SUMMARY: A shorter 12 to 16 week course of pegylated interferon plus ribavirin is not as effective overall for people with chronic hepatitis C virus (HCV) genotypes 2 or 3, according to a meta-analysis and 2 recent international trials. However, abbreviated treatment may be a viable option for selected patients with rapid virological response at 4 weeks, low HCV viral load, and inability to tolerate longer therapy.
By Liz Highleyman
HCV genotypes 2 and 3 are easier to treat than genotypes 1 or 4. The standard course of therapy for genotype 2 or 3 is pegylated interferon plus ribavirin for 24 weeks, increasing to 48 weeks for hard-to-treat genotype 1. Genotypes 2 and 3 also have a higher response rate of 70%-80% in most studies, compared with only about 50% for genotype 1.
Because chronic hepatitis C patients with genotypes 2 and 3 often respond rapidly to therapy -- and because interferon is expensive and can cause difficult side effects -- researchers have explored whether treatment for 12, 14, or 16 weeks might work as well as 24 weeks.
During hepatitis C treatment efficacy is assessed by measuring HCV viral load after 4 weeks (rapid virological response, or RVR), 12 weeks (early virological response, or EVR), 24 weeks (end-of-treatment response, or ETR), and 24 weeks after completion of therapy (sustained virological response, or SVR). Patients who experience RVR at week 4 are significantly more likely to go on to achieve SVR. People who still have undetectable viral load 24 weeks after finishing treatment are considered cured.
12-16 Weeks Meta-analysis
As reported in the September 2010 Journal of Clinical Gastroenterology, Ashwani Singal from the University of Texas Medical Branch in Galveston and colleagues performed a meta-analysis of prior studies of abbreviated treatment.
The study authors searched medical literature databases for studies that compared short-term (12 to 16 weeks) vs standard 24 week treatment using pegylated interferon plus 800 mg/day fixed-dose ribavirin for genotype 2 or 3 patients who had achieved RVR. They identified 6 relevant studies -- including a total of 2434 participants -- that reported data on ETR, SVR, and relapse rates.
After achieving RVR, patients treated for a total of 24 weeks were significantly more likely to achieve SVR than those treated for 16 weeks (79% vs 70%; P = 0.008). Conversely, 24 week patients had a significantly lower relapse rate (9% vs 23%, respectively; P < 0.00001). Results did not change when people with genotype 2 vs 3, or those with high vs low baseline viral load, were analyzed separately.
The pooled odds ratio for SVR using shorter treatment was 0.54, or about half as likely, while the pooled odds ratio for experiencing viral relapse was 3.12, or about 3 times more likely (P = 0.008 and < 0.00001, respectively).
However, people treated for 24 weeks were significantly more likely to discontinue therapy ahead of schedule than those receiving shorter-duration treatment (12% vs 5%; P < 0.0001). The researchers found that it would be cost-effective to reduce treatment duration to 12-16 weeks, and then re-treat patients who experience relapse with a second 24 week course of therapy.
"Advantages of short-term treatment include better patient compliance, lower rate of adverse effects, and cost," the authors concluded. "Short-term treatment may be an option for patients unable to tolerate treatment."
Scandinavian Trials
In the second study, published in the May 2010 European Journal Gastroenterology and Hepatology, Olav Dalgard from Rikshospitalet in Oslo and colleagues compared 14 vs 24 week treatment in chronic genotype 2 or 3 patients with RVR, defined as HCV RNA < 50 IU/mL after 4 weeks of therapy.
The analysis included participants in 2 Scandinavian studies, one a non-randomized pilot trial with 122 patients, the other a randomized controlled trial with 428 patients. In both trials, treatment-naive participants were treated with 1.5 mcg/kg/week pegylated interferon alpha-2b (PegIntron) plus 800-1400 mg/day weight-adjusted ribavirin (genotype 2 or 3 patients typically receive a fixed dose of 800 mg regardless of weight).
In the pilot trial, all patients with RVR were treated for 14 weeks, while in the larger trial participants with RVR were randomized to receive therapy for either 14 or 24 weeks.
In an analysis of all RVR patients treated per protocol, 91% of those who received 14 weeks of therapy achieved SVR, compared with 95% of those treated for 24 weeks. The difference of 4% fell well within the pre-determined 10% margin needed to show inferiority, allowing the researchers to conclude that 14 week treatment was non-inferior to 24 weeks.
