(Laurie Barclay, MD, April, 2004)

Hepatitis C (HCV) is a viral infection of the liver, previously termed parenterally transmitted non A, non B hepatitis until the causative agent, an enveloped RNA virus in the flaviviridae family, was identified in 1989.

Approximately 170 million persons are chronically infected with HCV worldwide, and there are 3 to 4 million new infections each year. The prevalence is higher in some countries in Africa, the eastern Mediterranean, southeast Asia and the Western Pacific than in some countries in North America and Europe.

In the U.S., lifetime prevalence of HCV is estimated at 3.9 million, including 2.7 million with chronic infection. Non- Hispanic African Americans have the highest HCV infection rate. Annual mortality from HCV is 8,000 to 10,000, which the Centers for Disease Control and Prevention (CDC) estimates will triple in the next one to two decades. Estimated medical and work loss cost is $600 million annually.

Transmission of HCV is predominantly by direct exposure to human blood, as in unscreened blood transfusions and inadequate sterilization of needles and syringes. Sexual and perinatal transmission occur less often.

Because the HCV virus genome is relatively mutable, chronic infection develops in 80% of cases. Different genotypes of HCV may influence disease severity and response to treatment, with genotype 1 being the most common and difficult to treat.

Most patients with HCV (60%-70%) are asymptomatic, even those with chronic infection, but symptoms may include fatigue, jaundice, and flu-like symptoms. The incubation period before symptom onset ranges from 15 to 150 days. Complications of chronic infection include cirrhosis in 10%-20%, and liver cancer in 1%-5%, developing over a period of 20 to 30 years. Nearly half of all liver transplants performed in the U.S. are for end-stage HCV. Re-infection of the transplanted liver by HCV is common, but this rarely requires a second transplant.

Commercially available diagnostic tests are based on enzyme immunosorbant assays (EIA) that detect HCV-specific antibodies. Sensitivity is greater than 95% for chronic infection but only 50% to 70% for acute infection. Supplemental tests include a recombinant immunoblot assay (RIBA) that identifies antibodies reacting with individual HCV antigens, and amplification tests that assess viral load and response to therapy.

Currently available treatment is in part limited by high cost. Antiviral drugs include injectable interferon used alone, which is effective in about 10% to 20% of patients, or combined with oral ribavirin, which is effective in about 30% to 50% of patients. Although 50% to 60% of patients initially respond to treatment, only 10% to 40% have lasting viral clearance. Treatment of children with HCV is being investigated but is not yet approved.

Adverse effects of interferon include flu-like symptoms, depression, thinning of hair, and bone marrow depression. Although the pegylated interferons are better tolerated than previous therapies, adverse effects still limit compliance. Ribavirin is linked to sudden, severe anemia, and birth defects.

As of yet there is no approved vaccine; development is hindered by the high mutability of the HCV genome and by lack of knowledge of any protective immune response following HCV infection.

Prevention includes screening and testing of blood and organ donors; virus inactivation of plasma-derived products; infection control practices in health care settings, including sterilization of equipment; and promotion of behavioral changes such as reduced use of injections, safe injection practices, and risk reduction counseling for persons engaging in high-risk drug use and sexual activity.

CenterWatch has identified 17 drugs in phase I through phase III development for HCV, including different interferon formulations, immune regulators, monoclonal antibodies, and antiviral agents.

Zadaxin (thymalfasin), a pure synthetic preparation of thymosin alpha 1, is in Phase III testing by SciClone Pharmaceuticals. This 28-amino acid peptide, which was originally isolated from the thymus gland, facilitates the immune response to viral infections. After subcutaneous administration of Zadaxin twice weekly, thymosin alpha 1 circulates at 50 to 100 times its normal level.

Two multicenter, randomized, double-blinded Phase III clinical trials in the U.S. are using Zadaxin with pegylated interferon alpha in patients with HCV who have failed previous therapy. If these trials are positive, SciClone hopes to obtain the first FDA approval for this indication and will also seek regulatory approval in Europe and Japan. Zadaxin plus pegylated interferon alpha would then be tested with or without ribavirin as first- line therapy for HCV.

In a 12-week, dose-ranging study, 31 patients with HCV who had failed previous therapy received Zadaxin plus pegylated interferon alpha, with dose-related early virologic response (EVR) rates ranging from 20% to 36%. A pooled analysis from several previous trials suggested that HCV patients failing first-line therapy had a 22% response rate to Zadaxin plus non- pegylated interferon alpha.

Viramidine, a purine nucleoside (guanisine) analogue structurally related to ribavirin, is in Phase III development by Valeant Pharmaceuticals International. In September 2001, Valeant began Phase I trials of oral Viramidine in Europe and filed an IND with the FDA in December 2001. In the U.S., Phase I trials began in March 2002, and a Phase II trial began in December 2002.

