September 13, 2012

Hepatitis C viral infection in patients with cirrhosis

Clinical Liver Disease

Volume 1, Issue 3, pages 65–68, July 2012

Review

Ranjeeta Bahirwani M.D., K. Rajender Reddy M.D.*

Article first published online: 23 JUL 2012

DOI: 10.1002/cld.43

Copyright © 2012 the American Association for the Study of Liver Diseases

Abstract

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eRVR, early rapid virological response; HAV, hepatitis A virus; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IL-28B, interleukin-28B; SVR, sustained virological response.

Hepatitis C virus (HCV) is a major public health problem affecting more than 180 million people worldwide. The prognosis for patients with HCV depends on the progression of fibrosis; the risk of cirrhosis development is as high as 25% over a 25- to 30-year period and is influenced by cofactors, including human immunodeficiency virus coinfection, alcohol abuse, and hepatic steatosis.1 In patients with cirrhosis, hepatic decompensation, which can manifest as one or more clinical events (including variceal bleeding, ascites, and encephalopathy), occurs at a rate of 30% over a period of 10 years.2 Patients with HCV cirrhosis are at increased risk for hepatocellular carcinoma (HCC); the incidence is approximately 5% to 15% over a period of 10 years.3 Additionally, in patients undergoing liver transplantation for HCV-related liver failure (currently the leading indication for transplantation in the United States), graft reinfection is universal; progression to graft cirrhosis occurs in up to 30% of these patients within 5 years after transplantation and leads to compromised patient and graft survival.4 The eradication of HCV is the only therapeutic intervention that can halt disease progression and improve the quality of life in infected patients. A recent Markov model constructed for a cohort of 4000 patients with genotype 1 disease found that in comparison with no treatment, HCV therapy for patients with compensated cirrhosis (Child-Pugh class A) saved $55,314 and led to a 0.950 increase in quality-adjusted life years; this resulted in 119 fewer deaths, 54 fewer cases of HCC, and 66 fewer liver transplants.5 Successful antiviral therapy has been observed to reduce the incidence of complications from progressive disease both before and after liver transplantation.6

The care of patients with HCV cirrhosis involves the prevention and management of recognized complications (Fig. 1). Furthermore, those with advanced fibrosis and cirrhosis are most in need of HCV therapy; however, interferon-based antiviral treatment in these patients is challenging because of the frequent comorbidities affecting patient adherence and tolerance, the risk of serious adverse events, and the hyporesponsiveness to therapy. Bridging fibrosis and cirrhosis are negative predictors of HCV treatment outcomes. Additionally, patients with cirrhosis are often male and older and have comorbidities (including diabetes mellitus, obesity, and alcohol consumption) that adversely affect the efficacy of antiviral therapy.7 In patients with compensated cirrhosis, the sustained virological response (SVR) rates with pegylated interferon in combination with ribavirin range from 10% to 44% for genotypes 1 and 4 and from 33% to 72% for genotypes 2 and 3, whereas in patients with decompensated cirrhosis, the SVR rates drop to less than 16% for genotypes 1 and 4 and to 44% to 57% for genotypes 2 and 38 (Table 1).

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Figure 1. Approach to the patient with HCV cirrhosis. Abbreviations: HAV, hepatitis A virus; HBV, hepatitis B virus; HE, hepatic encephalopathy.

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Although pegylated interferon and ribavirin remain the backbone of HCV therapy, the emergence of two nonstructural protein 3/4A protease inhibitors, boceprevir and telaprevir, has led to a substantial improvement in SVR rates in patients with genotype 1 disease. In patients with cirrhosis, treatment with either boceprevir or telaprevir in combination with pegylated interferon and ribavirin is recommended for 48 weeks; the SVR rates in treatment-naive patients range from 50% to 60%. However, SVR rates are lower with triple therapy in treatment-experienced patients who have cirrhosis (primarily prior null and partial responders), whereas relapsers have SVR rates comparable to the rates of patients without cirrhosis9 (Table 2). Patients with cirrhosis are not eligible for response-guided therapy with nonstructural protein 3/4A serine protease inhibitors, and treatment is recommended in this cohort for a fixed duration of 48 weeks with both boceprevir and telaprevir regimens.9

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*The data were taken from New England Journal of Medicine.10

†The data were taken from New England Journal of Medicine.11

‡The data were taken from New England Journal of Medicine.12

§Patients with undetectable HCV RNA at the end of treatment with pegylated interferon/ribavirin and without subsequent SVR.

∥The data were taken from New England Journal of Medicine.13

¶The data were taken from New England Journal of Medicine.14

#Patients with a ≥2-log drop in HCV RNA at week 12 with pegylated interferon/ribavirin but with detectable HCV RNA at week 24.

