January 31, 2011

Hepatology. 2011 Jan;53(1):14-22. doi: 10.1002/hep.24056.

Darling JM, Aerssens J, Fanning G, McHutchison JG, Goldstein DB, Thompson AJ, Shianna KV, Afdhal NH, Hudson ML, Howell CD, Talloen W, Bollekens J, De Wit M, Scholliers A, Fried MW.

University of North Carolina, Chapel Hill, NC.

Abstract

Polymorphisms of the IL28B gene are highly associated with sustained virological response (SVR) in patients with chronic hepatitis C treated with peginterferon and ribavirin. Quantitation of interferon-γ-inducible protein-10 (IP-10) may also differentiate antiviral response. We evaluated IP-10 levels in pretreatment serum from 115 nonresponders and 157 sustained responders in the Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C cohort, including African American (AA) and Caucasian American (CA) patients. Mean IP-10 was lower in sustained responders compared with nonresponders (437 ± 31 vs 704 ± 44 pg/mL, P < 0.001), both in AA and CA patients. The positive predictive value of low IP-10 levels (<600 pg/mL) for SVR was 69%, whereas the negative predictive value of high IP-10 levels (>600 pg/mL) was 67%. We assessed the combination of pretreatment IP-10 levels with IL28B genotype as predictors of treatment response. The IL28B polymorphism rs12979860 was tested in 210 participants. The CC, CT, and TT genotypes were found in 30%, 49%, and 21% of patients, respectively, with corresponding SVR rates of 87%, 50%, and 39% (P < 0.0001). Serum IP-10 levels within the IL28B genotype groups provided additional information regarding the likelihood of SVR (P < 0.0001). CT carriers with low IP-10 had 64% SVR versus 24% with high IP-10. Similarly, a higher SVR rate was identified for TT and CC carriers with low versus high IP-10 (TT, 48% versus 20%; CC, 89% versus 79%). IL28B genotype and baseline IP-10 levels were additive but independent when predicting SVR in both AA and CA patients. Conclusion: When IL28B genotype is combined with pretreatment serum IP-10 measurement, the predictive value for discrimination between SVR and nonresponse is significantly improved, especially in non-CC genotypes. This relationship warrants further investigation to elucidate the mechanisms of antiviral response and prospective validation. (Hepatology 2011;).

Copyright © 2010 American Association for the Study of Liver Diseases.

PMID: 21254158 [PubMed - in process]

Source
Hepatology. 2011 Jan;53(1):317-24. doi: 10.1002/hep.24074.

Charlton MR, Thompson A, Veldt BJ, Watt K, Tillmann H, Poterucha JJ, Heimbach JK, Goldstein D, McHutchison J.

Division of Gastroenterology and Hepatology and. charlton.michael@mayo.edu

Abstract

Polymorphism in the interleukin-28B (IL28B) gene region, encoding interferon (IFN)-λ3, is strongly predictive of response to antiviral treatment in the nontransplant setting. We sought to determine the prevalence and impact on clinical outcomes of donor and recipient IL28B genotypes among liver transplant recipients. The cohort study included 189 consecutive patients infected with hepatitis C virus (HCV) who underwent liver transplantation between January 1, 1995, and January 1, 2005, at the Mayo Clinic, Rochester, MN. Genotyping of the polymorphism rs12979860 was performed on DNA collected from all donors and recipients in the cohort. Sixty-five patients received IFN-based antiviral therapy. The CC IL28B variant was less common in the chronic HCV-infected recipients than in non-HCV donor livers (33% versus 47%, P = 0.03). IL28B recipient genotype was significantly predictive of fibrosis stage, with TT genotype being associated with more rapid fibrosis (Pearson chi-square P = 0.024 for the comparison G versus A). Donor and recipient IL28B genotype were independently associated with sustained virologic response (P < 0.005). The presence of IL28B CC variant in either the recipient (R) or donor (D) liver was associated with increased rate of sustained virologic response (D-non-CC/R-non-CC = 3/19 [16%] versus D-CC/R-non-CC = 11/22 [50%] versus D-non-CC/R-CC = 5/12 [42%] versus R-CC/D-CC = 6/7 [86%], P = 0.0095). IL28B genotype was not significantly associated with survival (overall/liver-related). Conclusion: Recipient IL28B TT genotype is associated with more severe histological recurrence of HCV. Recipient and donor liver IL28B genotype are strongly and independently associated with IFN-based treatment response in patients after orthotopic liver transplantation. The data suggest that CC donor livers might be preferentially allocated to patients with HCV infection. (Hepatology 2011;).

Copyright © 2010 American Association for the Study of Liver Diseases.

Source
Eur J Gastroenterol Hepatol. 2011 Jan 20. [Epub ahead of print]

Singal AK, Sagi S, Kuo YF, Weinman S.

aDepartment of Internal Medicine, Division of Gastroenterology bDepartment of Internal Medicine cBiostatististics, Center for Aging, University of Texas Medical Branch, Galveston, Texas dLiver Center and Department of Internal Medicine, University of Kansas, Kansas City, Kansas, USA.

Abstract

BACKGROUND AND AIMS: Limited information is available on the impact of hepatitis C virus (HCV) infection on the clinical course and outcome of acute alcoholic hepatitis (AH), a condition with a significant mortality. We designed this retrospective study to assess effect of HCV on the outcome of patients with AH.

METHODS: Medical charts of patients with a discharge diagnosis of AH (defined using rigorous clinical criteria) were reviewed. Patients were stratified based on the presence or absence of concomitant HCV infection. The disease severity was estimated at admission and at day 7 using model for end-stage disease and discriminant function index scores. Patient survival at 6 months was confirmed with the county death registry. RESULTS : A total of 76 (29 HCV positive) AH cases were analyzed. At admission, disease severity was similar in both groups with severe disease in 53% (49% of AH alone and 59% of AH+HCV; P=0.18). Although severity scores at day 7 were not available for all patients, disease severity tended to be worse for patients with AH+HCV. Kaplan-Meier survival curves showed a poor survival for AH+HCV compared with AH alone (69 vs. 91%; log-rank P=0.015). Although patients with AH+HCV were treated less often compared with AH alone (27 vs. 54%; P=0.05), HCV emerged as an independent risk factor for a poor outcome at 6 months (Cox proportional hazard ratio 8.45; P=0.01) after controlling for patient demographics, disease severity at admission, and treatment.

CONCLUSION: HCV may be a risk factor for patients with AH with a worse outcome at 6 months. If our findings are confirmed in larger databases, prospective studies are needed to examine mechanisms for this effect of HCV on the outcome of AH.

PMID: 21258239 [PubMed - as supplied by publisher]

Source
Public release date: 31-Jan-2011

Contact: John Heys
jheys@idsociety.org
703-299-0412
Infectious Diseases Society of America

Research suggests improvements in prevention and treatment efforts needed

[EMBARGOED FOR JAN. 31, 2011] A recent 20-year study of injection drug users (IDUs) in Baltimore found a significant decline in new cases of HIV infection but only a slight decline in new cases of hepatitis C virus (HCV) infection. The findings suggest that efforts to curb blood-borne transmission of these viral infections have had success but must be expanded against the highly transmissible HCV. Researchers from Johns Hopkins School of Public Health and other centers, led by Shruti H. Mehta, PhD, MPH, report the findings in the March 1 issue of The Journal of Infectious Diseases, now available online. (Please see below for a link to the embargoed study online.)

Previous data had suggested that HIV incidence among IDUs has declined. This trend is often attributed in part to harm reduction measures, including needle exchange programs and substance abuse treatment. However, these measures have not been as successful in lowering the rates of HCV incidence and prevalence. For example, HCV infection is nearly 10 times more transmissible by sharing needles than is HIV infection. Sharing a needle even once can be enough to transmit HCV.

The investigators found that new cases of HIV infection declined dramatically across four different time periods during the past 20 years, from 5.5 per 100 person-years (PY) in 1988-'89, to two per 100 PY in 1994-'95, and to zero cases in 1998 and 2005-'08. While researchers also observed reductions in new cases of HCV infection, these were not nearly as substantial: from 22 per 100 PY in 1988-'89, to 17.2 per 100 PY in 1994-'95, to 17.9 in 1998, and to 7.8 per 100 PY in 2005-'08. Overall, cases appeared to decline only among younger IDUs, who had started injecting drugs recently.

According to researchers, these data suggest that "current prevention efforts delay but do not prevent HCV at the population level and will need to be further intensified to reduce risk of HCV infection to the level of HIV." Efforts on both the prevention and the treatment fronts to reduce the reservoir of HCV-infected IDUs will have to be expanded, the investigators concluded.

In an accompanying editorial, Jason Grebeley, PhD, and Gregory J. Dore, MB BS, MPH, PhD, of the University of New South Wales in Australia, agreed that higher prevalence of HCV infection and greater transmission risk following an injection with a contaminated syringe as compared to HIV have hampered harm reduction measures. They also noted that current implementation of harm reduction measures in most settings is inadequate. Rates of equipment sharing remain high, and access to opioid substitution therapy and other drug treatment programs is limited.

The editorial authors also pointed out the impact that an HCV vaccine could have on new cases of HCV infection. Though a highly efficacious vaccine has not yet been discovered, efforts to do so are crucial. They suggested that even though the window for preventing HCV may be small, improvements in HCV prevention are feasible.

###

Fast Facts:

1) Among the community of injection drug users (IDUs) in Baltimore, HIV incidence declined dramatically over 20 years, while new cases of hepatitis C virus (HCV) infection declined only slightly.

2) HIV incidence decreased from 5.5 per 100 person-years (PY) in 1988-'89, to two per 100 PY in 1994-'95, and to zero in 1998 and 2005-'08. The declines in HCV infection were not nearly as substantial: from 22 per 100 PY in 1988-'89, to 17.2 per 100 PY in 1994-'95, to 17.9 in 1998, and to 7.8 per 100 PY in 2005-'08.

3) Prevention and treatment efforts must be expanded to reduce the number of HCV infections among IDUs.

NOTE: The study and the accompanying editorial are available online. They are embargoed until 12:01 a.m. EST on Monday, Jan. 31, 2011:

"Changes in Blood-borne Infection Risk Among Injection Drug Users" http://www.oxfordjournals.org/our_journals/jid/jiq112.pdf

"Prevention of Hepatitis C Virus in Injecting Drug Users: A Narrow Window of Opportunity" http://www.oxfordjournals.org/our_journals/jid/jiq111.pdf

Founded in 1904, The Journal of Infectious Diseases is the premier publication in the Western Hemisphere for original research on the pathogenesis, diagnosis, and treatment of infectious diseases; on the microbes that cause them; and on disorders of host immune mechanisms. Articles in JID include research results from microbiology, immunology, epidemiology, and related disciplines. JID is published under the auspices of the Infectious Diseases Society of America (IDSA). Based in Arlington, Va., IDSA is a professional society representing more than 9,000 physicians and scientists who specialize in infectious diseases. For more information, visit http://www.idsociety.org/.