Another antiviral agent is merimepodib (VX-497), for which Vertex Pharmaceuticals has completed Phase II testing. This novel inhibitor of inosine monophosphate dehydrogenase (IMPDH) blocks production of nucleotides needed for viral replication.

A six-month interim analysis of an ongoing Phase II trial of merimepodib in combination with pegylated interferon and ribavirin in HCV patients who failed earlier therapy revealed that merimepodib met its primary endpoint of safety and tolerability and was not associated with any serious adverse events. It also met its secondary endpoint of clinical activity, with a statistically significant, dose-dependent antiviral response in combination with pegylated interferon and ribavirin. Earlier Phase II studies in HCV showed that merimepodib reduced liver inflammation and showed a trend toward enhanced antiviral activity.

Amarillo Biosciences is in Phase II/III development of a low- dose, oral formulation of interferon alpha, hoping that this dose and route of administration will reduce the high cost and severe adverse effects of high-dose systemic interferon alpha. Many infectious agents that enter the body through inhalation or ingestion induce low concentrations of interferon in the nasal or pharyngeal secretions, so the rationale is that this product will mimic nature. Research suggests that interferon attracted by receptors in the oral mucosal surface effectively stimulates the immune system.

BioMedicines is in Phase II testing of omega interferon (Biomed 510), a genetically engineered human interferon made by recombinant technology in mammalian cells. The activity profile of this drug suggests activity in HCV even when alpha interferon is not active. In a multicenter European trial conducted as an open-label, rising dose study in interferon-naïve patients with chronic HCV, omega interferon was active in acutely reducing HCV replication.

Another recombinant interferon is Albuferon, in Phase I/II testing by Human Genome Sciences. This fused gene protein has characteristics of both interferon alpha and albumin, allowing the interferon alpha to be longer acting. Because of longer half- life, albumin fusion proteins, such as Albuferon, may allow a more convenient administration schedule, with similar or improved efficacy and safety compared with currently available interferons.

In a Phase I/II trial in chronic HCV, albuferon-alpha was well tolerated with a prolonged half-life (median 145 hours at doses of 80 mcg or higher) and biological activity. Of 28 Albuferon- treated patients, 16 (57%) had an antiviral response after a single dose, with reductions in viral load of at least 0.5 log or greater, and 13 of 16 patients experienced reductions of at least 0.9 log. Levels of alanine aminotransferase (ALT) reflecting liver cell damage were reduced significantly in 29% of the Albuferon treated patients with elevated baseline levels.

Most patients in this trial had been treated previously for approximately 68 weeks with interferon alpha or pegylated interferon, either alone or in combination with ribavirin, and 95% (61 of 69) had HCV genotype 1. No patient developed a detectable immune response to Albuferon. Higher single-doses and repeat-doses are being tested to seek the maximum biological response that can be achieved at a tolerable dose.

In June 2002, ISIS Pharmaceuticals began a Phase II study of ISIS 14803, an antisense inhibitor of HCV viral replication targeting the IRES/translation region, in combination with standard treatments for HCV. Patients enrolled in this trial received ISIS 14803 if they did not achieve an early response to treatment with pegylated interferon and ribavirin. Thirty patients with genotype 1, drug-resistant HCV are enrolled in an open-label, dose-escalation and safety study of ISIS 14803 twice weekly for three months along with conventional doses of pegylated interferon and ribavirin.

A three-month Phase II trial completed in October 2003 showed that ISIS 14803 produced up to 3.8 log dose-dependent reductions in plasma HCV levels. Most of these patients were HCV genotype 1, and 39 of 43 patients enrolled had been previously treated with interferon. Adverse events reported thus far have been minor.

A novel approach to immunotherapy is Ceplene (histamine dihydrochloride), in Phase II testing by Maxim Pharmaceuticals. This histamine-2 receptor agonist is thought to reduce oxidative stress and thereby enhance immune function by preventing the production and release of oxygen free radicals.

Preliminary results are encouraging from a randomized Phase I/II trial of Civacir, an immune globulin developed by Nabi Biopharmaceuticals, in 18 HCV patients who received liver transplant. This human polyclonal antibody is derived from human plasma enriched with HCV antibodies and is designed to prevent HCV re-infection of transplanted livers. Civacir was well- tolerated in both the high and low-dose treatment arms, and there was a trend toward a reduction in ALT.

Because HCV is a viral disease, therapeutic targets include enzymes required for viral RNA replication and immune modulators designed to enhance the body's natural defenses against invading microorganisms. Many of these new agents show promise and will hopefully prove to be safe and effective with ongoing development. Cost is still a significant consideration, especially given the large proportion of HCV in developing countries.