~Hepatitis C, Part 3 - Pharmacology

PHARMACOLOGY
  • Interferon-alpha (a)
  • Pharmacological Treatment Options
  • Non-Pharmacological Options
  • Prevention and Prophylaxis
  • Drugs under Development
  • Choosing a Treatment
Interferon-alpha (a)

Interferon-a is an antiviral protein produced naturally by cells that have been invaded by pathogens. It plays a vital role in the regulation of the immune system by controlling the body's reaction to viruses. Interferon-a increases the activity of natural killer cells, a type of white blood cell, and blocks the production of the genetic material produced by a virus. There are three types of interferon (a, ß, and y). Synthetic interferon-alpha (a) is genetically engineered and used as a treatment for HCV infection. Today, interferon is an integral part of most treatment regimes for CHC.

CHC can largely be prevented if an infection is treated with interferon when the virus is first contracted. Unfortunately, most acute cases of hepatitis C have no symptoms, so only a small percent of acute HCV infections are recognized and no treatment is given. Although the results to date are relatively disappointing, traditional antiviral treatment for CHC is evolving. Current treatment is three-pronged: antiviral medication, management of complications, and liver transplant.16 The primary treatment goal is long-term eradication of HCV RNA from the blood; secondary goals are reversal of damage to liver tissue and preservation of overall health and quality of life.

Treatment success is measured in terms of virological, biochemical, and histological responses.1,62 Virological response measures the decrease in viral load. The criterion for a cure is "sustained virological response" which indicates that a patient is free of virus 6 months after stopping treatment.62 Biochemical response is evaluated by changes in the levels of enzymes produced in the liver. It is a less reliable indicator of improvement than virological response because levels may fluctuate during treatment.22 The histological response is measured by the improvement in the condition of liver tissue. Improvement in liver histology is directly related to slowing of the disease and the avoidance of cirrhosis and liver cancer.1

Pharmacological Treatment Options

Interferon-a

All current treatment options are based on some type of synthetic interferon-a. Treatment with interferon-a alone can sometimes completely eradicate HCV infection.94 In general, however, 24 weeks of treatment with interferon-a usually results in sustained virological response in fewer than 20% of patients.77 Its anti-viral activity lasts only a short time and it has side effects that can affect the quality of life dramatically. Interferon-a alone is no longer a first-line treatment for HCV infection because better treatments have been developed. Today treatment with interferon-a alone is reserved for patients who cannot tolerate the newer drugs, such as Ribavirin.95-97

Pegylated Interferon-a and Ribavirin

Pegylated interferon-a remains in the blood longer than standard interferon-a; this gives it the advantage of a longer duration of action.98 On average, treatment with pegylated interferon-a yields a substantial increase in sustained virological response and a modest improvement in liver tissue compared with standard interferon-a. A combination of interferon-a plus the antiviral drug ribavirin has significant benefits over standard interferon-a alone: 48 weeks of interferon-a plus ribavirin treatment usually results in sustained virological responses ranging from 38 to 43%.77 Pegylated interferon-a plus ribavirin is significantly more effective than standard interferon-a plus ribavirin or pegylated interferon-a alone. It is the most effective pharmaceutical treatment for patients at risk for cirrhosis and other liver diseases.1 This combination has yielded the highest sustained virological response to date and produced significantly superior responses in some patients who are considered difficult to treat. Lengths of treatment with pegylated interferon-a and doses of ribavirin are based on HCV genotype. For example, patients with genotypes 2 and 3 are treated for 24 weeks with a standard dose of ribavirin; while patients with genotype 1 are treated for 48 weeks and with a higher dose of ribavirin. With either regime, the decision to continue therapy is based on a positive virological response at 24 weeks.99

Side Effects and Contraindications to Interferon and Ribavirin

The drugs currently used to treat CHC are contraindicated for patients who could be susceptible to the psychiatric side effects caused by interferon-a or who have a medical condition that could complicate interferon-a therapy. Coexisting psychiatric disorders and substance and alcohol abuse are the most common contraindications to antiviral therapy. Poorly controlled autoimmune disease, bone marrow compromise, certain blood disorders, hyperthyroidism, and pregnancy are contraindications to treatment; as well as active substance and alcohol abuse. Contraindications to ribavirin include marked anemia and/or kidney, coronary artery, and cerebrovascular disease.100,101 Corticosteroids are contraindicated in ordinary cases because they enhance viral replication and suppress the immune system.16