Source
J Gastroenterol Hepatol. 2011 Feb;26(2):228-39. doi: 10.1111/j.1440-1746.2010.06488.x.

Liu CH, Kao JH.

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.

Abstract

Hepatitis C virus (HCV) infection is a major health problem in patients with end-stage renal disease (ESRD). The incidence of acute HCV infection during maintenance dialysis is much higher than that in the general population because of the risk of nosocomial transmission. Following acute HCV infection, most patients develop chronic HCV infection, and a significant proportion develop chronic hepatitis, cirrhosis, and even hepatocellular carcinoma. Overall, chronic hepatitis C patients on hemodialysis bear an increased risk of liver-related morbidity and mortality, either during dialysis or after renal transplantation. Interferon (IFN) therapy is modestly effective for the treatment of HCV infection in ESRD patients. Conventional or pegylated IFN monotherapy has been used to treat acute hepatitis C in ESRD patients with excellent safety and efficacy. Regarding chronic hepatitis C, approximately one-third of patients can achieve a sustained virological response (SVR) after conventional or pegylated IFN monotherapy. The combination of low-dose ribavirin and conventional or pegylated IFN has further improved the SVR rate in treatment-naïve or retreated ESRD patients in clinical trials. Similar to the treatment of patients with normal renal function, baseline and on-treatment HCV virokinetics are useful to guide optimized therapy in ESRD patients. Of particular note, IFN-based therapy is not recommended at the post-renal transplantation stage because of the low SVR rate and risk of acute graft rejection. In conclusion, ESRD patients with HCV infection should be encouraged to receive antiviral therapy, and those who achieve an SVR usually have long-term, durable, virological, biochemical, and histological responses.

© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

PMID: 21261711 [PubMed - in process]

Source

Chemoprevention of hepatocellular carcinoma in chronic hepatitis C

Recent Results Cancer Res. 2011;188:85-99.

Morgan TR.

Gastroenterology Section, VA Long Beach Healthcare System, 5901 E. Seventh Street - 11, Long Beach, CA, 90822, USA, timothy.morgan@va.gov.

Abstract

Hepatitis C virus (HCV) infection causes chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma (HCC). The incidence of hepatocellular carcinoma in the United States tripled between 1975 and 2005, and is expected to increase further, and to remain elevated for more than 20 years. Curing hepatitis C infection in patients with cirrhosis through treatment with peginterferon and ribavirin reduces the risk of developing hepatocellular carcinoma. Several noncurative treatments also appear to reduce the risk of hepatocellular carcinoma in patients with chronic hepatitis C. Prospective studies report a reduced incidence of hepatocellular carcinoma among patients treated with a mixture of carotenoids with or without myo-inositol, with vitamin K(2), or with polyprenoic acid (an acyclic retinoid). Uncontrolled and/or retrospective studies have reported beneficial effects of treatment with Sho-saiko-to, glycyrrhizin and ursodeoxycholic acid on hepatocellular carcinoma incidence. Meta-analyses of epidemiologic studies show a reduced risk of hepatocellular carcinoma among liver disease patients who drink two or more cups of coffee per day. Numerous agents prevent or reduce hepatocarcinogenesis in animal models. An ongoing Phase II clinical trial is evaluating S-adenosylmethionine (SAMe) as a potential chemopreventive agent in hepatitis C cirrhosis. Overall, these data suggest that chemoprevention of hepatocellular carcinoma in patients with chronic hepatitis C is an achievable objective.

PMID: 21253791 [PubMed - in process]

Source
Jan 31, 2011 08:00 ET

Clinical Data From Targeted Antibody Bavituximab Expected in 2Q11

TUSTIN, CA--(Marketwire - January 31, 2011) - Peregrine Pharmaceuticals, Inc. (NASDAQ: PPHM), a clinical-stage biopharmaceutical company developing first-in-class monoclonal antibodies for the treatment of cancer and viral infections, today announced the completion of enrollment in the company's Phase Ib dose escalation safety study of bavituximab in patients coinfected with chronic hepatitis C virus (HCV) and HIV. Previously this month, Peregrine initiated a randomized Phase II HCV trial to evaluate 12 weeks of therapy with bavituximab, a phosphatidylserine (PS)-targeting monoclonal antibody with immune-modulating potential, in combination with the antiviral drug ribavirin versus standard of care, pegylated interferon alpha 2a and ribavirin.

"Completion of enrollment in our third Phase I HCV trial is an important milestone for our bavituximab antiviral program, and sets the stage for reporting clinical data at a medical conference in the second quarter of this year while we begin to evaluate combination treatment with the antiviral agent ribavirin in a recently initiated study," said Steven W. King, president and chief executive officer of Peregrine. "Though standard treatment for chronic HCV may soon evolve with the introduction of new targeted antiviral drug candidates, immune stimulation with interferon remains a critical component of therapy. Preclinical data support the potential combination of bavituximab and ribavirin and we look forward to seeing how this combination initially compares to standard interferon and ribavirin treatment for 12 weeks in our Phase II study for patients infected with HCV."

In prior HCV clinical trials, bavituximab administered as monotherapy in single and multiple doses demonstrated a positive safety profile with no dose-limiting toxicities or serious adverse events. Bavituximab as a monotherapy also showed promising on therapy antiviral activity of up to 1.5 log viral load reduction.

Bavituximab may address a fundamental "immune evasion" mechanism exploited by many infectious pathogens. A growing body of published data from researchers worldwide shows that bavituximab's PS target, exposed on the surface of cells infected by viruses and protozoan parasites, suppresses the immune system's ability to fight disease. PS-targeting antibodies such as bavituximab bind to PS and block the immunosuppressive signals created by the target, thereby allowing the immune system to mount a robust immune response against the pathogen.

About the Phase Ib HCV Trial

Peregrine's open-label, dose escalation safety study is designed to assess the safety and of bavituximab in up to 24 patients chronically infected with HCV and HIV. Patient cohorts received ascending dose levels of bavituximab weekly for up to 8 weeks. Primary endpoints include safety and pharmacokinetics, and secondary endpoints will measure HCV and HIV RNA by PCR. For further information about Peregrine's HCV trials, please visit http://www.peregrinetrials.com/ or http://www.clinicaltrials.gov/ct2/results?term=bavituximab.

About HCV

According to the U.S. Centers for Disease Control and Prevention, an estimated 3.2 million individuals in the United States have chronic hepatitis C virus (HCV) infection. Chronic HCV infection is a serious disease that can result in long-term health problems, including liver damage, liver failure, liver cancer, or death. It is the leading cause of cirrhosis and liver cancer and the most common reason for liver transplant in the United States. Approximately 8,000 to 10,000 people die every year from HCV-related liver disease.

About Bavituximab's Antiviral Approach

Bavituximab is the first in a new class of patented antibody therapeutics that target and bind to phosphatidylserine (PS), a specific phospholipid component of cell membranes. Bavituximab helps reactivate and direct the body's immune system to destroy infected cells and virus particles that exhibit this specific phospholipid on their surface. Since their target is host-derived rather than pathogen-derived, PS-targeting antibodies have the potential for broad-spectrum antiviral activity and are also expected to be much less susceptible to the viral mutations that often lead to drug resistance.

Researchers have found that PS is exposed on the outer membrane of cells infected with HCV, HIV, influenza, herpes viruses, hemorrhagic fever viruses, respiratory syncytial virus, measles as well as other viruses. A growing body of scientific publications, including Nature Medicine and The Journal of Experimental Medicine, has highlighted data on the role of PS and Peregrine's PS-targeting therapies in infectious diseases.

About Peregrine Pharmaceuticals

Peregrine Pharmaceuticals, Inc. is a biopharmaceutical company with a portfolio of innovative monoclonal antibodies in clinical trials for the treatment of cancer and serious viral infections. The company is pursuing multiple clinical programs in cancer and hepatitis C virus infection with its lead product candidate bavituximab and novel brain cancer agent Cotara®. Peregrine also has in-house cGMP manufacturing capabilities through its wholly-owned subsidiary Avid Bioservices, Inc. (www.avidbio.com), which provides development and biomanufacturing services for both Peregrine and outside customers. Additional information about Peregrine can be found at http://www.peregrineinc.com/.

Safe Harbor Statement: Statements in this press release which are not purely historical, including statements regarding Peregrine Pharmaceuticals' intentions, hopes, beliefs, expectations, representations, projections, plans or predictions of the future are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. The forward-looking statements involve risks and uncertainties including, but not limited to, the risk that results from the Phase Ib or Phase II HCV trials will not be consistent with results experienced in earlier HCV clinical trials and preclinical studies, the risk that investigators may experience delays in patient enrollment, risk that results may not support registration filings with the U.S. Food and Drug Administration, and the risk that Peregrine may not have or raise adequate financial resources to complete the planned clinical programs. Factors that could cause actual results to differ materially or otherwise adversely impact the company's ability to obtain regulatory approval for its product candidates include, but are not limited to, uncertainties associated with completing preclinical and clinical trials for our technologies; the early stage of product development; the significant costs to develop our products as all of our products are currently in development, preclinical studies or clinical trials; obtaining additional financing to support our operations and the development of our products; obtaining regulatory approval for our technologies; anticipated timing of regulatory filings and the potential success in gaining regulatory approval and complying with governmental regulations applicable to our business. Our business could be affected by a number of other factors, including the risk factors listed from time to time in the company's SEC reports including, but not limited to, the annual report on Form 10-K for the year ended April 30, 2010 and the quarterly report on Form 10-Q for the quarter ended October 31, 2010. The company cautions investors not to place undue reliance on the forward-looking statements contained in this press release. Peregrine Pharmaceuticals, Inc. disclaims any obligation, and does not undertake to update or revise any forward-looking statements in this press release.