The relapse rate was highest among participants older than 40 years, those with genotype 3, and those with a high baseline viral load. However, prolonging treatment from 14 to 24 weeks did not reduce the relapse rate substantially for any of these groups.
International Study
Finally, in the third study, described in the June 2010 issue of Hepatology, Moises Diago from Hospital General de Valencia in Spain and an international team of colleagues compared SVR and relapse rates among patients with RVR (again < 50 IU/mL) who were randomly assigned to receive treatment for 16 or 24 weeks in the ACCELERATE trial.
This study included 863 genotype 2 or 3 participants with RVR (66% of the initial 1309 eligible patients in the study). All were treated with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 800 mg/day ribavirin. The analysis included only those participants who took their assigned treatment for at least 80% of the planned duration.
The overall SVR rate was significantly higher among genotype 2 patients treated for 24 weeks rather than 16 weeks (91% vs 82%, respectively; P = 0.0006). The difference for participants with genotype 3, however, did not reach statistical significance (90% vs 84%, respectively; P = 0.1308). Among patients with low baseline viral load (HCV RNA <400.000 IU/mL), SVR rates with 24 or 16 weeks of treatment were also statistical equivalent (95% vs 91%, respectively; P = 0.2012).
Relapse rates were significantly lower among people randomized to 24 weeks of therapy vs 16 weeks, both overall (6% vs 15%; P < 0.0001) and when participants with genotype 2 (5% vs 17%; P = 0.0001) and those with genotype 3 (7% vs 14%; P = 0.0489) were analyzed separately.
Significant pre-treatment predictors of SVR included assigned treatment duration of 24 weeks (P = 0.0006), absence of advanced liver fibrosis or cirrhosis according to biopsy (P = 0.0032), lower HCV viral load (P = 0.0017), and lower body weight (P < 0.0001).
"The standard 24-week regimen of [Pegasys] plus ribavirin is significantly more effective than an abbreviated 16-week regimen in genotype 2/3 patients who achieve an RVR," the study authors concluded. "Abbreviated regimens may be considered in patients with a low baseline viral load who achieve an RVR."
Overview
In an editorial accompanying Singal's meta-analysis, Donald Jensen from the University of Chicago Medical Center attempted to make sense of the conflicting findings from studies to date of shorter treatment durations for genotype 2 or 3 patients. Even previous meta-analyses, which are intended to resolve such questions, have produced contradictory results.
Along with baseline viral load and genotype 2 vs 3, ribavirin dose may be an important factor, he suggested, since it reduces the chances of relapse after completion of treatment.
"In summary, finding convincing evidence to support RVR-guided duration shortening in all genotypes 2 and 3 subjects is still not available," Jensen wrote. "The difference in SVR rates, however, remains small (< 10%) and narrower still for those patients with low baseline viral load."
"As the authors point out, it may not be unreasonable in selected cases -- perhaps those with an RVR yet poorly tolerant of side effects -- to strongly consider shortening therapy and if relapse occurs, retreat for a longer duration," he concluded.
Investigator affiliations:
Singal study: Department of Gastroenterology and Hepatology, University of Texas Medical Branch, Galveston, TX; Department of Gastroenterology and Hepatology, Michael DeBakey VA Medical Center, Baylor College of Medicine, Houston, TX.
Dalgard study: Medical Department, Rikshospitalet, Oslo, Norway. Diago study: Hepatology Section, Hospital General de Valencia, Valencia, Spain; Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA; Department of Hepatology and Gastroenterology, INSERM U724, CHU de Nancy, Vandoeuvre-les-Nancy, France; J.W. Goethe University Hospital, Frankfurt, Germany; Fundacion de Investigacion de Diego, Santurce, Puerto Rico; St Luke's Center for Liver Disease, Houston, TX; Roche, Basel, Switzerland; University of Florida, Gainsville, FL.
10/26/10
References
AK Singal and BS Anand. Tailoring Treatment Duration to 12 to 16 Weeks in Hepatitis C Genotype 2 or 3 With Rapid Virologic Response: Systematic Review and Meta-analysis of Randomized Controlled Trials. Journal of Clinical Gastroenterology 44(8): 583-587 (Abstract). September 2010.
O Dalgard, K Bjoro, H Ring-Larsen, and H Verbaan. In patients with HCV genotype 2 or 3 infection and RVR 14 weeks treatment is noninferior to 24 weeks. Pooled analysis of two Scandinavian trials. European Journal Gastroenterology and Hepatology 22(5): 552-556 (Abstract). May 2010.