Nearly all patients experienced side effects—more so with pegylated interferon-a than with interferon-a. The most common side effects of interferon-a and ribavirin combinations are fatigue, flu-like symptoms, gastrointestinal disturbance, depression, and blood abnormalities.102 Other frequently seen adverse events are headache, fever, bone and muscle pain, nausea, anorexia, weight loss, hair loss, and itching.103 Rates as high as 50% for myalgia, fatigue, and headache are not unusual;102 and blood count abnormalities are a common reason for reduction of the dose of pegylated interferon-a. Ribavirin can cause hemolytic anemia that requires a dose reduction in as many as 10% of patients. The potential for fetal injury with ribavirin requires diligent contraception during treatment.104 Treatment with interferon-a and ribavirin often result in discontinuation or dose reduction, particularly in longer courses of treatment.77 This is problematic because the dose and duration of interferon-a and ribavirin significantly influence the likelihood of achieving a sustained virological response.

Non-Pharmacological Options

Liver Transplant

CHC is the most common reason for adult liver transplantation.16 Although HCV infection recurs after transplant, the course of the disease is generally indolent, and long-term survival rates are relatively high.16 In a study that followed patients after transplantation, the 5-year survival rate was approximately 80% in spite of the fact that more than 95% of the recipients had virus in their blood.105 Unfortunately, many CHC patients are not eligible for a liver transplant either because of medical history or cost.

Iron Reduction

All microorganisms need iron to reproduce, including HCV. HCV-positive patients with higher serum iron levels are more likely to develop chronic infections, and those with lower levels are more likely to resolve infections spontaneously. Larger stores of hepatic iron in the body appear to accelerate cirrhosis and hepatocellular carcinoma and impede interferon (IFN). Decreases in serum iron concentrations (hypoferremia) that occur with infections and inflammatory conditions are a defense mechanism to fight infection.106 This reaction is due mainly to interleukin-1, a mediator of the inflammatory response.82 Iron reduction by phlebotomy (bloodletting) can reduce ALT levels107 and, in some cases, result in a decrease in viral load. Using interferon after iron reduction can result in larger decreases in viral load and significant improvement in biochemical and virological responses.23 The reasons for the interaction of iron and HCV are unclear. There is experimental evidence that iron increases oxidative stress and enhances peroxidation of lipids. On the other hand, iron also damages T-cells and impairs humoral immunity.106

Ursodeoxycholic Acid (Ursodiol)

Ursodeoxycholic acid is a bile acid that can be beneficial in chronic inflammatory conditions of the liver.106 It is currently approved for the treatment of cholesterol-based gallstones and primary biliary cirrhosis. Ursodiol's "off label" benefits include lowering elevated liver enzymes and alleviating some of the clinical symptoms of liver disease such as itching. The mechanism by which ursodiol limits hepatocyte injury in chronic liver diseases and retards the progression of liver disease in primary biliary cirrhosis is unclear. Ursodiol's immunomodulatory effect has been demonstrated in studies; it may inhibit cytotoxic cytokine production which in turn may reduce lipid peroxidation in hepatocytes. In the laboratory, ursodeoxycholic acid protected hepatocytes against apoptosis induced by alcohol. Many viral genomes encode proteins that repress apoptosis to escape immune defenses. If apoptosis of liver cells contributes to the pathogenesis of hepatitis, the ability of the anti-apoptotic ursodeoxycholic acid to limit hepatocyte injury makes sense.93

Ursodeoxycholic acid has been the subject of many clinical trials in which it reduced ALT levels, in the both the absence and the presence of interferon. It demonstrated the ability to potentate the effect of interferon in interferon-resistant patients. A combination of interferon and ursodeoxycholic acid prolonged the effects of interferon by delaying or reducing the severity of a biochemical relapse.108 Although ursodeoxycholic acid produces no anti-viral effect, it does reduce disease activity108,109 and appears to a suitable substitute for patients who can not tolerate interferon.110 When ursodeoxycholic acid was used in combination with interferon-a, it was no more effective than interferon alone in inducing a biochemical response in previously untreated patients.111 The most common side effects of ursodeoxycholic acid are constipation, gas, indigestion, nausea, and vomiting.112

Prevention and Prophylaxis

Vaccine

There is no vaccine against HCV. A vaccine has been difficult to develop because the HCV viral protein is highly variable and the titers of the antibodies produced by patients in response to HCV are of low and of specific subtypes.113

Immune Globulin

It is not clear if immune globulin is effective and it usefulness as prophylaxis is debatable.16 When immune globulin was used before transfusion in a clinical trial, it conferred significant protection against HCV.114

Drugs under Development

There are a number of promising new drugs in early stages of development to treat CHC.