**Patients with a <2-log drop in HCV RNA at week 12 with pegylated interferon/ribavirin.

Testing for single-nucleotide polymorphisms in the interleukin-28B (IL-28B) gene on chromosome 19 may be helpful in determining the likelihood of achieving an SVR. Among the baseline host and viral factors, the predictive value of the IL-28B genotype is superior to the fibrosis stage, HCV RNA, age, and sex with respect to SVR, and it is useful even in patients on triple therapy with protease inhibitors. A recent cost-effectiveness study of the utility of protease inhibitor therapy for HCV revealed that both universal triple therapy and IL-28B–guided triple therapy were cost-effective for patients with advanced fibrosis: the costs were $51,500 per quality-adjusted life year for universal triple therapy and $36,300 per quality-adjusted life year for IL-28B–guided triple therapy in comparison with standard therapy with pegylated interferon and ribavirin.15

Pegylated interferon and ribavirin are associated with a host of adverse effects, which include a flulike syndrome, depression, fatigue, and hematological abnormalities (neutropenia, thrombocytopenia, and anemia). HCV therapy in patients with compensated cirrhosis is safe with a discontinuation rate of approximately 10%. Completing the full dosing and duration of therapy, however, is difficult for genotype 1/4 patients with cirrhosis because of the longer course of therapy (48 weeks) in comparison with patients with genotype 2 or 3 (24 weeks). Dose modifications are required for 30% of the patients with compensated disease, mainly because of the increased rate of cytopenias in the setting of portal hypertension, with rates of anemia, thrombocytopenia, and neutropenia ranging from 20% to 35%. Ribavirin dose reduction and the addition of erythropoiesis-stimulating agents are suggested for patients with hemoglobin levels of 10 g/dL or less; granulocyte colony-stimulating factors can be used in those with an absolute neutrophil count less than 750/mm3. Interferon dosing can be reduced for patients with platelet counts less than 70,000 × 103/μL; more recently, the thrombopoietin agonist eltrombopag has been shown to prevent severe thrombocytopenia in patients on antiviral therapy.16 The threshold for treatment discontinuation for thrombocytopenia has varied, with the lower limit being approximately 20,000 × 103/μL. Because antiviral therapy presents a potentially increased risk of bacterial infections in patients with cirrhosis, spontaneous bacterial peritonitis prophylaxis with norfloxacin is advised for patients with cirrhosis who are receiving interferon and ribavirin therapy.17 Adverse events occur more frequently in patients with genotype 1 disease with the addition of protease inhibitors to pegylated interferon and ribavirin (Table 3). Overall, the adverse events reported with telaprevir include rash (56% versus 34% with pegylated interferon/ribavirin alone), anemia (36% versus 17% with pegylated interferon/ribavirin alone), and nausea (39% versus 28% with pegylated interferon/ribavirin alone). Boceprevir use has been associated with higher rates of anemia (45%-50% versus 20%-30% with pegylated interferon/ribavirin alone) as well as dysgeusia (35%-44% versus 11%-16% with pegylated interferon/ribavirin alone). Although there are no data in the registration trials on the rates of rash and anemia in patients with cirrhosis, recent data from a French observational study of triple therapy in patients with advanced fibrosis and cirrhosis showed high rates of cytopenias and an increased need for blood transfusions.20

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The rate of decompensation in patients with compensated cirrhosis enrolled in randomized clinical trials of HCV therapy has been reported to be 0% to 3% and likely reflects careful patient selection. HCV therapy is poorly tolerated in patients with Child-Pugh class C cirrhosis because of the high risk of cytopenias and hepatic decompensation as well as the increased risk of infection21, 22 and is, therefore, considered investigational and not recommended in this patient population.

Treatment-induced improvements in liver histology and lower rates of hepatic decompensation have been reported in multiple studies examining the favorable impact of SVR in the context of HCV cirrhosis. Rates of liver-related complications, mortality, and HCC are lower in SVR patients versus non-SVR patients. Importantly, the risk of HCC is not eliminated in patients who achieve viral eradication, so continued HCC surveillance is critical in these patients.23

In summary, HCV eradication is associated with lower mortality and fewer liver-related complications; this is particularly important for patients with cirrhosis because of the lower rates of decompensation and HCC development once SVR is achieved. Treatment in patients with cirrhosis poses significant challenges because of the inferior SVR rates, the higher rates of adverse events, and the lower tolerance to therapy. Nonetheless, aggressive therapy in such patients is strongly supported and leads to improved outcomes.

References

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Findings on Alternate Doses Illustrate Robust Power of FDA-Approved Drug

By Anne Holden on September 12, 2012

New research from an international team of HIV/AIDS experts has reaffirmed the effectiveness of Truvada — the first and only medication approved by the FDA for HIV prevention.

Led by UCSF-affiliated Gladstone Investigator Robert Grant, MD, MPH, and Peter Anderson, PharmD, at the University of Colorado, the research provides the first estimate of the drug concentration levels needed for Truvada to prevent the spread of HIV/AIDS — expanding our understanding of Truvada’s potency and opening the door to new dosing strategies.