M Diago, ML Shiffman, JP Bronowicki, and others. Identifying hepatitis C virus genotype 2/3 patients who can receive a 16-week abbreviated course of peginterferon alfa-2a (40KD) plus ribavirin. Hepatology 51(6): 1897-1903 (Abstract). June 2010.
DM Jensen. Treatment duration for genotypes 2 and 3: still confusing after all these years (Editorial). Journal of Clinical Gastroenterology 44(8): 527-528 (Free full text). September 2010.
Source
October 26, 2010
IL28B and the Control of Hepatitis C Virus Infection
Gastroenterology. 2010 Oct 12. [Epub ahead of print]
Balagopal A, Thomas DL, Thio CL.
Division of Infectious Diseases, Viral Hepatitis Center, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
Abstract
Treatment-induced and spontaneous clearance of hepatitis C virus (HCV) infection are affected by various host factors. Polymorphisms in the region of the gene IL28B are associated with HCV clearance, implicating the gene product, interferon (IFN)-λ 3, in the immune response to HCV. Although it is not clear how the IL28B haplotype affects HCV clearance, IFNλ3 upregulates interferon-stimulated genes (ISGs), similar to interferon-α and β, but via a different receptor. There is also evidence that IFNλ3 affects the adaptive immune response. The IL28B genotype can be considered, along with other factors, in predicting patient responses to therapy with pegylated interferon-α and ribavirin. We review the genetic studies that uncovered the association between IL28B and HCV clearance, the biology of IFNλ3, the clinical implications of the genetic association, and areas of future research. All studies published in Gastroenterology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
PMID: 20950615 [PubMed - as supplied by publisher]
Source
Balagopal A, Thomas DL, Thio CL.
Division of Infectious Diseases, Viral Hepatitis Center, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
Abstract
Treatment-induced and spontaneous clearance of hepatitis C virus (HCV) infection are affected by various host factors. Polymorphisms in the region of the gene IL28B are associated with HCV clearance, implicating the gene product, interferon (IFN)-λ 3, in the immune response to HCV. Although it is not clear how the IL28B haplotype affects HCV clearance, IFNλ3 upregulates interferon-stimulated genes (ISGs), similar to interferon-α and β, but via a different receptor. There is also evidence that IFNλ3 affects the adaptive immune response. The IL28B genotype can be considered, along with other factors, in predicting patient responses to therapy with pegylated interferon-α and ribavirin. We review the genetic studies that uncovered the association between IL28B and HCV clearance, the biology of IFNλ3, the clinical implications of the genetic association, and areas of future research. All studies published in Gastroenterology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
PMID: 20950615 [PubMed - as supplied by publisher]
Source
Vertex loss widens, drug application nears
Mon Oct 25, 2010 5:32pm EDT
* Loss widens as costs of telaprevir studies grow
* Expects to seek telaprevir approval in coming weeks
NEW YORK Oct 25 (Reuters) - Vertex Pharmaceuticals on Monday reported a wider third-quarter loss as it stepped up research on its promising experimental treatment for hepatitis C, and said it plans to seek U.S. approval for the medicine in coming weeks.
Vertex (VRTX.O) said it had a net loss $209 million, or $1.04 per share, in the third quarter, as it spent heavily on mid-stage and late-stage trials of its telaprevir treatment for the liver disease. That compared with a net loss of $149.6 million, or 84 cents per share, a year ago.
Analysts on average expected a loss of 93 cents per share in the most recent quarter, according to Thomson Reuters I/B/E/S.
Vertex reported third quarter revenue of $23.8 million. Wall Street was expecting revenue of $30.3 million.
The Cambridge, Massachusetts-based company, which is also developing treatments for inflammation, cystic fibrosis, and other diseases, said it continues to expect a net loss of $750 million for full-year 2010. Excluding special items, it expects a loss of $600 million.
Telaprevir is widely expected to become a game changer in the treatment of hepatitis C, which can severely damage the liver over a period of decades after infection with the virus. Some analysts believe the drug could eventually garner annual sales of more than $4 billion.
The lofty expectations are based on telaprevir's ability to cure a far higher percentage of patients than the tough to tolerate standard drugs, and its potential to cut the current 48-week treatment duration in half when used in combination with interferon and ribavirin.
