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Treating Hepatitis C in "Difficult-to-Treat" Patients
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New England Journal of Medicine
COMMENTARY
Volume 351:422-423 July 29, 2004 Number 5
Jean-Michel Pawlotsky, M.D., Ph.D.
From the Department of Virology, INSERM Unité 635, Henri Mondor Hospital, University of Paris XII, Créteil, France.
The current standard treatment for chronic hepatitis C is the combination of pegylated interferon alfa and ribavirin, a synthetic guanosine analogue. In the pegylated form of interferon, the interferon alfa molecule is linked to a polyethylene glycol molecule to ensure sustained interferon concentrations after single weekly injections. Pegylated interferon alfa potently inhibits the replication of hepatitis C virus (HCV) and has immunomodulatory properties that probably accelerate the clearance of infected cells. Ribavirin exerts a weak and transient early antiviral effect and acts primarily by preventing relapses during and after therapy in patients who have had an initial response. Ribavirin's mechanisms of action are unknown.
The main end point of therapy is a "sustained virologic response," defined by an undetectable HCV RNA level in the patient's blood 24 weeks after the end of treatment. In the vast majority of patients in whom a sustained virologic response is achieved, HCV infection appears to be definitively cured. The "difficult-to-treat" patients are those in whom no sustained virologic response is achieved with the standard treatment. A substantial proportion of such patients can be identified early in the course of therapy. Indeed, in patients who do not have a reduction in HCV RNA of at least 2 log10 international units or an undetectable HCV RNA level by the 12th week of treatment, there is virtually no chance of achieving a sustained virologic response. These patients can stop therapy at week 12 — a course of action that was recommended for patients with HCV genotype 1 by the National Institutes of Health's 2002 consensus conference on hepatitis C. However, not all patients who have a reduction of 2 log10 international units in HCV RNA or who are HCV RNA--negative at week 12 will subsequently have a sustained virologic response.
The failure to achieve a sustained virologic response to standard therapy is multifactorial and is related to the treatment schedule, host factors, disease-related characteristics, and viral factors. The pegylation of interferon significantly reduced failure rates by optimizing the pharmacokinetics and pharmacodynamics of interferon alfa with weekly administration. The administered dose of ribavirin per kilogram of body weight is crucial, and underdosing — related to inadequate tailoring to the patient's body weight or dose reductions that are required when severe hemolytic anemia occurs — results in an increased rate of relapse during or after therapy.
An important cause of treatment failure is poor adherence or nonadherence to therapy. Another risk factor is addictive behavior, such as active alcohol or intravenous drug use. Certain characteristics of patients, such as older age, male sex, and high body weight, are associated with lower rates of a sustained virologic response. Race also appears to be an important determinant of the treatment outcome. Indeed, blacks have been reported to have significantly lower response rates than the white and Asian populations, although the underlying mechanisms remain unclear. Patients with advanced fibrosis or cirrhosis are also less likely to have a response to therapy. The role of extrahepatic manifestations of HCV infection remains unclear.
Viral factors also play a role in treatment failure, as suggested by the significantly higher rates of a sustained virologic response to pegylated interferon alfa and ribavirin among patients infected with HCV genotype 2 or 3 than among those infected with genotype 1 or 4. The study of the replication kinetics of HCV during therapy suggests that treatment failure is associated with a combination of HCV-induced alterations of the antiviral and immunomodulatory effects of therapy, the mechanisms of which remain largely unknown. In vitro studies have led to several hypotheses regarding the cause of resistance to the antiviral effect of interferon alfa, but the relevance of these models has not been proved in vivo. In addition, no viral-sequence signature has been identified that predicts or is associated with the success or failure of treatment. This is not surprising, given that interferon alfa and ribavirin act primarily through host antiviral mechanisms.
Because of shared routes of transmission, approximately one third of patients infected with human immunodeficiency virus (HIV) are also infected with HCV. Coinfected patients receiving highly active antiretroviral therapy have been shown to have higher rates of HCV-related morbidity (i.e., accelerated progression to cirrhosis, end-stage liver disease, and hepatocellular carcinoma) and mortality than patients who are infected with HCV alone. Two studies reported in this issue of the Journal by Torriani and colleagues (pages 438--450) and Chung and colleagues (pages 451--459) show that a sustained virologic response can be achieved with pegylated interferon alfa and ribavirin therapy in a substantial proportion of coinfected patients. These results, together with the poor prognosis for HIV-positive patients with HCV infection, justify broad use of antiviral therapy in the treatment of coinfected patients. However, it is apparent from these two studies that infection is eradicated in a substantially higher proportion of patients with HCV alone than of coinfected patients. The lower rates of a sustained virologic response among coinfected patients could be at least partially explained by lower rates of adherence to therapy, poorer tolerance of pegylated interferon alfa and ribavirin, and drug--drug interactions that lead to more frequent discontinuation of treatment or reductions of doses. HIV-induced immune perturbations and direct HIV--HCV interactions in the cells infected by both viruses could also play a role, through mechanisms that remain largely unknown.
Future improvements in treatment outcomes in difficult-to-treat patients, including those who are coinfected with HCV and HIV, will require novel therapeutic approaches. The availability of four classes of therapeutic interventions for HCV infection is foreseeable in the next 5 to 10 years: interferons, including new interferon molecules with enhanced activity and further improved pharmacologic properties; ribavirin and ribavirin-like molecules that mimic ribavirin's effects but have a better tolerance profile; specific inhibitors of HCV replication, including HCV protease inhibitors, HCV polymerase inhibitors, HCV helicase inhibitors, and inhibitors of the HCV internal ribosome entry site; and immune therapies, such as new immune modulators and therapeutic vaccines. There is little doubt that the combination of several different approaches tailored to the individual patient and to the early virologic response to treatment will result in the clearance of HCV in a substantial proportion of the patients who are currently classified as difficult to treat. For patients in whom infection cannot be cleared and whose liver disease is likely to progress (such as those who are coinfected with HIV and HCV), "suppressive," noncurative therapy inducing a sustained and profound inhibition of HCV replication might remain the only therapeutic option.
Dr. Pawlotsky reports having served as a consultant for Hoffmann--La Roche, Schering-Plough, Vertex Pharmaceuticals, and Abbott; having served as a paid speaker for Schering-Plough, Hoffmann--La Roche, and Valeant; and having received grant support from Isis Pharmaceuticals and Schering-Plough.
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