmacological and endoscopic therapies for the initial treatment of the acute bleeding. Vasoactive drugs (preferable somatostatin or terlipressin) should be started as soon as a variceal bleeding is suspected (ideally during transfer to hospital) and maintained afterwards for 2-5 d. After stabilizing the patient with cautious fluid and blood support, an emergency diagnostic endoscopy should be done and, as soon as a skilled endoscopist is available, an endoscopic variceal treatment (ligation as first choice, sclerotherapy if endoscopic variceal ligation not feasible) should be performed. Antibiotic prophylaxis must be regarded as an integral part of the treatment of acute variceal bleeding and should be started at admission and maintained for at least 7 d. In case of failure to control the acute bleeding, rescue therapies should be immediately started. Shunt therapies (especially transjugular intrahepatic portosystemic shunt) are very effective at controlling treatment failures after an acute variceal bleeding. Therapeutic developments and increasing knowledge in the prognosis of this complication may allow optimization of the management strategy by adapting the different treatments to the expected risk of complications for each patient in the near future. Theoretically, this approach would allow the initiation of early aggressive treatments in high-risk patients and spare low-risk individuals unnecessary procedures. Current research efforts will hopefully clarify this hypothesis and help to further improve the outcomes of the severe complication of cirrhosis.

Augustin S, González A, Genescà J. Acute esophageal variceal bleeding: Current strategies and new perspectives. World J Hepatol 2010; 2(7): 261-274 Available from: URL: http://www.wjgnet.com/1948-5182/full/v2/i7/261.htm DOI: http://dx.doi.org/10.4254/wjh.v2.i7.261

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Several trial judges in Canada have stated that disclosure
of HIV-positive status is not required when a condom is used.
Photo credit: © 2010 Jupiterimages Corp.

August 3, 2010

Many of the criminal cases involving HIV-positive people who don't disclose their status are based on ‘80s era panic rather than sound science, according to advocates of people living with HIV/AIDS in Canada.

The high number of unwarranted charges and confusion around what does and does not constitute an offence is also likely to set back gains made in prevention and anti-stigma campaigns, say groups such as the Canadian Legal HIV/AIDS Network, Ottawa Gay Men's Wellness Initiative and the AIDS Committee of Toronto.

"The legislation should be informed by scientific guidelines about risk and not driven by panic or phobia," says Richard Elliott, the executive director of the Canadian Legal HIV/AIDS Network.

However, Inspector Joan McKenna, co-chair of the Ottawa Police Service's Liaison Committee for Lesbian, Gay, Bisexual and Transgender, says the law is straightforward. "If there is non-disclosure, that's the big issue. If you disclose, there is no problem."

The Joint United Nations Programme on HIV/AIDS (UNAIDS) has recommended that cases should only be prosecuted when actual transmission has occurred. The international body also says convictions should only occur when "malicious intent" can be proven. In other words, those who selfishly prioritize unprotected sex over their partner's health should be held liable, but those who don't disclose for other reasons, such as a lack of awareness about how HIV is spread, should not be criminally prosecuted.

"Regardless of the risk you're exposing someone to, if you quite realistically fear that you will be beaten up if you disclose your status, then you shouldn't be held criminally liable for not disclosing," says Elliott.

During last month's XVIII International AIDS Conference in Vienna, Austria, a panel on HIV criminalization noted that 600 cases involving exposure or transmission have been recorded around the world; the actual number is likely higher. In Canada, the Canadian HIV/AIDS Legal Network reports that there have been 100 criminal cases.

Despite the UNAIDS recommendation, Canada and many other countries prosecute people for putting others at a risk of HIV, not just spreading the virus. Individuals have been prosecuted for acts where transmission of HIV would be impossible or extremely unlikely. In 2008, an HIV-positive Texas man was sentenced to 35 years for spitting at a police officer. In several countries, including Canada, Singapore and the US, HIV-positive individuals have faced judges for engaging in unprotected oral sex.

The Supreme Court of Canada has stated that convictions should only occur when the accused put the victim at "significant risk" of contracting HIV. However, what is and what is not considered a "significant risk" is up to individual judges to decide.

As a result, oral sex can be considered a "significant risk" in one case and not worth prosecuting in another. In the 2009 case of Johnson Aziga, the first man in Canada to be convicted of murder for not disclosing that he was HIV-positive, one of his "aggravated assault" convictions was based on the fact that he had oral sex with a woman, even though she did not become infected. However, in April, the crown stayed charges against an HIV-positive man who had oral sex without telling his partner on the grounds that the risk involved was too low.

While Elliott says that only prosecuting cases involving transmission would be "a sensible place to draw the line," given that Canada's justice system has already decided exposure to HIV counts as a legitimate legal issue, his organization is urging Canada's justice system to set reasonable, science-based limits on when exposure amounts to a "significant risk."