The new study, available online today in Science Translational Medicine, builds on the 2010 “iPrEx” clinical study in which Grant and his colleagues found that Truvada — which had been used for years to treat HIV-positive patients — could also prevent new infections in people likely to come in contact with the virus. But questions about the drug’s real-world effectiveness at preventing HIV transmission remained — particularly concerning the issue of adherence to a regimen of taking a pill every day.

“After the initial iPrEx study, there was concern that the protective effect of Truvada was fragile, and that individuals taking the drug would need to adhere perfectly to daily regimen for it to work,” said Grant, who is also a professor at the University of California, San Francisco (UCSF). “This new study suggests that Truvada can help block the virus even if the person on a daily regimen doesn’t always adhere perfectly.”

Perfect adherence to drug regimens is notoriously difficult for people to accomplish. But finding out whether patients are taking medications as prescribed is also challenging — they tend to over-report their adherence because they think that is what the clinicians want to hear. So the research team had to find a better way to calculate Truvada’s effectiveness while taking into account differing adherence levels.

The team developed a clinical trial in which they gave different amounts of the drug (two, four or seven doses per week) to a cohort of 24 people without HIV. This resulted in different drug concentrations in blood drawn from each participant, thereby mimicking different levels of adherence. They then used a model to compare the drug concentrations in the blood of these participants to the concentrations of original iPrEx study participants in order to determine how well iPrEx participants adhered to the daily regimen, and how well they were protected against HIV at different levels of adherence.

“Surprisingly, we found that the iPrEx participants didn’t have to adhere perfectly to the drug regimen to reap Truvada’s benefits,” said Grant. “Even in those patients who didn't adhere perfectly, their risk of contracting HIV still dropped by more than 90 percent — offering a high level of protection against the virus.”

Traditionally, adherence to preventative drugs such as Truvada has been measured in qualitative terms, such as “adequate” or “perfect.” But this study is the first to establish an objective, quantitative method that estimates drug concentration levels and then correlates those levels with the drug’s effectiveness at preventing transmission. These results could open the door to the exploration of ways to optimize dosing — which would make it less costly, more convenient and more adaptable to people’s habits.

“Our immediate next step, however, is to take the methods we’ve developed and create simple yet powerful tools that can measure drug adherence to help doctors monitor how well Truvada is working in their patients,” said Anderson. “Yet until these and other efficacy studies of alternative dosing strategies have been completed, the only regimen that that should be used in clinical practice is the FDA-approved one Truvada each day.”

“Patients should still take one pill a day to achieve the best results, and we encourage people to explore multiple methods to prevent HIV — such as regular condom use, early treatment of HIV infection in partners, good communication and male circumcision,” Grant said. “We hope that our findings lead to more effective use of prevention tools that finally squash the HIV/AIDS epidemic.”

Senior Research Associate Vanessa MacMahan also participated in this research at Gladstone. Other research participants include UCSF Professor David Glidden, PhD, and San Francisco Department of Public Health Investigator Albert Liu, MD. The research was funded by the US National Institutes of Health with co-funding from the Bill and Melinda Gates Foundation.

Truvada is manufactured by Gilead Sciences, which donated the drug for the studies but was not otherwise involved in the research. Truvada is one tablet that contains two medications (emtricitabine and tenofovir disoproxil fumarate). The medications are available in generic forms at cost in the poorest countries of the world.

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New health education website launched

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3:34 pm | Thursday, September 13th, 2012

A new health education website, HepBsmart.com, sponsored by Gilead Sciences, Inc., intended for audiences in the United States, is now online.

Launched last September 7, HepBsmart.com contains practical information about chronic hepatitis B (CHB), a potentially life-threatening liver disease that affects an estimated two million people in the United States and is the leading cause of liver cancer.

Chronic hepatitis B is caused by a virus and can slowly damage the liver, without causing obvious symptoms. Chronic hepatitis B can be diagnosed with a simple blood test, prevented with a vaccine, and managed with appropriate care – but alarmingly, most people living with the disease don’t know they are infected.

Without treatment, 1 in 4 people with CHB may die of disease-related complications. The impact of chronic hepatitis B in the United States is more severe among Asian American communities.

HepBsmart.com features:

• Information on how to prevent CHB, testing for the disease, and management of CHB.

• An innovative animated video depicting a CHB patient’s journey from diagnosis to care (available in 14 languages with subtitles).

• Educational brochures in 14 languages, including Chinese, Korean, Vietnamese, and Tagalog among others.

HepBSmart.com is an educational website created by Gilead Sciences, a maker of medicines for chronic hepatitis B. The website is part of Gilead’s ongoing effort to raise community awareness of chronic hepatitis B.

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