The standard of care for HCV treatment since the early 1990s has been interferon, which aimed to boost the immune system rather than attacking the HCV directly. Two new protease inhibitors, boceprevir and telaprevir, approved by the FDA in May 2011, have the potential to transform the management of HCV. The main goal of treatment of chronic hepatitis C is to eliminate detectable viral RNA from the blood. Lack of detect able HCV RNA from blood 6 months after completing therapy is known as a sustained response and has a very favorable prognosis that may be equivalent to a cure. Other, more subtle benefits of treatment may include slowing the progression of fibrosis in patients who do not achieve a sustained response.

All current treatment protocols for hepatitis C are based on the use of various preparations of IFN-α, a naturally occurring glycoprotein secreted by cells in response to viral infections. It exerts its effects by binding to a membrane receptor, which initiates a series of intracellular signaling events that ultimately lead to enhanced expression of certain genes. This leads to enhancement and induction of certain cellular activities, including augmentation of target cell killing by lymphocytes and inhibition of virus replication in infected cells.

Interferon alfa-2a (Roferon-A; Hoffmann-La Roche, Basel, Switzerland), IFN-alfa-2b (Intron-A; Merck/Schering-Plough Pharmaceuticals, North Wales, Pa), and IFN-alfacon-1 (Infer gen; Intermune, Kadmon, New York, NY) are all approved in the United States as single agents for the treatment of adults with chronic hepatitis C. Treatment is administered for 6 months to 2 years. Treatment with IFN alone leads to a sustained response in less than 15% of subjects. Because of this low response rate, these IFNs alone are rarely used for the treatment of patients with chronic hepatitis C.

More recently, peginterferon alpha, sometimes called pegylated IFN, has become available for the treatment of chronic hepatitis C. There are two preparations—peginterferon alfa-2b (Peg-Intron; Schering-Plough) and peginterferon alfa 2a (Pegasys; Hoffmann-La Roche). With peginterferon alfa-2a alone, approximately 30% to 40% of patients achieve a sustained response to treatment for 24 to 48 weeks. The addition of ribavirin to IFN-α is superior to IFN-α alone in the treatment of chronic hepatitis C.

Ribavirin is a synthetic nucleoside that has activity against a broad spectrum of viruses. The FDA did not approve ribavirin alone for hepatitis C, but the FDA did approve IFN-alfa-2b plus ribavirin (1998) for the treatment of individuals with chronic hepatitis C who relapsed after previous IFN-α therapy. Relapsers were defined as patients who had normal liver serum enzymes ALT activity at the end of up to 18 months of IFN-α therapy, with abnormal liver serum enzyme activity within 1 year after the end of the most recent course of therapy. The FDA has approved the combination of peginterferon alpha plus ribavirin for the treatment of chronic hepatitis C. For eligible patients with chronic hepatitis C, peginterferon alpha plus ribavirin is likely to be the best treatment option. Clinical trials have shown that a sustained response rate is seen in approximately 50% of patients given this combination for 24 to 48 weeks.

Most studies have indicated that genotypes 1a and 1b are more resistant to treatment with any IFN-α–based therapy than non–type 1 genotypes. Thus, some physicians may prescribe longer a duration of treatment for patients infected with viral genotype 1a or 1b. The best available current treatment for chronic hepatitis C, peginterferon alpha plus ribavirin, leads to an overall sustained response rate in more than 50% of all patients. The sustained response rates are even better for individuals infected with non–type 1 genotypes of the hepatitis C virus.

Several drugs, known as immune modifiers or immunomodulators, that alter the immune response have been tested (some with IFN-α) in clinical trials for chronic hepatitis C. These drugs alter the inflammatory response against liver cells infected with the virus; however, their mechanisms of action are poorly understood. Compounds tested in human beings include thymosin alpha-1 (Zadaxin; SciClone Pharmaceuticals, San Mateo, Calif) and histamine dihydrochloride (Ceplene; EpiCept Tarrytown, NY).

New medications and approaches to treatment are needed for HCV infection. Most promising for the immediate future are newer forms of long-acting IFNs. In addition, promising molecular therapies consist of using ribozymes, enzymes that break down specific viral RNA molecules, and antisense oligo nucleotides, small complementary segments of DNA that bind to viral RNA and inhibit viral replication.

Therapeutic vaccines are also being developed to enhance the immune response against the HCV. In contrast to a preventive vaccine (likely a distant development for hepatitis C), a therapeutic vaccine is administered to already infected individuals to stimulate the immune system to fight the infection. Several therapeutic vaccines are in preclinical development for hepatitis C. The most promising of these are DNA vaccines involving the injection of DNA copies of the HCV RNA genome, which are taken up by certain immune system cells. Theoretically, these cells then express viral proteins, stimulating an immune response against the virus.

Who Should and Who Should Not Be Treated?

 Patients with anti-HCV, HCV RNA, elevated liver serum enzyme ALT levels, and evidence of chronic hepatitis on liver biopsy, and with no contraindications, should be offered therapy with a combination of IFN-α and ribavirin. The National Institutes of Health Consensus Development Conference Panel has recommended that therapy for hepatitis C be limited to patients who have histologic evidence of progressive disease without signs of decompensation. According to current recommendations, all patients with fibrosis or moderate to severe degrees of inflammation and necrosis on liver biopsy should be treated and patients with less severe histologic disease should be managed on an individual basis. Patient selection should not be based on the presence or absence of symptoms, mode of acquisition, genotype of HCV RNA, or serum HCV RNA levels.

Interferon and combination therapy have not been shown to improve survival or the ultimate outcome in patients with preexisting cirrhosis. The benefit of treatment in patients older than 60 years has not been well documented. The role of IFN therapy in children with hepatitis C remains uncertain.

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مواضيع ذات صلة

DNA Tumor Viruses

Rhabdoviridae

Human T-cell Lymphotropic Viruses, Types 1 and 2

Treatment of HIV

Congenital Rubella Infection

Acute and Chronic Hepatitis C

Hepatitis C

Pathogenesis and clinical significance of HIV

Transmission of HIV

HIV replication

Hepatitis D

Prevention and Treatment of hepatitis B