The HIV/AIDS Legal Network argues that if, for example, someone practices safer sex, then criminal charges for not disclosing are not justified. While several trial judges have stated that disclosure is not required when a condom is used, at least two men in Canada have been convicted of aggravated sexual assault for not disclosing their status even though they wore a condom during vaginal sex, according to Elliot.

"If on the one hand, the key public health message is ‘practice safer sex, protect yourself' and on the other hand people are criminally charged when they practice safe sex, that is a completely contradictory message."

While there is no statistical evidence on how the recent spate of criminal HIV-related cases affects health-seeking behaviours, Elliott thinks the hard line Canada's courts have taken could discourage people from testing themselves. Those who have tested positive, perhaps at an anonymous site, may also be less likely to seek out medical services and counseling for fear their health providers will turn them over to the police, according to Elliott.

"It puts up a barrier in the relationship between the health provider and the individual," says Elliott, who adds that public health professionals are uncertain about their own responsibility to report patients, given the lack of clear guidelines. "People are asking us, ‘How does it affect the therapeutic role if I have to play the role of cop?'"

Last week, Brent Bauer of the Ottawa Gay Men's Wellness Initiative complained to the Ottawa police board that they had infringed on privacy when they released a photo of 29-year-old Steven Paul Boone, a man who allegedly infected an 18-year-old man and may have infected others.

But McKenna says the police weighed the interests of "community safety" over Boone's privacy in their decision to share his photo. "It is important that his past partners have this information that affects their own personal health."

Elliott suggests that public health authorities, rather than police, should intervene in all but the most egregious of cases. "It's a more flexible way of intervening. [Public health authorities] can order people into counselling. They take into account mental health issues."

DOI:10.1503/cmaj.109-2235
— Wendy Glauser, Toronto, Ont.
 
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No end in sight for adult hepatitis B vaccine shortage

Merck & Co., Inc. does not anticipate that the adult formulation
of its hepatitis B vaccine will be available for the rest of 2010.
Photo credit: ©2010 Jupiterimages Corp.

The lengthy and ongoing shortage of adult hepatitis B vaccine has baffled some public health doctors.

“Why is there a shortage for a stable vaccine that has been around for years?” asks Dr. Vinita Dubey, associate medical officer of health for Toronto Public Health’s division of communicable diseases. “This is a real public health concern.”

The shortage recently prompted Ontario’s Ministry of Long-Term Care to announce that it was suspending the Grade 7 hepatitis B program for the upcoming school year. According to the Public Health Agency of Canada (PHAC), other provinces and territories have also been forced to amend immunization programs.

“There are logistical challenges of trying to catch people up on immunizations that may have been delayed due to the shortage,” Charlene Wiles, a PHAC media relations advisor, writes in an email. “Canadian jurisdictions have been offering hepatitis B immunization routinely for children and high-risk groups now for many years. However it is possible that those not previously immunized and at risk as an adult could be vulnerable.”

The shortage began in January 2009, when Merck & Co., Inc. announced that equipment upgrades at its vaccine plant in West Point, Pennsylvania, would disrupt production of the adult version of its hepatitis B vaccine (Recombivax HB®). The vaccine will likely remain unavailable for the near future.

“We do not anticipate availability of the adult formulation of our Hepatitis B vaccine for the rest of 2010 and will provide an update on availability of the adult formulation when more information is available,” Jennifer Allen Woodruff, a spokeswoman for Merck, writes in an email. “Over the last couple of years, supply disruptions have occurred due to unexpected manufacturing issues that prompted modification to some of our processes and equipment. As a result, some of our vaccines have been in backorder and other vaccines have been unavailable for order for some time.”

Woodruff says that Merck is addressing its production issues in several ways: by investing in manufacturing capabilities to increase capacity and create redundancy; by building new vaccine-production facilities in Durham, North Carolina, and Carlow, Ireland; by expanding vaccine manufacturing in Elkton, Virginia, and Mirabel, France; and by modernizing equipment and processes at its West Point facility.

“Of course, these changes take time because of the complexity of the vaccine manufacturing process and because some require regulatory approvals moving forward,” writes Woodruff.

In the mean time, GlaxoSmithKline (GSK) has been attempting to address the shortage by ramping up production of its adult hepatitis B vaccine (Adult Engerix-B®).

“The shortage of hepatitis B vaccines is not limited to Canada, this is a global supply shortage,” Liana N. Del Medico, a GSK product communications manager, writes in an email. “GSK has made significant efforts to increase our supply and has been actively filling the market void created by our competitor’s supply shortage on hepatitis vaccines.”

Del Medico says that GSK is working with various Canadian jurisdictions to help meet the needs of school-based hepatitis B programs. “GSK hopes to have supply for the coming school year.”

Canada has purchased more than 350 000 doses of GSK’s vaccine, according to PHAC. Though the adult version of the hepatitis B vaccine is in short supply in Canada, there is sufficient supply of the pediatric version.

DOI:10.1503/cmaj.109-3324
— Roger Collier, CMAJ
 
Source
J Coll Physicians Surg Pak. 2010 Aug;20(8):514-8.