Peregrine Contact:
Amy Figueroa
Peregrine Pharmaceuticals
(800) 987-8256
info@peregrineinc.com

Source

Hepatitis C virus Resistance to Protease Inhibitors

Philippe Halfon a, Stephen Locarnini b

Received 13 December 2010; received in revised form 20 January 2011; accepted 20 January 2011. published online 31 January 2011.
Accepted Manuscript

Abstract

Recent advances in molecular biology have led to the development of novel small molecules that target specific viral proteins of the hepatitis C virus (HCV) life cycle. These drugs, collectively termed directly acting antivirals (DAA) against HCV, include a range of non-structural (NS) 3/NS4A protease, NS5B polymerase and NS5A inhibitors at various stages of clinical development. The rapid replication rate of HCV, along with the low fidelity of its polymerase, gives rise to the generation of mutations throughout the viral genome resulting in remarkable sequence variation in the HCV population, known as a quasispecies. The efficacy of DAAs is limited by the presence of these mutations resulting in amino-acid substitutions within the targeted proteins which affect viral sensitivity to these compounds. Thus, due to the high genetic variability of HCV, variants with reduced susceptibility to DAA can occur naturally even before treatment begins, but usually at low levels. Not surprisingly then, these changes are selected in patients either breaking through or not responding to potent DAA treatment. Six major position mutations in the NS3 HCV Protease (36, 54, 155, 156, 168, and 170) have now been reported in vitro or in vivo associated with different levels of resistance. The amino acid composition at several of the drug resistance sites can vary between the HCV genotypes/ subtypes, resulting in different consensus amino acids leading to a reduction in replicative fitness as well as reduced DAA sensitivity. Different amino acid diversity profiles for HCV genotypes/subtypes suggest differences in the position/ type of immune escape and drug resistance mutations. Also, different pathways of resistance profiles based on the chemical scaffold (linear or macrocyclic) of the protease inhibitors have been described. This review first describes how resistance to a protease inhibitor can develop and then provides an overview of the mechanism of how particular mutations confer varying levels of resistance to protease inhibitor, which have been identified and characterized using both genotypic and phenotypic tools. Future potential therapeutic strategies to assist patients who do develop resistance to protease inhibitors are also outlined. The challenge developing new HCV protease inhibitors should take in consideration not only the antiviral potency of the drugs, the occurrence and importance of side effects, the frequency of oral administration, but also the resistance profiles of these agents

a Virological Departement Laboratoire Alphabio, Hôpital Ambroise Paré, Marseille, France
b Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia

PII: S0168-8278(11)00079-1
doi:10.1016/j.jhep.2011.01.011
© 2011 Published by Elsevier Inc.

Source

January 29, 2011

Gastroenterology
Volume 140, Issue 2 , Pages 459-468.e1, February 2011

Patrick Marcellin, Xavier Forns, Tobias Goeser, Peter Ferenci, Frederik Nevens, Giampiero Carosi, Joost P. Drenth, Lawrence Serfaty, Koen De Backer, Rolf Van Heeswijk, Donghan Luo, Gaston Picchio, Maria Beumont

Abstract

Background & Aims
Recent studies have shown that 12 weeks of treatment with telaprevir, administered every 8 hours (q8h), combined with pegylated interferon (peginterferon) alfa-2a plus ribavirin significantly increased the rate of hepatitis C virus (HCV) eradication (sustained virologic response [SVR]) in patients infected with HCV genotype 1 compared with approved therapy. We investigated the efficacy, safety, tolerability, and pharmacokinetics of telaprevir given q8h or every 12 hours (q12h) in combination with peginterferon alfa-2a or alfa-2b.

Methods
Treatment-naive patients (n = 161) infected with HCV genotype 1 were randomly assigned to groups that were given open-label telaprevir (750 mg q8h or 1125 mg q12h) in combination with standard doses of peginterferon alfa-2a (180 μg/wk) and ribavirin (1000–1200 mg/day) or peginterferon alfa-2b (1.5 μg·kg−1·wk−1) and ribavirin (800–1200 mg/day). Patients received triple therapy for 12 weeks, followed by 12 or 36 additional weeks of treatment with peginterferon alfa and ribavirin, based on virologic response.

Results
Baseline characteristics were similar for all groups. SVR rates were 81.0% to 85.0% among groups; most patients received 24 weeks of therapy (68.0%). There were no significant differences in SVR rates (intent-to-treat analysis) among groups (P ≥ .787), between the pooled q8h and q12h groups (P = .997), or between the pooled peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin groups (P = .906). The safety profile was similar among all groups.

Conclusions
A high proportion (>80%) of patients achieved an SVR regardless of the telaprevir dosing frequency (q8h or q12h) or type of peginterferon alfa used (alfa-2a or alfa-2b).

Source
Gastroenterology
Volume 140, Issue 2 , Pages 450-458.e1, February 2011

Kathleen B. Schwarz, Regino P. Gonzalez–Peralta, Karen F. Murray, Jean P. Molleston, Barbara A. Haber, Maureen M. Jonas, Philip Rosenthal, Parvathi Mohan, William F. Balistreri, Michael R. Narkewicz, Lesley Smith, Steven J. Lobritto, Stephen Rossi, Alexandra Valsamakis, Zachary Goodman, Patricia R. Robuck, Bruce A. Barton, Peds-C Clinical Research Network

Abstract

Background & Aims
Although randomized trials of adults infected with hepatitis C virus (HCV) have shown that ribavirin increases the efficacy of pegylated interferon (PEG), such trials have not been performed in children. We conducted a randomized controlled trial of PEG and ribavirin, compared with PEG and placebo, in children 5 to 17 years old with chronic hepatitis C.

Methods
HCV RNA–positive children from 11 university medical centers were randomly assigned to receive either PEG alfa-2a (PEG-2a; 180 μg/1.73 m2 body surface area, subcutaneously each week; n = 55) and ribavirin (15 mg/kg orally in 2 doses daily) or PEG-2a and placebo (n = 59) for 48 weeks. The primary end point was sustained virologic response (SVR; lack of detectable HCV RNA at least 24 weeks after stopping therapy).

Results
SVR was achieved in 53% of children treated with PEG-2a and ribavirin, compared with 21% of children who received PEG-2a and placebo (P < .001). Early virologic response (HCV RNA reduction >2 log10 IU at 12 weeks) had a negative predictive value of only 0.89 in children with genotype 1, indicating that these children might benefit from 24 weeks of therapy before stopping treatment. Side effects, especially neutropenia, led to dose modification in 40% of children. Eighty-two percent of the PEG/ribavirin and 86% of the PEG/placebo group were in compliance with the year 2 follow-up visit; the durability of virologic response was 100% in both groups.

Conclusions
The combination of PEG and ribavirin is superior to PEG and placebo as therapy for chronic hepatitis C in children and adolescents.

Source

January 28, 2011

Vitamins in the treatment of chronic viral hepatitis

Br J Nutr. 2011 Jan 24:1-8. [Epub ahead of print]

Fiorino S, Conti F, Gramenzi A, Loggi E, Cursaro C, Di Donato R, Micco L, Gitto S, Cuppini A, Bernardi M, Andreone P.

Operative Unit of Internal Medicine, Budrio Hospital, Budrio, BO, Italy.

Abstract

Hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related chronic infections represent a major health problem worldwide. Although the efficacy of HBV and HCV treatment has improved, several important problems remain. Current recommended antiviral treatments are associated with considerable expense, adverse effects and poor efficacy in some patients. Thus, several alternative approaches have been attempted. To review the clinical experiences investigating the use of lipid- and water-soluble vitamins in the treatment of HBV- and HCV-related chronic infections, PubMed, the Cochrane Library, MEDLINE and EMBASE were searched for clinical studies on the use of vitamins in the treatment of HBV- and HCV-related hepatitis, alone or in combination with other antiviral options. Different randomised clinical trials and small case series have evaluated the potential virological and/or biochemical effects of several vitamins. The heterogeneous study designs and populations, the small number of patients enrolled, the weakness of endpoints and the different treatment schedules and follow-up periods make the results largely inconclusive. Only well-designed randomised controlled trials with well-selected endpoints will ascertain whether vitamins have any role in chronic viral hepatitis. Until such time, the use of vitamins cannot be recommended as a therapy for patients with chronic hepatitis B or C.

PMID: 21255469 [PubMed - as supplied by publisher]

Source
Debika Bhattacharya, MD; T. Umbleja, MS; F. Carrat, MD, PhD; R. T. Chung, MD; M. G. Peters, MD; F. Torriani, MD; J. Andersen, PhD; J. S. Currier, MD, MSc

Posted: 01/27/2011; J Acquir Immune Defic Syndr. 2010;55(2):170-175. © 2010 Lippincott Williams & Wilkins

Abstract and Introduction

Abstract

Background: In HIV/ hepatitis C virus (HCV) coinfection, adverse events (AEs) during HCV therapy account for 12%-39% of treatment discontinuations. It is unknown whether sex influences complications.

Methods: Meta-analysis to study the effect of sex and other predictors of AEs in 3 randomized trials, ACTG 5071, APRICOT, and ANRSHCO2-RIBAVIC of Interferon (IFN) and Pegylated IFN (PEG), both with and without Ribavirin, in HIV/HCV coinfection. Primary endpoints were AEs requiring treatment discontinuation (AETD) or first dose modification (AEDM). Multi-covariate stratified logistic regression was used to study predictors and assess interactions with sex.

Results: Twenty-one percent of 1376 subjects were women; 61% had undetectable HIV RNA; 14% were antiretroviral (ARV) therapy naive at entry; median CD4 was 485 cells per cubicmillimeter. Seventeen percent had an AETD and 50% AEDM; women had more AETD than men (24% vs. 16% P = 0.003) and AEDM (61% vs. 48% P < 0.0001). AETD and AEDM occurred earlier in women; but the types of AETD and AEDM were similar between sexes. Seventy-four percent of AETDs and 49% of AEDMs involved constitutional AEs; 18% of AETD depression; and 26% of AEDM neutropenia. We identified interactions with sex and body mass index (BMI) (P = 0.04, continuous) and nonnucleoside reverse transcriptase inhibitor (P = 0.03); more AETDs were seen in men with lower BMI (P = 0.01) and in women on nonnucleoside reverse transcriptase inhibitors (P = 0.009). More AEDMs were seen with PEG [odds ratio (OR) = 2.07]; older age (OR = 1.48 per 10 years); decreasing BMI (OR = 1.04 per kg/m2); HCV genotype 1, 4 (OR = 1.31); Ishak 5, 6 (OR = 1.42); decreasing Hgb (OR = 1.23 per g/dL); and decreasing absolute neutrophil count (1.04 per 500 cells/mm3). Interactions between sex and ARV-naive status (P = 0.001) and zidovudine (P = 0.001) were identified: There were more AEDMs in ARV-naive women (P = 0.06) and ARV-experienced men (P = 0.001) and higher AEDMs in women with zidovudine (P = 0.0002).

Conclusions: Although there was no difference in type of AE, AETD and AEDM were more frequent and occurred earlier in women. In women, ARV regimen may be an important predictor of AETDs during HCV therapy and should be explored as a predictor of AEs in HIV/HCV coinfection trials.