In September, Vertex said telaprevir in a pivotal late-stage trial cured 65 percent of patients who had previously failed to be cured by standard drugs.
Telaprevir, from a new class of hepatitis C treatments, is an antiviral drug that is expected to compete with a similar medicine being developed by Merck & Co (MRK.N) called boceprevir. But analysts have been virtually unanimous in their belief that telaprevir is the superior medicine.
Merck has completed phase III trials. (Reporting by Ransdell Pierson; Editing by Carol Bishopric)
Source
Also See:
-- Vertex Quarter Blemished by Hep C Hiccup
-- Vertex Pharmaceuticals Reports Third Quarter 2010 Financial Results and Highlights Progress in Hepatitis C and Cystic Fibrosis Development Programs
* Loss widens as costs of telaprevir studies grow
* Expects to seek telaprevir approval in coming weeks
NEW YORK Oct 25 (Reuters) - Vertex Pharmaceuticals on Monday reported a wider third-quarter loss as it stepped up research on its promising experimental treatment for hepatitis C, and said it plans to seek U.S. approval for the medicine in coming weeks.
Vertex (VRTX.O) said it had a net loss $209 million, or $1.04 per share, in the third quarter, as it spent heavily on mid-stage and late-stage trials of its telaprevir treatment for the liver disease. That compared with a net loss of $149.6 million, or 84 cents per share, a year ago.
Analysts on average expected a loss of 93 cents per share in the most recent quarter, according to Thomson Reuters I/B/E/S.
Vertex reported third quarter revenue of $23.8 million. Wall Street was expecting revenue of $30.3 million.
The Cambridge, Massachusetts-based company, which is also developing treatments for inflammation, cystic fibrosis, and other diseases, said it continues to expect a net loss of $750 million for full-year 2010. Excluding special items, it expects a loss of $600 million.
Telaprevir is widely expected to become a game changer in the treatment of hepatitis C, which can severely damage the liver over a period of decades after infection with the virus. Some analysts believe the drug could eventually garner annual sales of more than $4 billion.
The lofty expectations are based on telaprevir's ability to cure a far higher percentage of patients than the tough to tolerate standard drugs, and its potential to cut the current 48-week treatment duration in half when used in combination with interferon and ribavirin.
In September, Vertex said telaprevir in a pivotal late-stage trial cured 65 percent of patients who had previously failed to be cured by standard drugs.
Telaprevir, from a new class of hepatitis C treatments, is an antiviral drug that is expected to compete with a similar medicine being developed by Merck & Co (MRK.N) called boceprevir. But analysts have been virtually unanimous in their belief that telaprevir is the superior medicine.
Merck has completed phase III trials. (Reporting by Ransdell Pierson; Editing by Carol Bishopric)
Source
Also See:
-- Vertex Quarter Blemished by Hep C Hiccup
-- Vertex Pharmaceuticals Reports Third Quarter 2010 Financial Results and Highlights Progress in Hepatitis C and Cystic Fibrosis Development Programs
HIV and HCV health beliefs in an inner-city community
J Viral Hepat. 2010 Oct 18. doi: 10.1111/j.1365-2893.2010.01383.x. [Epub ahead of print]
Krauskopf K, McGinn TG, Federman AD, Halm EA, Leventhal H, McGinn LK, Gardenier D, Oster A, Kronish IM.
Division of General Internal Medicine, Mount Sinai School of Medicine, New York, NY Division of General Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX Institute of Health, Health Care Policy and Aging Research, Rutgers, The State University of New Jersey, New Brunswick, NJ Ferkauf Graduate School of Psychology, Yeshiva University, Albert Einstein College of Medicine, New York, NY Charles B. Wang Community Health Center, New York, NY, USA.