HCV Protease Inhibitors

The success of protease inhibitors in HIV treatment has generated interest in them for hepatitis. Unlike interferon-a and ribavirin, which act through general mechanisms, protease inhibitors have the potential to target HCV specifically. HCV enzyme NS3 serine protease is essential for viral replication; protease inhibitors block the NS3 serine protease. HCV protease also appears to inhibit cellular defenses against viral infection. HCV protease inhibits interferon-a regulatory factor-3 and consequently blocks infected cells from triggering interferon-a defense pathways. Theoretically, HCV protease inhibitors could work synergistically with interferon-a, making it more effective with lower doses.115 VX-950 is a protease inhibitor in early phase I studies.

Interferon and Interleukin

Interferon Beta (Interferon-ß). In a small trial, interferon-ß had some very modest success when it was used for retreatment of patients with genotype Ib who had responded to interferon-a in the past but relapsed.116

Interferon gamma-1b (Interferon-y 1b) (Actimmune™). This drug is a naturally occurring protein that stimulates the immune system. Preclinical studies demonstrated strong synergistic effects between interferon alfacon-1 and interferon gamma-1b. In a trial enrolling patients with CHC and advanced cirrhosis who had failed standard treatment, Actimmune did not meet its primary endpoint, the reversal of liver fibrosis. In a study that retreated patients with interferon alfacon-1 and interferon gamma-1b for 48 weeks, 38% of patients achieved undetectable viral loads at the end of 12 weeks and 65% had a decline in viral load or were HCV RNA negative. All patients had a reduction in serum ALT that was below the upper limit of normal.115

Alphaferon (Albuferon™). Alphaferon is a protein genetically engineered by fusing interferon to human albumin in order to extend the half-life to increase the effectiveness of interferon.117

IL-10. A small study of IL-10 achieved significant reduction in serum ALT and hepatic inflammation, but increased HCV viral burden via alterations in immunologic viral surveillance.118

Antivirals

Amantadine. Results were mixed in several studies conducted to test a combination of interferon-a plus ribavirin with and without amantadine. In a clinical trial, amantadine caused a significant decline in ALT: 9% of patients cleared the virus and 7% had a sustained virologic response 6 months after treatment.119

Viramidine. This prodrug of ribavirin has demonstrated antiviral activity comparable to ribavirin and may be a safer substitute for ribavirin. A recent trial of a viramidine and pegylated interferon-a combination showed significantly lower incidence of hemolytic anemia compared with amantadine.120

Immunomodulating Agents

Thymalfasin (Zadaxin). When this immunomodulating agent was used in combination with pegylated interferon-a, it increased the early virologic response rates from 20 to 36% in patients who had previously failed therapy.121

Isatoribine. Isatoribine activates the innate immune response by stimulating natural killer cells and macrophages and induction of cytokines including interferon-a. It achieved some reduction in viral load in a small preliminary study.

Drugs That Disrupt the Viral Lifecycle

SCH 6. In laboratory studies, SCH 6 effectively inhibited HCV replication and did not appear to induce cytotoxic morphological changes or apoptosis.122

ISIS 14803 (Antisense Inhibitor). ISIS 14803 inhibits HCV replication and protein expression in cell culture and mouse models. In two very small preliminary studies, ISIS caused transient reductions in HCV RNA levels, as well as flares in serum ALT levels that were up to five times the upper limit of normal. Investigators attribute the transient reductions in plasma HCV RNA levels to an antiviral effect.123

Merimepodib (VX-497). Merimepodib indirectly reduces cellular GTP—the molecule required for DNA and RNA synthesis. In a small study, merimepodib demonstrated a statistically significant antiviral response in combination with pegylated interferon-a and ribavirin.124

Ribozymes (HepBzyme™). Ribozymes appear to disrupt the viral lifecycle of HBV and HCV by cleaving RNA. HepBzyme significantly reduced HBV in animal studies and appears to be as effective as lamivudine. Combinations of HepBzyme and interferon or HepBzyme and lamivudine resulted in additive downregulation of the production of the HBV antigen.125

Drugs to Reduce Side Effects of Interferon and Ribavirin

Epoetin Alfa. Interferon-a and ribavirin combinations sometimes induce anemia severe enough to force dose reduction or discontinuation of ribavirin. When epoetin alfa was added to the combination treatment in a 16-week trial, patients were able to maintain their ribavirin dose and hemoglobin levels.126 In anemic patients, epoetin corrected anemia and enabled 84% of patients to maintain their ribavirin dose.127

Dronabinol. Anorexia, nausea and vomiting are common side effects of ribavirin and interferon-a as well as major causes of discontinuation of treatment. Dronabinol is a synthetic cannabinoid approved for treatment of side effects AIDS patients on cancer chemotherapy. In a clinical trial, 40% of the patients agreed that dronabinol was an effective treatment of major side effects caused by ribavirin and interferon-a.128