Introduction

HIV and hepatitis C virus (HCV) coinfection is common, with reported prevalences of 16%-33% in HIV-infected individuals in the United States.[1,2] Liver-related mortality is the leading cause of death among HIV-infected persons in the United States in the highly active antiretroviral therapy era.[3] When compared with HCV monoinfection, hepatitis C therapy is less effective in HIV- and HCV-coinfected individuals due, in part, to high rates of treatment discontinuation.[4–6] In HCV infection without HIV, the percentage of discontinuations secondary to adverse events (AEs) or laboratory abnormalities ranged from 7% to 21%,[7–9] whereas in HIV coinfection, treatment discontinuations occurred in 12%-39%.[4–6] Understanding the role of factors such as sex and its relationship with the development of adverse drug reactions will be critical to improving treatment outcomes in HIV and HCV coinfection.

In HCV monoinfection, women are more likely to experience anemia with interferon and ribavirin therapy[10] and may be more likely to develop depression.[11–13] In HIV infection, studies with nucleoside analogue therapy suggested that women were more likely to require dose modifications, to develop severe symptoms, and to experience AEs related to didanosine.[14,15] There is little known, however, about the sex differences in AEs during HCV therapy in HIV/HCV coinfection. Additionally, the relationship between female sex, AEs during therapy, and other factors potentially related to AEs such as body mass index (BMI) and antiretroviral (ARV) regimen have not been well described in HIV and HCV coinfection.

The aim of our study was to investigate whether female sex was associated with an increased incidence and/or more rapid onset of AEs requiring treatment modification or discontinuation. In addition, we examined whether factors such as ARV regimen and BMI were important in predicting AEs in women and men.

Methods

We performed a meta-analysis of the AIDS Clinical Trials Group (ACTG) A5071, AIDS Pegasys Ribavirin International Coinfection Trial (APRICOT), and Agence Nationale de Recherches sur le SIDA (ANRS) HCO2-RIBAVIC HCV treatment studies in HIV/HCV coinfection, conducted by different clinical trial networks between 2000 and 2003. Subject-level data were obtained for each study. Only subjects who initiated HCV treatment were included in the analysis. Detailed inclusion criteria, study design, and criteria for treatment discontinuation and dose modifications are described in detail elsewhere.[4–6] In A5071, subjects were randomized to receive 180 μg of peginterferon alfa-2a weekly for 48 weeks and dose-escalated ribavirin or 6 million IU of interferon alfa-2a 3 times weekly for 12 weeks followed by 3 million IU 3 times weekly for 36 weeks with dose-escalated ribavirin.[5] Ribavirin was administered as 600 milligrams per day for 4 weeks, 800 milligrams per day for 4 weeks, and then 1000 milligrams per day for the remainder of the study. In APRICOT, subjects were randomized to peginterferon alfa-2a (180 μg/wk) plus ribavirin (800 mg/d), peginterferon alfa-2a plus placebo, or interferon alfa-2a (3 million IU 3 times a week) plus ribavirin (800 mg/d).[6] In RIBAVIC, subjects were randomized to 1.5 μg/kg peginterferon alfa-2b once a week or subcutaneous injections of 3 million units of interferon alfa-2b 3 times a week for 48 weeks. All subjects also received 800 mg of ribavirin daily.[4] Laboratory toxicities, signs and symptoms, and clinical events, excluding death, were considered AEs. The primary endpoints were adverse events requiring treatment discontinuation (AETD) or first dose modification (AEDM). The primary endpoints were decided a priori and were selected because identification of factors responsible for treatment discontinuations and drug dose modifications may lead to implications for patient selection and management before and during therapy. Because the present analyses used data on subject level, the overall results are weighted by study, giving the greatest weight to APRICOT (62% of the N = 1376 subjects) followed by ANRSHCO2-RIBAVIC (28%) and A5071 (10%).

Statistical Analysis

Breslow-Day tests were used to ensure that it was appropriate to combine estimates from the 3 studies. Cochran-Mantel-Haenszel tests stratified by study were used to test statistical significance of differences in categorical variables between 2 groups. Stratified Wilcoxon rank-sum tests were used to test the statistical significance of differences between 2 groups in continuous variables. Predictors of AETD and AEDM were examined using simple logistic regression models, stratified by study. In addition to sex, predictors considered in analysis were HCV treatment (pegylated interferon-containing vs. not); race (white vs. non-white); age (continuous); BMI (continuous); HCV genotype (1, 4 vs. other); baseline Ishak fibrosis score (1–4 vs. higher); baseline HCV RNA (<800,000 vs. ≥800,000 IU/mL); baseline HIV-1 RNA (detectable vs. undetectable per definition of each study); baseline CD4 cell count (<500 vs. ≥500 cells/mm3); ARV naive at baseline; stavudine use at baseline; zidovudine (AZT) use at baseline; ARV regimen at baseline, nucleoside reverse transcriptase inhibitors only; containing nonnucleoside reverse transcriptase inhibitors (NNRTI) but no protease inhibitor (PI); containing any PI; baseline absolute neutrophil count (ANC, continuous); baseline platelets (continuous); baseline hemoglobin (continuous); baseline alanine aminotransferase (continuous); and baseline aspartate aminotransferase (continuous). Variables and their interactions with sex that were significant at 0.2 significance level in simple stratified logistic regression were considered in multi-covariate logistic regression models, stratified by study.

Kaplan-Meier estimates were used to summarize time-to-event results. Log-rank tests stratified by study were used to compare times to event between men and women. Stratified Cox proportional hazards model were used to provide an estimate for the magnitude of sex effect. Because AETD and AEDM are competing risks, times to AETD and AEDM were also analyzed using the competing risk methods[16] (treating death, nonresponse, loss to follow-up (LFU), and other known reason (primarily administrative) for treatment discontinuation as competing risks. The results were very similar to the results from Kaplan-Meier and Cox proportional hazards models, and the conclusions on the effect of sex were the same in both analyses. Therefore, the results of standard Kaplan-Meier analysis along with Cox proportional hazards model are provided for simpler interpretation. Results were considered statistically significant if P < 0.05 (2 sided).

Results

One thousand three hundred seventy-six subjects were included in the analysis, 288 (21%) of whom were women; 133 (10%), 860 (62%), and 383 (28%) subjects were from A5071, APRICOT, and ANRSHCO2-RIBAVIC, respectively. Subjects from A5071 were more likely to be non-white (52%), older (median age 45 years), overweight, or obese (57%) and have HCV genotype 1 or 4 (80%) than the subjects from APRICOT (21%, 39 years, 39% and 68%) or from ANRSHCO2-RIBAVIC (5%, 39 years, 18% and 61%).

Overall, 67% of subjects were infected with HCV genotype 1 or 4, and 83% had Ishak fibrosis score <4 (Table 1). Treatment regimens included pegylated interferon and ribavirin in 40%, interferon and ribavirin in 39%, and pegylated interferon alone in 21%; 40% of men and 40% of women received pegylated interferon and ribavirin therapy. Seventeen percent of women and 13% of men were ARV naive (P = 0.16); 48% of women and 42% of men were on D4T-containing regimens (P = 0.11); 18% of women and 11% of men were on nucleoside reverse transcriptase inhibitor-only regimens (P = 0.004); 29% of women and 34% of men were on AZT-containing regimens (P = 0.15); and 26% of women and 28% of men were on NNRTI-containing regimens (P = 0.47).

Fifty-three percent of women vs. 67% of men completed study treatment as specified by the respective study protocol; 24% vs. 16% discontinued treatment early due to toxicities, 11% vs. 9% due to nonresponse, 9% vs. 6% due to other known reasons; 1 woman of 288 vs. 1 man of 1088 died, and 3% of both women and men were lost to follow-up (P = 0.002, stratified by study) (not shown in Table 1).

Adverse Events Requiring Treatment Discontinuation

Women were more likely to experience an AETD than men, 24% vs. 16% (P = 0.003). Primary etiologies of AETD among the 238 who experienced an AETD included constitutional or other symptoms in 176 (74%) and depression in 44 (18%). Discontinuation due to hematologic abnormalities was not common; anemia, thrombocytopenia, and neutropenia were involved in 5%, 5%, and 3% of the treatment discontinuations, respectively, and there was no difference observed by sex. In a post hoc analysis that examined detailed etiologies of AETD among the 176 subjects with constitutional or other symptoms, 68 (39%) included fever, fatigue, weight loss, or gastrointestinal symptoms; 42 (24%) neurologic or psychiatric side effects, and 15 (9%) elevations in hepatic transaminases or lactic acid. The type of AETD was similar between the 2 sexes.

Predictors of AETD

In simple stratified analysis, female sex [odds ratio (OR) = 1.63] was a predictor of AETD. In addition, older age and lower baseline hemoglobin were statistically significant and lower baseline BMI was a marginally significant risk factor of AETD (Table 2). There was no evidence of association between AETD and the other factors listed in Methods-Statistical Analysis. In multicovariate analysis, age (P < 0.0001) and interactions between sex and BMI (P = 0.04) and between sex and NNRTI (P = 0.03) were statistically significant (Table 2). Men with higher BMIs were less likely to experience AETD than men with lower BMIs (OR = 0.94). This association was not observed in women. Women on NNRTI-containing regimens were more likely to have an AETD than ARV-naive women or women on other ARV regimens (OR = 2.23), whereas in men, no association between NNRTI-containing regimen and AETD was observed. Of the 69 women with an AETD, depression was responsible for 16 of 69 AETDs (23%); women on NNRTI therapy were more likely to experience depression, 8 of 25 (32%) than those who were on other ARV or not on ARV 8 of 44 (18%); (P = 0.02).

Adverse Events Requiring Treatment Modification

Women were more likely to experience an AEDM than men, 61% vs. 48% (P < 0.0001). Neutropenia and anemia were the primary hematologic etiologies of AEDM, involved in 26% and 17% of the AEDMs, respectively, and 49% of AEDMs involved constitutional AEs, but the type of AEDM was similar in men and women. An analysis that examined only subjects who received pegylated interferon and ribavirin, the standard of care regimen, demonstrated similar results (not shown).

Predictors of AEDM

In simple stratified analysis, female sex was a predictor of AEDM (OR = 1.72). In addition, pegylated interferon-containing regimen; non-white race; older age; lower baseline BMI; HCV genotype 1 or 4; Ishak fibrosis score 5 or 6; CD4 cell count <500; ARV experienced; AZT use; and lower baseline ANC, Hgb, and alanine aminotransferase were statistically significant predictors of AEDM (Table 3). The other factors listed in the Methods-Statistical Analysis were not statistically significantly associated with AEDM. In multicovariate analysis, receipt of pegylated interferon therapy (OR = 2.07, P < 0.0001), increasing age (OR = 1.48 per 10 years), decreasing BMI (OR = 1.04 per kg/m2), HCV genotype 1, 4 (OR = 1.31), Ishak 5, 6 (OR = 1.42), decreasing ANC (OR = 1.04 per 500 cells/mm3), and decreasing Hgb (OR = 1.23 per g/dL) remained statistically significant (Table 3).