Abstract
Summary. Chronic infection with the hepatitis C virus (HCV) is more prevalent than human immunodeficiency virus (HIV) infection, but more public health resources are allocated to HIV than to HCV. Given shared risk factors and epidemiology, we compared accuracy of health beliefs about HIV and HCV in an at-risk community. Between 2002 and 2003, we surveyed a random patient sample at a primary care clinic in New York. The survey was organized as domains of Common Sense Model of Self-Regulation: causes ('sharing needles'), timeline/consequences ('remains in body for life', 'causes cancer') and controllability ('I can avoid this illness', 'medications may cure this illness'). We compared differences in accuracy of beliefs about HIV and HCV and used multivariable linear regression to identify factors associated with relative accuracy of beliefs. One hundred and twenty-two subjects completed the survey (response rate 42%). Mean overall health belief accuracy was 12/15 questions (80%) for HIV vs 9/15 (60%) for HCV (P < 0.001). Belief accuracy was significantly different across all domains. Within the causes domain, 60% accurately believed sharing needles a risk factor for HCV compared to 92% for HIV (P < 0.001). Within the timeline/consequences domain, 42% accurately believed HCV results in lifelong infection compared to 89% for HIV (P < 0.001). Within the controllability domain, 25% accurately believed that there is a potential cure for HCV. Multivariable linear regression revealed female gender as significantly associated with greater health belief accuracy for HIV. Thus, study participants had significantly less accurate health beliefs about HCV than about HIV. Targeting inaccuracies might improve public health interventions to foster healthier behaviours and better hepatitis C outcomes.
© 2010 Blackwell Publishing Ltd.
Source
Krauskopf K, McGinn TG, Federman AD, Halm EA, Leventhal H, McGinn LK, Gardenier D, Oster A, Kronish IM.
Division of General Internal Medicine, Mount Sinai School of Medicine, New York, NY Division of General Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX Institute of Health, Health Care Policy and Aging Research, Rutgers, The State University of New Jersey, New Brunswick, NJ Ferkauf Graduate School of Psychology, Yeshiva University, Albert Einstein College of Medicine, New York, NY Charles B. Wang Community Health Center, New York, NY, USA.
Abstract
Summary. Chronic infection with the hepatitis C virus (HCV) is more prevalent than human immunodeficiency virus (HIV) infection, but more public health resources are allocated to HIV than to HCV. Given shared risk factors and epidemiology, we compared accuracy of health beliefs about HIV and HCV in an at-risk community. Between 2002 and 2003, we surveyed a random patient sample at a primary care clinic in New York. The survey was organized as domains of Common Sense Model of Self-Regulation: causes ('sharing needles'), timeline/consequences ('remains in body for life', 'causes cancer') and controllability ('I can avoid this illness', 'medications may cure this illness'). We compared differences in accuracy of beliefs about HIV and HCV and used multivariable linear regression to identify factors associated with relative accuracy of beliefs. One hundred and twenty-two subjects completed the survey (response rate 42%). Mean overall health belief accuracy was 12/15 questions (80%) for HIV vs 9/15 (60%) for HCV (P < 0.001). Belief accuracy was significantly different across all domains. Within the causes domain, 60% accurately believed sharing needles a risk factor for HCV compared to 92% for HIV (P < 0.001). Within the timeline/consequences domain, 42% accurately believed HCV results in lifelong infection compared to 89% for HIV (P < 0.001). Within the controllability domain, 25% accurately believed that there is a potential cure for HCV. Multivariable linear regression revealed female gender as significantly associated with greater health belief accuracy for HIV. Thus, study participants had significantly less accurate health beliefs about HCV than about HIV. Targeting inaccuracies might improve public health interventions to foster healthier behaviours and better hepatitis C outcomes.
© 2010 Blackwell Publishing Ltd.
Source
Management of Recurrent Hepatitis C Following Liver Transplantation: Fibrosing Cholestatic Hepatitis C
Posted by James
Although it occurs in less than 10% of transplant recipients with chronic HCV, a severe and rapidly progressive form of recurrent HCV infection characterized by cholestatic disease has a major impact on survival. In contrast to a chronic hepatitis observed in most patients with recurrent HCV, this syndrome is defined by a total serum bilirubin of more than 6 mg/dL, elevated alkaline phosphatase or gamma glutamyltransferase levels more than 5 times the upper limit of normal, high serum HCV RNA levels, and histologic features including central hepatocyte ballooning without necrosis, cholangiolar proliferation without loss of bile ducts, and intrahepatic cholestasis in the absence of significant inflammation, biliary obstructive disease, or vascular complications.15,18 Onset typically occurs within the first 6 months following liver transplantation, and rapid progression to allograft failure may occur within 1 year. In addition, patient survival following repeat liver transplantation for fibrosing cholestatic HCV is severely compromised; thus, retransplantation is not an acceptable management option in this case.