Mumtaz K, Ahmed US, Abid S, Baig N, Hamid S, Jafri W.
Department of Medicine, The Aga Khan University Hospital, Karachi.

Abstract

Objective: To determine precipitants of hepatic encephalopathy (HE) and their impact on hospital stay and mortality. Study Design: Cross-sectional, analytical study. Place and Duration of Study: The Aga Khan University Hospital, from January 2005 to December 2007. Methodology: Consecutive patients admitted with different grades of HE were evaluated between January 2005 and December 2007. The precipitants of HE were correlated with the different grades of HE, and length of hospital stay and mortality. Chi-square test was used to compare the proportion of precipitating factors versus hospital stay and grade with significance at p < 0.05. Results: Of the 404 patients 252 (62%) were males. Hepatitis C virus was the cause of cirrhosis in 283 (70%); Child Turcotte Pugh (CTP) class C was present in 317 (78%) patients. On presentation, 17% patients had grade 1 HE while 44%, 29% and 10% had grades 2, 3 and 4 respectively. The most common precipitant of HE was spontaneous bacterial peritonitis in 83 (20.5%), constipation in 74 (18.3%) and urinary tract infection in 62 (15.3%). One hundred and forty (35%) patients had (3) 2 precipitating factors while no precipitant was noted in 50 (12%) patients. Mean hospital stay was 4+/-3 days. The lesser the number of precipitants, shorter was the length of stay (p < 0.01) and lesser was the grade of HE (p=0.025). Complete reversal of HE was noted in 366 patients (91%) while the remaining had grade 1 HE on discharge. Nine (2.2%) patients died during the hospital stay. No mortality was noted in patients without precipitants. Conclusion: Patients presenting with (3) 2 precipitating factors and advanced grade of HE had a prolonged hospital stay. Moreover, patients without precipitants had better outcomes.

PMID: 20688015 [PubMed - in process]

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Inflammatory bowel diseases and hepatitis C virus infection.

Hepatobiliary Pancreat Dis Int. 2010 Aug;9(4):398-401.

Li YD, Lin JJ, Zheng SS.
Department of General Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.lee1952@163.com.

Abstract

BACKGROUND: Data on the prevalence of hepatitis C in patients with inflammatory bowel diseases (IBD) are limited and conflicting. This study was to assess the prevalence of hepatitis C virus (HCV) infection in IBD patients and to define the clinical and immunologic profile of IBD associated with HCV infection. METHODS: Ten patients (seven females and three males) with IBD and HCV infection were consecutively recruited in our department between June 2005 and May 2010. We analyzed the clinical and serologic description of all patients. RESULTS: The mean age of the 10 patients was 41 years and the median disease duration was 7 years. With present and/or past HCV infection, the patients had clinical manifestations and were positive for endoscopic study or histological test. Compared with the HCV-negative IBD group, the HCV-positive IBD group have a higher positive rate of autoantibodies (antinuclear antibodies, antieutrophil cytoplasmic antibody, and anti-SSa/SSb). In the HCV-positive group, 8 patients were positive for p-antieutrophil cytoplasmic antibody, 4 positive for antinuclear antibodies, and 3 positive for anti-SSa/SSb. Four patients had an elevated level of transaminase (alanine transminase, and aspartate transminase). CONCLUSIONS: HCV positive in IBD may induce autoanti-bodies (antinuclear antibodies, antieutrophil cytoplasmic antibody, anti-SSa/SSb) and damage of liver function. In managing IBD patients, physicians should be aware of screening of HCV and prescribe antiviral treatment.

PMID: 20688604 [PubMed - in process]

Source
J Antimicrob Chemother. 2010 Aug 4. [Epub ahead of print]

Naggie S, Patel K, McHutchison J.
Duke Clinical Research Institute, Durham, NC, USA.

Abstract

Chronic hepatitis C virus (HCV) infection is a global health problem, but the current therapy is effective in <50% of patients infected with genotype 1. With advances in cell culture systems over the past decade, the development of directly acting antivirals (DAAs) for HCV has become possible. There are currently >50 active clinical trials in this therapeutic area and NS3/4A protease inhibitors are now entering Phase III study. To date, we have learned that DAAs are potent inhibitors of HCV replication, resulting in rapid declines in serum HCV RNA levels, and have the potential to allow shortening of therapy. However, these agents drive selective pressure for mutant viruses that can develop rapidly and have reduced susceptibility to the drug. Therefore, for now, the current standard of care including pegylated interferon alpha (pegIFN) and ribavirin remains a crucial part of new drug development. Furthermore, the adverse event profile for the early DAAs has added to the concerns of tolerability that are so common for the current standard of care. Ongoing issues include the optimal duration of therapy, how and when to combine DAAs, and the long-term role of pegIFN and ribavirin. Here, we summarize the current information regarding the effectiveness of protease inhibitors in treating chronic HCV and discuss the key challenges now facing the field.

PMID: 20688770 [PubMed - as supplied by publisher]

Source