We also identified interactions between sex and ARV-naive status (P = 0.001) and between sex and AZT use (P = 0.001). Interestingly, ARV-naive women were more likely to experience AEDMs than ARV-experienced women (OR = 1.96, P = 0.06), but ARV-naive men were less likely to experience AEDMs (OR = 0.51, P = 0.001). In women, more AEDMs were seen with AZT compared with non-AZT regimens or no ARV (OR 3.56, P = 0.0002); but this association was not seen in men (P = 0.59). In a subgroup analysis examining etiologies of dose modifications in 175 women with AEDM, women on AZT-containing therapy were more likely to experience neutropenia and anemia: 20 of 67 (30%) vs. 21 of 108 (19%) (P = 0.12) and 23 of 67 (34%) vs. 13 of 108 (12%) (P = 0.0004), respectively.

Time to AETD and AEDM

Women discontinued therapy and required dose modification earlier than men. The Cox proportional hazards ratio for time to AETD was 1.54 (95% CI: 1.16 to 2.04) for women compared with men (P = 0.003), whereas the Cox proportional hazards ratio for time to AEDM was 1.43 (95% CI: 1.20 to 1.70) for women compared with men (P < 0.0001) (Fig. 1). The median time to AEDM was 24 weeks in women and 48 weeks in men. There was also a trend toward more rapid platelet decline in women; the median time to the lowest platelet level was 15.6 (12.1–18.1) vs. 18.1 (16.1–18.9) weeks (P = 0.05).

Figure 1. A, Sex effect on the Time to AE requiring treatment discontinuation. B, Sex effect on the Time to AE requiring first study treatment dose modification.

Discussion

In a meta-analysis of 3 large HIV/HCV coinfection trials, women were more likely to experience an AETD or AEDM during HCV therapy in HIV infection. However, the observed types of AEs were similar between sexes. Additionally, AETD and AEDM occurred earlier in women. When exploring the effect modification by sex, women on regimens containing an NNRTI without a PI experienced more AETD and women on AZT-containing regimens experienced more AEs requiring interferon or ribavirin dose modification.

This is the first study to demonstrate that HIV-infected women on hepatitis C therapy experience more AETDs. Although similar sex effects on treatment discontinuation were not reported in large trials of HIV-uninfected HCV-infected women receiving interferon and ribavirin therapy,[7–9] other hepatitis C monoinfection analyses have demonstrated that women experience some AEs (depression and anemia) more commonly than men.[10,11] The relatively lower proportion of women enrolled in the landmark registration trials[7–9] may have precluded analysis of sex effects and discontinuation rates.

When examining the HIV literature, our findings of higher treatment discontinuations in women are similar to some[17,18] but not all[14,19,20] studies in HIV infection. In the CASCADE collaboration, women were more likely to discontinue ARV therapy (HR = 1.61, 95% CI: 1.15 to 2.27),[17] whereas in the ICONA study group, women were twice as likely to discontinue treatment secondary to toxicity.[18] Conversely, 3 other studies did not find higher overall rates of treatment discontinuations among women.[14,19,20]

A sex effect on ARV modifications has also been noted in HIV studies; Currier et al[14] demonstrated that women were 1.25 times more likely to modify didanosine dosage. In HIV infection, women are also more likely to experience AEs while on therapy with descriptions of increased rates of rash and hepatitis with nevirapine[21] and lactic acidosis with nucleoside analogues.[22] The reasons for heightened rates of AEs in women are poorly understood. Differences in body weight and composition, renal clearance, cellular kinase activity, and P-glycoprotein activity may all play a role.

Our finding that women on NNRTI regimens were more likely to discontinue HCV therapy than men is in agreement with other studies examining ARV regimen discontinuation in HIV infection. Women were more likely to discontinue efavirenz (EFV)-based regimens with 38.8% (95% CI: 28.8% to 48.7%) stopping EFV by 48 weeks of treatment compared with 28.3% of men (95% CI: 23.4% to 33.2%).[23] In our analysis, among women with AETD, women receiving NNRTI-based regimens had more depression. This finding, along with the findings that women are more likely to have elevated plasma EFV concentrations[24] are more likely to have mood disorders[25] and may be more likely to experience depression while on interferon therapy,[11] raise the possibility that neuropsychiatric side effects from interferon and EFV-based regimens may be accentuated in women. These findings should be interpreted with caution in this study, however, as we did not have data on type of NNRTI regimen and the number of women on NNRTI regimens who discontinued was small.

The finding that women were more likely to have AEDMs with AZT-containing regimens and a subgroup analysis demonstrating that the majority of AEDM on AZT-containing regimens were hematologic are not unexpected. Women are at an increased risk of developing anemia during ribavirin therapy,[10] and our study suggests that AZT may also play a role in hematologic toxicities in women receiving ribavirin. In hepatitis C monoinfection trials, Sulkowski et al[10] found that the incidence of reaching a Hgb <10 g/dL was 4-fold higher in women, whereas an analysis of interferon alpha-2a trials also found that women were more likely to have anemia.[26] One study demonstrated higher levels of AZT in women,[27] suggesting a possible mechanism for the additive toxicity of ribavirin and AZT. Anderson et al found that women had significantly higher intracellular concentrations of AZT with a female to male ratio of 2:3. Interestingly, we did not find a statistically significant sex difference in the rates of anemia leading to treatment discontinuation; the respective rates were small among both men and women, suggesting that these AEs were well managed in this clinical trial setting.

We also found that older age was independently associated with the incidence of AETD and dose modification. This is supported by Sulkowski et al[10] who also found that older age was associated with hemoglobin decrease in hepatitis C monoinfection studies. The authors speculated that older age may impact hematopoietic reserves in bone marrow, leading to more bone marrow suppression than in younger subjects.[10]

One limitation of our analysis was the heterogeneity of treatment protocols. In ACTG 5071, ribavirin was dose escalated from 600 to 800 mg, and subjects who experienced severe AEs stopped therapy. This dose escalation, however, would only have masked severe AEs. Additionally, the 3 protocols included varying regimens of interferon and ribavirin, with 40% of individuals receiving combination therapy with pegylated interferon and ribavirin. Subgroup analyses on this group with combination therapy, however, demonstrated similar results to that of all regimens. Another limitation of the study included the extensive use of ARVs (AZT and stavudine) that are less common in clinical practice today. Newer more tolerable ARV regimens such as the nuclesos(t)ide transcriptase inhibitor combinations (ie, tenofovir/emtricitabine and abacavir/lamivudine), boosted atazanavir, and raltegravir may lead to a reduced rate of adverse reactions attributable to concomitant ARV and HCV therapy. Analyses of these newer regimens with hepatitis C therapy, and their interactions with sex, are needed. We also acknowledge the presence of competing risks such as LFU, death, nonresponse, and unknown reasons for discontinuation. Therefore, time to AETD and time to first dose modification, respectively, were also analyzed in the competing risks setting, treating death, nonresponse, LFU, and other known reason for treatment discontinuation as competing risks. The results were very similar to the results from Kaplan-Meier and Cox proportional hazards model, and the conclusions on the effect of sex were the same in both analyses. Competing risks may have also reduced the observed AEs and, if dropout secondary to competing risks was associated with covariates, then confounding may have been introduced. Finally, the overall numbers of women experiencing AETDs and AEDMs were low at 69 and 175, respectively, leading us to interpret the interactions and subgroup analyses, including comparisons of types of AEs between men and women, with caution.

In conclusion, women are more likely to experience AEs, leading to hepatitis C treatment dose modification and discontinuation in the setting of HIV/HCV coinfection. Women on NNRTI regimens were more likely to discontinue therapy, and women on AZT-containing regimens were more likely to require dose modifications, suggesting an important sex-mediated role of ARV regimen on the impact of AEs during hepatitis C therapy. ARV regimen may be an important predictor of treatment discontinuation and modification in women and should be further explored as predictors of AEs in HIV/HCV coinfection trials.

References

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2.Staples CT Jr, Rimland D, Dudas D. Hepatitis C in the HIV (human immunodeficiency virus) Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study (HAVACS): the effect of coinfection on survival. Clin Infect Dis. 1999;29:150–154.

3.Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis. 2001;32:492–497.

4.Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA. 2004;292:2839–2848.

5.Chung RT, Andersen J, Volberding P, et al. Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004;351:451–459.

6.Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004;351:438–450.

7.Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–982.

8.Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958–965.

9.McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1485–1492.

10.Sulkowski MS, Wasserman R, Brooks L, et al. Changes in haemoglobin during interferon alpha-2b plus ribavirin combination therapy for chronic hepatitis C virus infection. J Viral Hepat. 2004;11:243–250.

11.Gohier B, Goeb JL, Rannou-Dubas K, et al. Hepatitis C, alpha interferon, anxiety and depression disorders: a prospective study of 71 patients. World J Biol Psychiatry. 2003;4:115–118.

12.Koskinas J, Merkouraki P, Manesis E, et al. Assessment of depression in patients with chronic hepatitis: effect of interferon treatment. Dig Dis. 2002;20:284–288.

13.Fontana RJ, Schwartz SM, Gebremariam A, et al. Emotional distress during interferon-alpha-2B and ribavirin treatment of chronic hepatitis C. Psychosomatics. 2002;43:378–385.

14.Currier JS, Spino C, Grimes J, et al. Differences between women and men in adverse events and CD4+ responses to nucleoside analogue therapy for HIV infection. The Aids Clinical Trials Group 175 Team. J Acquir Immune Defic Syndr. 2000;24:316–324.

15.Moore RD, Fortgang I, Keruly J, et al. Adverse events from drug therapy for human immunodeficiency virus disease. Am J Med. 1996;101:34–40.

16.Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Statist Assoc. 1999;94:496–509.

17.Touloumi G, Pantazis N, Antoniou A, et al. Highly active antiretroviral therapy interruption: predictors and virological and immunologic consequences. J Acquir Immune Defic Syndr. 2006;42:554–561.

18.d'Arminio Monforte A, Lepri AC, Rezza G, et al. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. I.CO.N.A. Study Group. Italian Cohort of Antiretroviral-Naive Patients. AIDS. 2000;14:499–507.

19.Mocroft A, Youle M, Moore A, et al. Reasons for modification and discontinuation of antiretrovirals: results from a single treatment centre. AIDS. 2001;15:185–194.