Risk Factors for Severe Liver Disease
Several recipient, donor, and viral factors, as well as the use of specific immunosuppressive agents, have been identified as risk factors for increased severity of disease progression, allograft loss, and decreased survival in patients with HCV who undergo liver transplantation (Table 1). The presence of a severe histologic grade of inflammation early in the post-transplant course, particularly within the first year, may be predictive of more rapid fibrosis progression and cirrhosis at 5 years. Elevated serum HCV RNA levels both prior to undergoing transplant and during the post-transplant period may also be associated with progressive disease. Donor age has been identified as a major risk factor, as increased age, particularly over 50 years, is associated with more rapid disease progression, development of cirrhosis, and HCV-associated graft failure. Additional factors that may potentially be associated with severe recurrent disease include infectionwith HCV genotype 1, presence of cryoglobulinemia, female gender, increased recipient age, non-white ethnicity of recipient, donor steatosis, and cold ischemia time. However, data that strongly support these factors, specifically in association with HCV disease progression, are limited or, in some cases, conflicting. viagra plus
Table 1. Established Risk Factors for Severe Recurrent Hepatitis C
Virus (HCV) Following Liver Transplantation:
• Fibrosing cholestatic HCV syndrome
• Increased serum HCV RNA levels (pre- or posttransplantation)
• Early recurrence or severe histologic inflammatory activity within 1 year
• Use of high-dose intravenous pulse corticosteroids or muromonab-CD3
• Increased donor age
• Cytomegalovirus infection
• HIV-HCV co-infection
Cytomegalovirus (CMV) infection is common in liver transplant recipients and is a major risk factor for severe recurrence of HCV-associated liver disease. HCV patients who develop CMV viremia following liver transplantation are at an increased risk of advanced histologic changes, including periportal and bridging necrosis, lobular inflammatory activity, and development of cirrhosis. The greatest risk of CMV disease occurs in the setting of donor CMV seropositivity and recipient sero- negativity. Prophylaxis or preemptive therapy have been described as a means of preventing CMV infection in at-risk individuals. Prophylaxis with valganciclovir for 3 months following liver transplantation has been reported as the most common strategy utilized in this population. Immunosuppression may have a significant impact on the risk of disease progression following transplant. Viral kinetics studies have described a rapid increase in serum HCV RNA levels in patients who receive high- dose intravenous corticosteroids intraoperatively or in the treatment of acute cellular rejection. Further studies have identified the use of pulse intravenous corticosteroid therapy or muromonab-CD3 (Orthoclone OKT3, Ortho Biotech; an anti-CD3 monoclonal antibody) as independent risk factors for development of cirrhosis and graft failure. Results of prospective studies evaluating outcomes in HIV-HCV co-infected individuals have revealed significantly reduced post- transplant survival in co-infected patients compared to other HIV-positive or non-HIV transplant recipients, with 3- and 5-year survival rates as low as 56% and 33%, respectively. In particular, HIV-HCV co-infected patients with CD4+ cell counts less than 200 cells/pL are at an increased risk, indicating the negative impact of an immunocompromised state in the setting of immunosuppressive therapy following transplantation. Additional factors associated with decreased survival in this population include elevated post-transplant HIV or HCV viral load, intolerance to antiretroviral therapy, and African American ethnicity. kamagra tablets
Post-Transplant Monitoring
The most accurate means of testing for the presence of HCV-associated disease resulting from recurrent HCV infection is a liver biopsy. Although elevations in serum aminotransferase and HCV RNA levels may occur in the setting of HCV recurrence, histopathologic assessment by an experienced pathologist provides the most definitive diagnostic information and is critical to distinguishing between recurrent HCV and other disease processes, including acute or chronic rejection, biliary disease, or other viral infections such as CMV. Annual liver biopsies are recommended in HCV liver transplant recipients in order to assess for progressive allograft fibrosis and potential candidacy for antiviral therapy, as combination peginterferon alfa (PegIFN) and ribavirin (RBV) should be considered in patients with histologic evidence of recurrent HCV and stage 2 fibrosis.
Source
Although it occurs in less than 10% of transplant recipients with chronic HCV, a severe and rapidly progressive form of recurrent HCV infection characterized by cholestatic disease has a major impact on survival. In contrast to a chronic hepatitis observed in most patients with recurrent HCV, this syndrome is defined by a total serum bilirubin of more than 6 mg/dL, elevated alkaline phosphatase or gamma glutamyltransferase levels more than 5 times the upper limit of normal, high serum HCV RNA levels, and histologic features including central hepatocyte ballooning without necrosis, cholangiolar proliferation without loss of bile ducts, and intrahepatic cholestasis in the absence of significant inflammation, biliary obstructive disease, or vascular complications.15,18 Onset typically occurs within the first 6 months following liver transplantation, and rapid progression to allograft failure may occur within 1 year. In addition, patient survival following repeat liver transplantation for fibrosing cholestatic HCV is severely compromised; thus, retransplantation is not an acceptable management option in this case.