20.Tedaldi EM, Absalon J, Thomas AJ, et al. Ethnicity, race, and gender. Differences in serious adverse events among participants in an antiretroviral initiation trial: results of CPCRA 058 (FIRST Study). J Acquir Immune Defic Syndr. 2008;47:441–448.

21.Bersoff-Matcha SJ, Miller WC, Aberg JA, et al. Sex differences in nevirapine rash. Clin Infect Dis. 2001;32:124–129.

22.Boxwell DE SB. Lactic acidosis (LA) in patients receiving nucleoside reverse transcriptase inhibitors (NRTIs) [abstract 1284]. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 26–29, 1999, San Francisco, CA.

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24.Burger D, van der Heiden I, la Porte C, et al. Interpatient variability in the pharmacokinetics of the HIV non-nucleoside reverse transcriptase inhibitor efavirenz: the effect of gender, race, and CYP2B6 polymorphism. Br J Clin Pharmacol. 2006;61:148–154.

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Source

Scientific finding aids anti-HCV therapy


2011/01/28 18:04:59

Taipei, Jan. 28 (CNA) Taiwan's top research institute Academia Sinica announced new findings Friday on the hepatitis C virus (HCV) that could help refine anti-HCV therapies in the future.

The team, led by research fellow Steve Chen, found that autophagy, a condition in which cells digest themselves, plays an important role in HCV replication, a process linked to the spread of infection in the body, the institute said.

The study offers medical scientists a direction for seeking more effective drugs for hepatitis C sufferers, Chen said, adding that drugs developed to suppress autophagy can be effective in stopping the virus from multiplying in the host body.

The findings were published in the Jan. 4 issue of the Journal of Clinical Investigation.

Although there are six major genotypes of HCV, only two drugs -- interferon and ribavirin -- are currently used for hepatitis C patients, who sometimes do not respond well to the drugs, Chen said.

"We hope that by understanding the mechanism by which HCV works, we can find ways to curb it," he added.

"This is only the first step in a long journey to find an effective drug for treating HCV," he said. "More work still needs to be done in this field." (By Nancy Liu) ENDITEM/J

Source

January 27, 2011

Liver International
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.
Volume 31, Issue Supplement s1, pages 53–57, January 2011

David R. Nelson

Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02391.x
© 2011 John Wiley & Sons A/S

Author Information

Clinical and Translational Science Institute, University of Florida, FL, USA

* Correspondence: Correspondence David R. Nelson, Clinical and Translational Science Institute, University of Florida, 1600 SW Archer Rd, Gainsville, FL, 32610, USA Tel: +352 273 9500 Fax: +352 392 7393 e-mail: nelsodr@ufl.edu

Keywords:
boceprevir; direct-acting antiviral agents; hepatitis C; novel therapies; protease inhibitors; resistant mutations; telaprevir

Abstract

Abbreviations
BOC, boceprevir; DAA, direct acting antiviral agents; PEG-IFN, pegylated interferon; SOC, standard of care; SVR, sustained virological response; TPR, telaprevir.

Hepatitis C virus (HCV) infection is a global problem with an estimated prevalence of 170 million worldwide and 4 million (1.6%) in the US (1–3). Most patients with acute HCV infection become chronically infected, which increases the risk of developing further complications associated with advanced liver disease (4). Given the projected increase in HCV-related cirrhosis (the proportion of chronic HCV infection with cirrhosis is now 25% and projected to reach 45% in 2030) and hepatocellular carcinoma (HCC), optimal treatment of chronic HCV is a high priority (5). Current standard therapy for HCV includes pegylated interferon (PEG-IFN) and ribavirin (RBV), a combination which is effective in approximately 40–50% of genotype 1-infected patients and 80% of genotype 2 and 3-infected patients (6–8). Unfortunately, most patients in the US and Western Europe are infected with HCV genotype 1. The relatively low response rates in treating genotype 1-infected patients, as well as the long treatment durations and adverse side effects has meant that a small minority of patients opt for treatment. Less than 20% of the HCV-infected population in the US is estimated to have been treated. However, the introduction of oral, direct-acting antiviral agents (DAA) is now on the horizon with anticipated higher cure rates, and potentially shorter treatment durations. Approval of the first oral inhibitors is expected by mid-2011 and many patients are awaiting these new therapies.

Direct-acting antiviral agents: protease inhibitors

The class of drugs in the latest stages of development is HCV serine protease NS3–NS4A inhibitors. The NS3/4A protease is essential to viral replication and is responsible for cleaving the HCV polyprotein and releasing most of the nonstructural proteins. The design of NS3/4A inhibitors is complicated because the active site of the NS3/4A protease is located in a very shallow groove composed of three highly conserved amino acid residues. This key concept explains why most NS3/4A protease inhibitors under development display high antiviral efficacy but a low genetic barrier to resistance and will frequently cause the selection of resistant mutants which can lead to viral breakthrough. The most mature protease inhibitors are telaprevir (TVR) and boceprevir (BOC), which have now completed phase II and III trials and will probably be approved in mid 2011. These programmes have yielded some consistent early lessons for the protease inhibitor class. For naïve, genotype 1 patients, higher cure rates and a shorter duration of therapy can be expected, which will be partially offset by new issues of resistance and increased adverse events.

Protease Inhibition for Viral Evaluation 1 and 2: telaprevir trials

The recently published Protease Inhibition for Viral Evaluation (PROVE 1 and 2, evaluating TVR) and Serine Protease Inhibitor Therapy (SPRINT-1, evaluating BOC) studies evaluated protease inhibitors in combination with PEG-IFN/RBV in genotype 1, naïve patients. In PROVE 1, TVR was dosed at 750 mg every 8 h for 12 weeks in combination with PEG-IFN and RBV followed by an additional 12 weeks or 36 weeks of standard of care (SOC). The results were compared with 48 weeks of SOC (see Table 1). The sustained virological response (SVR) rate in SOC was 41%, compared with 61% (P=0.02) in the 24-week treatment group and 67% (P=0.002) in the 48–week treatment group (9). Relapse rates were highest in the control group (23%) compared with the 24- (2%) and 48-week TVR treatment group (6%). However, more patients discontinued therapy in the TVR treatment groups secondary to adverse side effects, with a rash being the most common reason for discontinuation. In the PROVE 2 trial, shorter treatment duration was investigated with treatment groups receiving triple therapy (TVR+PEG-IFN/RBV) for only 12 weeks (with and without RBV) compared with an additional 12 weeks of SOC (See Table 1). SVR was 46% in the control group, compared with 36% in the non-RBV group (P=0.20), 60% in the 12 weeks triple therapy TVR group (P=0.12) and 69% in the 24 weeks triple therapy TVR group (P=0.004) (10). Relapse rates were highest in the non-RBV treated group (48%) compared with the control group (22%), 12 weeks triple therapy group (30%) and 24 weeks triple therapy group (14%). The most important side effects with TVR were rash, gastrointestinal disorders and anaemia. Although severe rash may require treatment discontinuation, moderate forms can be successfully treated with topical steroids. The median decline in blood haemoglobin concentrations with TVR was approximately 1 g/dl.

The PROVE 1 and 2 seem to indicate that TVR can help overcome negative host and viral factors. A recent pooled analysis looked at a subgroup of patients with characteristics associated with low virological response (11). The overall SVR for the pooled TVR treatment groups was 65 vs. 44% in the control group (P<0.001). SVR rates were significantly higher with TVR-based vs. SOC among patients with baseline HCV RNA ≥800 000 IU/ml (P<0.05), patients with genotype 1a HCV infection (P<0.05), patients with genotype 1b HCV infection (P<0.05), men (P<0.05), patients >50 years of age (P<0.05) and those with bridging fibrosis (P<0.05). The conclusion of this analysis is that TVR is effective in all subgroups of patients who have traditionally been considered difficult to treat. Another phase II trial with TVR was recently released (Study C208) that suggests that SVR rates in naïve patients may be higher than previously reported, especially when a response-guided duration is followed. In this study, treatment-naïve, genotype 1 patients (n=161) were administered triple therapy for 12 weeks with the subsequent PEG-IFN/RBV treatment duration determined according to a response-guided strategy (12). Patients who achieved a rapid virological response (RVR) received a total of 24 weeks of therapy and those who did not have RVR continued PEG-IFN/RBV to weeks 48. The SVR rates in this study ranged from 81 to 85%, higher than those observed in the phase II PROVE trials. These high overall SVR rates emphasize the potential of the triple therapy approach. Results may be explained in part by experienced study centres with very low discontinuation rates (5%) compared with the PROVE studies. In addition, treatment duration was shortened to 24 weeks in patients who achieved RVR, while the remaining patients received 48 weeks of therapy. Between 80 and 83% of patients treated with PEG-IFN-α2a, and 67–69% of patients treated with PEG-IFN-α2b achieved RVR and could therefore be treated for 24 weeks. This study clearly suggests that response-guided therapy based on RVR at week 4 may optimize SVR and provides a useful guide for determining which patients should be treated for 24 vs. 48 weeks.

Serine Protease Inhibitor Therapy-1: boceprevir trial

In the phase II SPRINT-1 trial, triple combination therapy with BOC and the current SOC, PEG-IFN and RBV, was found to induce high rates of SVR (54–75%) in genotype 1 treatment-naive patients, depending on the duration of therapy (13). Unlike TVR, BOC was administered for the duration of treatment. The treatment regimens included a control group treated with 48 weeks of SOC compared with five BOC treatment regimens (4 weeks of PEG-IFN/RBV lead-in followed by triple therapy for 24 or 44 weeks; triple therapy for 28 or 48 weeks; triple therapy, but with low-dose RBV for 48 weeks). The ideal duration of therapy appears to depend upon early viral kinetics. Patients who cleared the virus by week 4 of triple therapy had 82 and 94% chances of achieving SVR after 28 and 48 weeks of treatment respectively. If HCV RNA is detectable after week 4, but becomes undetectable by week 12, 48 weeks of treatment resulted in a 79% SVR rate; shortened treatment was significantly inferior, with only 21% of patients achieving SVR after 28 weeks. Clearance after week 12 was associated with a negligible chance of SVR and appears to indicate an early stopping rule at week 12. In addition to the expected side effects associated with the SOC, treatment with a BOC-containing regimen was associated with increased dysgeusia and anaemia. Anaemia (defined as a decline in haemoglobin level <10 g/dl) occurred in 52–56% of patients in the triple-therapy groups despite administration of epoetin-αat the investigator's discretion, compared with 34% in controls. Higher rates of discontinuation secondary to adverse side effects and viral breakthrough occurred in the BOC treatment groups compared with the control group and anaemia appeared to be a significant problem, with up to 50% of patients receiving erythropoietin. Of note, the highest reported viral breakthrough was seen in the low-dose RBV group.

Ribavirin is required to maximize efficacy with protease inhibitors

As shown above, early phase II studies strongly suggest that RBV is needed in protease inhibitor drug regimens. Patients who did not receive RBV in the PROVE trials and those with low-dose RBV (400–1000 mg) in the SPRINT-1 trial had increased viral breakthrough, higher relapse and lower SVR. This data strongly indicates that standard-dose RBV is needed to optimize response to these first generation protease inhibitors by reducing the development of resistance/breakthrough. It is also clear that the initial rapid decrease in HCV viral levels with protease combination therapy is because of inhibition of wild type virus that then leads to the ‘uncovering’ of pre-existing resistant variants. Resistant variants are present in most patients at very low rates (<1%) and are usually detected after near complete suppression of the dominant, wild type virus. The continued replication of these variants can then lead to a virological breakthrough. To date, mutations conferring TVR-resistance have been identified at four positions, V36A/M/L, T54A, R155K/M/S/T and A156S//T (14). A detailed kinetic analysis of TVR-resistant variants was performed in genotype 1 patients during 14 days of TVR monotherapy and combination therapy with PEG-IFN. TVR monotherapy initially led to a rapid decline in HCV RNA in all patients as a result of a strong reduction in the wild-type virus. In patients who developed a viral rebound during TVR monotherapy, the single mutation variants R155K/T and A156/T were mainly uncovered by wild-type reduction and became dominant after day 8. These single mutation variants were selected from pre-existing quasispecies. The combination of TVR and PEG-IFN was sufficient to inhibit the breakthrough of resistant mutations in a 14-day study (15). It is important to note that low to medium levels of V36 and R155 variants were still observed in single patients up to 3 years after TVR treatment. Antiviral resistance is also a concern with BOC. Mutations were frequently associated with virological breakthrough, and most substitutions occurred at locations comparable to those with TVR. Of note, the time to revert back to wild type varied with the specific mutation in patients who developed resistance mutations. Another important finding from the TVR Phase II trials is the different rates of viral resistance and breakthrough detected between genotype 1a and 1b (much higher for 1a). This can be explained by a difference in the genetic barrier to resistance between the subtypes. For example, the mutation most frequently associated with resistance to TVR is R155K; changing R to K at position 155 requires one nucleotide change in HCV subtype 1a and 2 nucleotide changes in subtype 1b isolates. Thus HCV subtyping may play an important role in helping to select future treatment regimens and predict the development of resistance.

Phase III data for telaprevir and boceprevir

Phase III clinical trials evaluating TVR in combination with PEG-IFN and RBV have now been completed with top-line SVR data being released. The ADVANCE trial enrolled treatment-naïve HCV genotype 1 patients to evaluate 24 weeks of TVR-based therapy. TVR was dosed at 750 mg every 8 h and given for 8 or 12 weeks in combination with PEG-IFN and RBV followed by PEG-IFN and RBV alone until treatment week 24. Patients who did not achieve RVR were treated with PEG-IFN and RBV until week 48. A significantly greater proportion of patients achieved SVR with 12-week and 8-week TVR-based combination regimens (75 and 69% respectively) than in the SOC arm (44%) (16). Relapse rates were reduced three-fold (9%) compared with SOC (28%). In the ILLUMINATE trial, TVR was given for 12 weeks in combination with PEG-IFN and RBV followed by PEG-IFN and RBV alone until treatment week 24 or 48. The aim of the ILLUMINATE trial was to assess whether extending treatment beyond 24 weeks of total therapy improves SVR rates in patients with RVR or EVR. 72% of all subjects achieved SVR, while those with extended RVR (virus negative from week 4 to week 12) achieved SVR rates of 92 and 88% in randomized 24- and 48-week treatment groups respectively (17). Thus, data from these two phase III trials support the use of 24-week TVR-based therapy in a response-guided regimen for patients with RVR. Of note, treatment discontinuation from adverse events were double that of SOC but were much lower than that in Phase 2 trials. The most common adverse events reported in the ILLUMINATE study, were, in order of frequency, fatigue, pruritus, nausea, anaemia, rash and headache. Most of these adverse events were mild or moderate. Adverse events leading to discontinuation of all study drugs during the 12-week TVR dosing period occurred in 6.9%, while treatment discontinuation of all drugs because of anaemia and rash occurred in 1.1 and 0.6% of people in this study, respectively, during the TVR dosing period (Figs 1 and 2).

Figure 1. ILLUMINATE: Phase 3: response-guided therapy optimal for eRVR Patients. eRVR, extended rapid virological response; SVR, sustained virological response.

Figure 2ADVANCE: Phase 3: 12-week duration telaprevir optimal. PEG-IFN, pegylated interferon; RBV, ribavirin; RVR, rapid virological response; SVR, sustained virological response; TVR, telaprevir.

The phase III clinical trial (SPRINT-2) evaluating BOC in over 1000 treatment-naïve patients was also recently completed. Equivalent to the SPRINT-1 study design, patients (two separate cohorts were enrolled; one African American and the other non) received 800 mg BOC three times daily in combination with PEG-IFN and weight-based RBV for 24 or 48 weeks. A lead-in strategy for 4 weeks with PEG-IFN and RBV was utilized in all investigational arms. In this study, 66% of the patients in the BOC 48-week treatment group and 63% of the patients in the response-guided therapy group achieved SVR respectively, compared with 38% of patients in the control group (18). Among the non-African American patients in the BOC 48-week treatment group, 69% achieved SVR, and 67% achieved SVR in the response-guided therapy, compared with 40% in the control SOC group. Among African American patients, 53% of patients in the 48-week treatment group and 42% of patients in the response-guided therapy group achieved SVR, compared with 23% in the control group. This data is less clear than TVR phase 3 studies on the utility of response-guided therapy in all genotype 1 populations and suggest that extending therapy may be beneficial in African Americans. Further details from this study will help clarify the importance of host factors in response-guided therapy durations. In the HCV SPRINT-2 study, the most common treatment-emergent adverse events reported for the BOC 48-week treatment group, BOC response-guided therapy group and control group, respectively, were: fatigue (57, 53 and 60%), headache (46, 46 and 42%), nausea (43, 48 and 42%), anaemia (49, 49 and 29%) and pyrexia (fever) (32, 33 and 33%). Treatment was discontinued because of anaemia in 2% of each of the BOC groups compared with 1% in the control group, although erythropoietin use was allowed to maintain RBV dosing. Overall treatment discontinuations from adverse events were 16 and 12% for the BOC groups, respectively, compared with 16% for the control group. The utility of erythropoietin in these patients is currently under investigation in another phase 3 trial.

Conclusion

In conclusion, clinical trials have shown that the addition of protease inhibitors to standard therapy results in potent viral suppression and shortened duration of therapy. SVR rates approaching 75% can now be anticipated for genotype 1 patients, which should lead to increased treatment opportunities for many HCV populations. However, new issues of viral resistance and increased adverse events will increase the importance of close medical management. A new era of DAA is upon us and offers new hopes for HCV-infected patients.

Conflicts of interest

David Nelson has received research funding and is on advisory boards or a consultant for Vertex, Merck, Genentech, Pharmassett, Bayer-Onyx and GSK. He has received research funding from BMS, Gilead and Tibotech and is a consultant for Abbott.

References

1 Armstrong GL, Wasley A, Simard EP, et al. The prevalence of Hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 2006; 144: 705–14.

2 Seeff LB. Natural history of chronic hepatitis C. Hepatology 2002; 36: S35–46.

3 Marcellin P, Asselah T, Boyer N. Fibrosis and disease progression in hepatitis C. Hepatology 2002; 36: S47–56.

4 Verna EC, Brown RS. Hepatitis C and liver transplantation: enhancing outcomes and should patients be retransplanted. Clin Liver Dis 2008; 12: 637–59.

5 Davis GL, Alter MJ, El-Serag H, et al. Aging of hepatitis C-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology 2010; 138: 513–21.

6 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic Hepatitis C virus infection. N Engl J Med 2002; 347: 975–82.

7 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with Interferon alfa-2b plus ribavirin for initial treatment of chronic Hepatitis C: a Randomised Trial. Lancet 2001; 358: 958–65.

8 Asselah T, Benhamou Y, Marcellin P. Protease and polymerase inhibitors for the treatment of hepatitis C. Liver Int 2009; 29 (Suppl. 1): 57–67.

9 McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with Peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360: 1827–38.

10 Hézode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839–50.

11 Everson GT, Dusheiko GM, Ferenci P, et al. Telaprevir, peginterferon alfa-2a and ribavirin improved rates of sustained virologic response (SVR) in ‘difficult-to-cure’ patients with chronic Hepatitis C (CHC): a pooled analysis from the PROVE1 and PROVE2 trials. Hepatology 2009; 50: 1565.

12 Marcellin P, Forns X, Goeser T, et al. Virologic analysis of patients receiving telaprevir administered q8h or q12h with Peginterferon-alfa-2a or -alfa-2b and ribavirin in treatment-naïve patients with genotype 1 hepatitis: study C208. Hepatology 2009; 50: 194.

13 Kwo P, Lawitz E, McCone J, 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; 376: 705–16.

14 Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 2007; 132: 1767–77.

15 Kieffer TL, Sarrazin C, Miller JS, et al. Telaprevir and pegylated interferon-alpha 2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 2007; 46: 631–9.

16 Vertex Pharmaceuticals. 75% of treatment-naive patients with chronic hepatitis C achieve SVR (viral cure) with telaprevir-based treatment in Phase 3 trial. Press release, 25 May 2010.

17 Vertex Pharmaceuticals. Phase 3 ILLUMINATE Study supports 24-week telaprevir-based therapy within a response-guided regimen for people with hepatitis C who had not received prior treatment. Press release, 10 August 2010.

18 Poordad F, McCone J, Bacon BR, et al. Boceprevir combined with peginterferon alfa-2b/Ribavirin for treatment-naïve patients with hepatitis C virus genotype. 1: SPRINT-2 final results. Hepatology 2010; 52: 107A.