Risk Factors for Severe Liver Disease
Several recipient, donor, and viral factors, as well as the use of specific immunosuppressive agents, have been identified as risk factors for increased severity of disease progression, allograft loss, and decreased survival in patients with HCV who undergo liver transplantation (Table 1). The presence of a severe histologic grade of inflammation early in the post-transplant course, particularly within the first year, may be predictive of more rapid fibrosis progression and cirrhosis at 5 years. Elevated serum HCV RNA levels both prior to undergoing transplant and during the post-transplant period may also be associated with progressive disease. Donor age has been identified as a major risk factor, as increased age, particularly over 50 years, is associated with more rapid disease progression, development of cirrhosis, and HCV-associated graft failure. Additional factors that may potentially be associated with severe recurrent disease include infectionwith HCV genotype 1, presence of cryoglobulinemia, female gender, increased recipient age, non-white ethnicity of recipient, donor steatosis, and cold ischemia time. However, data that strongly support these factors, specifically in association with HCV disease progression, are limited or, in some cases, conflicting. viagra plus
Table 1. Established Risk Factors for Severe Recurrent Hepatitis C
Virus (HCV) Following Liver Transplantation:
• Fibrosing cholestatic HCV syndrome
• Increased serum HCV RNA levels (pre- or posttransplantation)
• Early recurrence or severe histologic inflammatory activity within 1 year
• Use of high-dose intravenous pulse corticosteroids or muromonab-CD3
• Increased donor age
• Cytomegalovirus infection
• HIV-HCV co-infection
Cytomegalovirus (CMV) infection is common in liver transplant recipients and is a major risk factor for severe recurrence of HCV-associated liver disease. HCV patients who develop CMV viremia following liver transplantation are at an increased risk of advanced histologic changes, including periportal and bridging necrosis, lobular inflammatory activity, and development of cirrhosis. The greatest risk of CMV disease occurs in the setting of donor CMV seropositivity and recipient sero- negativity. Prophylaxis or preemptive therapy have been described as a means of preventing CMV infection in at-risk individuals. Prophylaxis with valganciclovir for 3 months following liver transplantation has been reported as the most common strategy utilized in this population. Immunosuppression may have a significant impact on the risk of disease progression following transplant. Viral kinetics studies have described a rapid increase in serum HCV RNA levels in patients who receive high- dose intravenous corticosteroids intraoperatively or in the treatment of acute cellular rejection. Further studies have identified the use of pulse intravenous corticosteroid therapy or muromonab-CD3 (Orthoclone OKT3, Ortho Biotech; an anti-CD3 monoclonal antibody) as independent risk factors for development of cirrhosis and graft failure. Results of prospective studies evaluating outcomes in HIV-HCV co-infected individuals have revealed significantly reduced post- transplant survival in co-infected patients compared to other HIV-positive or non-HIV transplant recipients, with 3- and 5-year survival rates as low as 56% and 33%, respectively. In particular, HIV-HCV co-infected patients with CD4+ cell counts less than 200 cells/pL are at an increased risk, indicating the negative impact of an immunocompromised state in the setting of immunosuppressive therapy following transplantation. Additional factors associated with decreased survival in this population include elevated post-transplant HIV or HCV viral load, intolerance to antiretroviral therapy, and African American ethnicity. kamagra tablets
Post-Transplant Monitoring
The most accurate means of testing for the presence of HCV-associated disease resulting from recurrent HCV infection is a liver biopsy. Although elevations in serum aminotransferase and HCV RNA levels may occur in the setting of HCV recurrence, histopathologic assessment by an experienced pathologist provides the most definitive diagnostic information and is critical to distinguishing between recurrent HCV and other disease processes, including acute or chronic rejection, biliary disease, or other viral infections such as CMV. Annual liver biopsies are recommended in HCV liver transplant recipients in order to assess for progressive allograft fibrosis and potential candidacy for antiviral therapy, as combination peginterferon alfa (PegIFN) and ribavirin (RBV) should be considered in patients with histologic evidence of recurrent HCV and stage 2 fibrosis.
Source
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