Source

The role of triple therapy in HCV genotype 1-experienced patients

Liver International
Special Issue: Proceedings of the 4th Paris Hepatitis Conference. The publication of this supplement was supported by an unrestricted educational grant from F. Hoffmann-Laroche Ltd.
Volume 31, Issue Supplement s1, pages 58–61, January 2011

Michael W. Fried

Article first published online: 4 JAN 2011
DOI: 10.1111/j.1478-3231.2010.02410.x
© 2011 John Wiley & Sons A/S

Author Information
UNC Liver Center, University of North Carolina, Chapel Hill, NC, USA

* Correspondence: Correspondence Michael W. Fried, University of North Carolina, CB# 7584, Room 8015 Burnett-Womack Building, Chapel Hill, NC 27514, USA Tel: +1 919 966 2516 Fax: +1 919 966 1700 e-mail: mfried@med.unc.edu

Keywords:
boceprevir; hepatitis C; non-responder; peginterferon; relapser; telaprevir

Abstract

The ability to achieve a sustained virological response (SVR) to peginterferon (PEG-IFN) and ribavirin (RBV) depends on numerous host and virological factors, as well as adherence to a prescribed treatment regimen. Patients who have failed to achieve a SVR to PEG-IFN and RBV have limited options for retreatment. Emerging data from phase II and phase III clinical trials of direct-acting antiviral agents suggest that new therapeutic regimens will be available for many patients. Treatment with protease inhibitors such as PEG-IFN, RBV, ribavirin. and boceprevir, combined with PEG-IFN and RBV, has been shown to produce high rates of virological response in both prior relapsers and, to a lesser extent, prior non-responders. The benefits of these novel treatment regimens for each individual patient must be weighed against the side effects, costs and potential of developing viral resistance. Regulatory approval of telaprevir and boceprevir is expected to begin in mid-late 2011.

Treatment-experienced patients with genotype 1 who do not achieve a sustained virological response (SVR) to peginterferon (PEG-IFN) and ribavirin (RBV) represent a continuing challenge for management. Permanent eradication of hepatitis C virus (HCV) from these patients remains the only acceptable goal of future therapeutic combinations. The ability to achieve SVR is dependent upon numerous factors including host and virological factors, a well as the efficacy of the therapeutic regimens for these difficult-to-treat patients.

Defining non-sustained response

A non-SVR includes patients who have relapsed or those who were non-responders to an initial course of therapy with PEG-IFN and RBV. Data from preliminary studies of triple therapy combinations including a protease inhibitor (telaprevir or boceprevir) combined with PEG-IFN and RBV in treatment-experienced patients reinforce the importance of correctly categorizing the initial response to dual combination therapy since it is an important predictor of the likelihood of response to triple combination therapy.

Non-responders are patients who fail to achieve undetectable viraemia at any point during treatment (1). Non-responders may be further categorized as null responders or partial responders. Null responders are those who achieve minimal viral suppression (usually less than one-log fold decrease in HCV RNA) during the first 4 weeks of treatment while partial responders are those with a greater decrease in HCV RNA (usually multiple log-folds) but who remain HCV RNA positive throughout treatment. In contrast, relapsers are patients who achieve undetectable viraemia during the prescribed treatment regimen with PEG-IFN and RBV, but then relapse with the reappearance of HCV RNA once treatment is discontinued (1). As we shall see below, patients who relapse with PEG-IFN and RBV have a greater chance of responding to triple therapy combinations than non-responders.

Host interferon pathways are critical for triple therapy combinations

On-treatment viral kinetics are highly predictive of treatment outcome in both treatment-naïve and treatment-experienced patients, and may be considered a surrogate for the responsiveness of host IFN pathways. Rapid virological response (RVR), defined as undetectable viraemia at week 4 of treatment, is associated with an ∼90% rate of SVR and has been shown to be more predictive of treatment success than other pretreatment demographical, virological or histological factors (2, 3). Conversely, a slow virological response, with delayed or lack of clearance of HCV RNA, is a pharmacodynamic marker for suboptimal IFN/RBV-associated therapeutic response.

Recent data suggest that polymorphisms in the interleukin (IL)28B region are highly associated with a SVR as well as an early virological response to PEG-IFN and RBV (4). Approximately 80% of treatment-naïve patients with the favourable IL28B CC genotype will achieve a SVR to combination therapy. The presence of the CC genotype is also associated with a higher probability of achieving an RVR, which occurred in almost 30% of patients treated with PEG-IFN and RBV (5). The IL28B genotype has also been associated with the differential expression of IFN signalling genes in hepatic tissue (6, 7). The impact of the IL28B genotype on treatment-experienced patients has just begun to be explored but a similar relationship seems to exist for this population as well. However, since the minority of non-responders will be CC genotype, other factors will also be important.

The presence of a robust IFN signalling pathway is important for triple therapy combinations since the IFN–RBV backbone minimizes the viral resistance that is inevitable with protease inhibitor monotherapy (8). Thus, previous non-responders to PEG-IFN and RBV have a greater likelihood of virological breakthrough to triple combination therapy with a protease inhibitor than prior relapsers.

Telaprevir for treatment-experienced patients: phase II results

Prove-3 was a study of the protease inhibitor telaprevir in treatment-experienced patients that enrolled both non-responders (∼60%) and relapsers (∼40%) (9). A schematic of the study design is shown in Figure 1. The various treatment arms evaluated the impact of different durations of triple therapy, different total treatment durations and the importance of RBV for this difficult-to-treat population.

Figure 1. PROVE 3 study design in prior non-responders and relapsers. PEG-IFN, peginterferon; RBV, ribavirin; TVR, telaprevir. Adapted from McHutchison et al. (9).

Strict stopping rules were used to minimize the development of viral resistance and exposure to therapy in case of no response. Thus, in patients treated with telaprevir, HCV RNA was required to be undetectable by week 4 in order to continue treatment. The final results of the study are shown in Figure 2.

Figure 2. Final results of PROVE 3 in prior non-responders and relapsers. P, PEG-IFN; PEG-IFN, peginterferon; R, RBV; RBV, ribavirin; T, telaprevir. Adapted from McHutchison et al. (9).

Prior relapsers had the best chance of achieving SVR, with a rate of 76% in those treated with 24 weeks of triple therapy, followed by 24 weeks of dual PEG-IFN and RBV (total duration=48 weeks) (9). The SVR rate in patients treated with only 12 weeks of triple therapy and an additional 12 weeks of dual combination therapy (total duration=24 weeks) was 69%. Prior non-responders had substantially lower rates of SVR, although nearly 40% achieved SVR with similar regimens. Interestingly, when telaprevir and PEG-IFN were used without RBV, the rate of SVR was substantially diminished, emphasizing the importance of RBV in triple therapy combinations.
 
As discussed previously, the risk of virological breakthrough, defined as an increase of HCV RNA of more than one-log from baseline or to more than 100 IU/ml if previously undetectable, was more frequent in previous non-responders than previous relapsers. By week 24 of treatment, up to 13% of prior relapsers and 45% of prior non-responders had evidence of virological breakthrough (9).
 
Telaprevir for treatment-experienced patients: phase III results
 
Phase III data from the REALIZE trial of telaprevir in treatment-experienced patients have only been reported to date as a company press release (10), but we will describe it briefly to provide the most current data. Nevertheless, it must be remembered that this is a preliminary non-peer-reviewed report. The study design included triple therapy with PEG-IFN, RBV and telaprevir for 12 weeks begun simultaneously or with a prior lead-in of PEG-IFN and RBV, followed by PEG-IFN and RBV for a total of 48 weeks. In previous non-responders, the SVR rate was 86% in the combined telaprevir arms and 57% in partial responders. The SVR rate in previous null responders was only 31%, showing the differential response based on prior experience with dual combination therapy.
 
Boceprevir for treatment-experienced patients
 
Full results of a comparable phase II study with boceprevir in treatment-experienced patients have not been reported. However, data from the Sprint-1 study of treatment-naïve patients suggest that the protease inhibitor boceprevir also benefited patients with a poor early response to PEG-IFN and RBV (11). The study design of Sprint-1, and subsequent phase III studies with boceprevir, used a lead-in phase of treatment for 4 weeks with PEG-IFNα-2b+RBV, followed by the addition of boceprevir. Kwo et al. (11) performed a retrospective analysis of patients based on the HCV RNA response during these first 4 weeks of dual combination therapy. Patients with less than a one-log decrease in viraemia by week 4 had only a 24% rate of SVR when treated with PEG-IFN and RBV alone, while those patients who received boceprevir at week 4 subsequently achieved an SVR of 62% (Fig. 3).
 
Figure 3. SPRINT 1: analysis of virological response and sustained virological response. P, PEG-IFN; R, RBV; T, telaprevir. aOne patient who was positive at week 24 became undetectable at week 30 onwards. bTwo patients were missing polymerase chain reaction (PCR) at week 24, but later had detectable PCR. Adapted from Kwo et al. (11). Presented at: AASLD; 30 October–3 November 2009, Boston, MA, USA.

It should be noted that this analysis did not include non-responders who had completed a previous full course of treatment. Nevertheless, the strong association of treatment failure with null response during the first 4 weeks of antiviral therapy suggests that these results are of interest.
 
RESPOND-2 is a recent phase III trial reported at the 2010 AASLD in non-responders and relapsers treated with boceprevir (12). The three-arm study compared a response-guided regimen including boceprevir to a fixed-duration 48-week triple regimen vs 48 weeks of PEG-IFN and RBV. Top-line results indicate that 75% of prior relapsers and 52% of prior non-responders treated with a fixed triple therapy boceprevir regimen achieved SVR. Relapsers and non-responders in the response-guided arm also had significant SVR rates of 69 and 40% respectively (12).
 
Considerations for the selection of candidates for triple therapy
 
Recommendations for the use of protease inhibitor triple therapy combinations are still evolving and will be dependent upon rigorous peer-reviewed analyses of phase III clinical trial data, as well as the interpretation and recommendations of various pharmaceutical regulatory agencies worldwide, such as the US Food and Drug Administration and the European Medicines Agency. Nevertheless, currently available data clearly show that triple therapies including a protease inhibitor provide exciting new therapeutic options for treatment-experienced individuals. These therapies will be most useful in prior virological relapsers, although many prior non-responders, particularly partial responders, will achieve successful viral eradication with triple therapies. The benefits of these novel treatments for each individual patient must be weighed against the side effects, cost and potential of developing viral resistance.
 
Conflicts of interests
 
Dr Fried is funded, in part, by K24 DK066144, NIH Mid-Career Mentoring Award. Dr Fried serves as a consultant for and/or receives research grants from Genentech, Vertex, Merck, Tibotec, Bristol Myers Squibb, Anadys. He is a consultant and stockholder of Pharmasset.

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8 Kieffer TL, Sarrazin C, Miller JS, et al. Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 2007; 46: 631–9.

9 McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 362: 1292–303.

10 Anonymous. Vertex press release: REALIZE study. 2010.

11 Kwo PY, Lawitz EJ, McCone J, 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 376: 705–16.

12 Bacon BR, Gordon SC, Lawitz EJ, et al. HCV respond-2 final results: high sustained virological response among genotype 1 previous non-responders and relapsers to peginterferon/ribavirin when retreated with boceprevir plus pegintron(peginterferon alfa-2a)/ribairinv. Hepatology 2010; 52: 430, (abstract).

Source