Combination Treatments

With Pegalated Interferon-a. There were favorable results in all arms of a trial of pegylated interferon-a in combination with mycophenolate mofetil, amantadine, and ribavirin for the treatment of relapsers and non-responders to interferon-a. All pegylated interferon-a combinations had appreciable virologic response rates. Pegylated interferon-a plus amantadine and ribavirin had the most favorable benefits.126

NM283. NM283 is being developed for use by patients, including liver transplant patients who cannot use interferon. Clinical trials are planned for mid-2004.129

Choosing a Treatment

In principle, all patients with an HCV infection are candidates for antiviral drugs, but the impact of interferon-a on long-term outcome in CHC is unclear. There is reluctance to use interferon because of the poor overall response to treatment, numerous side effects, and the risk of anemia.100 Further, interferon is expensive64 and must be given by injection. Often patients cannot tolerate the side effects or they have contraindications. Most people who discontinue treatment relapse; successful long-term viral suppression is only about 35% overall. Usually long-term low-dose maintenance is required.16

Successful treatment with interferon varies widely with genetic makeup, race, ethnic group, gender, and dose and length of treatment.1 Viral genetics also play an important role in the response to pegylated interferon-a.130 Factors that predict a positive response to interferon-a include low serum levels of HCV RNA, HCV genotype 2 or 3, younger age, female sex, and lack of advanced cirrhosis before treatment starts.64 About half of HCV-positive individuals in the U.S. are infected with genotype 1 and have high viral loads.131 People with HCV genotype 1 infection, regardless of viral load, have a poorer response to interferon-a than other HVC genotypes.132,133

There are compelling reasons to opt for interferon treatment: frequently symptoms lessen, liver enzyme levels return to normal, and—although fibrosis may progress—inflammation of the liver subsides.16 Most importantly, the risk of cirrhosis and liver cancer can be lessened.1 Interferon might provide some long-term improvement in liver histology.134 Studies found a modest but significant reduction in hepatocellular carcinoma in patients who respond completely to interferon.135 There is some evidence that people whose liver enzymes normalize may have a decreased risk of hepatocellular carcinoma and decreased progression of liver disease.1

One large trial demonstrated that interferon-a treatment, regardless of response, conferred some long-term benefits.1 The current thinking is that interferon-a is most beneficial for those at greatest risk for cirrhosis. Ironically, the people at greatest risk for cirrhosis, such as alcoholics and individuals with HCV-HIV co-infections,43 are the least likely to tolerate the side effects of treatment with antiviral drugs and the least able to commit to a year-long course of treatment.136 Those who can be treated with interferon-a are also excellent candidates for alternative treatment either as a replacement or as an adjunct to their traditional pharmaceutical regime.

It is difficult to draw conclusions or generalize about the effectiveness of a traditional treatment because most clinical trials that test interferon-a, alone or in combination, exclude so called "difficult-to-treat" patients. People who are HIV-positive, mentally ill, or use recreational intravenous drugs cannot enroll in a trial. Previous treatment with interferon-a or complicating conditions, such as kidney disease and hemophilia, warrant exclusion. There are methodological limitations among the studies that make comparisons of interferon-a to alternative treatments problematic, as well. In clinical trials, for example, the success of treatment with interferon-a is measured in terms of sustained virological response at 6 months. Treatment lasts 24 weeks or 48 weeks for patients with genotype 1; frequently trial participants are followed-up for 6 years.51 This is not the case with alternative treatment in which there are no uniform parameters, and trials cannot be extrapolated to standard treatment comparisons. Response to interferon-a is modified by a number of factors, such asgenotype and viral load; it is not known if alternative treatment is effected in the same way.69 Individuals who have failed to respond to treatment with interferon-a are excluded from additional interferon trials, but included in alternative trials.

Factors that Predict a Response to Interferon

Only a minority of patients respond to treatment with interferon. Because of the cost, side effects, and inconvenience of 24 to 48 weeks of treatment, it is useful to know the factors associated with a greater or lesser likelihood of response to interferon when deciding on treatment. Early response to treatment (i.e., reduction in viral load during the first month) is the best identifier of a person who will respond positively.137 Greater likelihood of response is also associated with a younger age, women, low body weight, low pretreatment viral load, viral genotypes other than type 1, absence of fibrosis or cirrhosis, higher or longer doses of interferon, and low hepatic iron levels.138 Unfortunately, none of these factors is sufficiently predictive to accurately identification of all patients.139

Factors that Affect the Decision to Use Interferon

About 15% of HCV-positive individuals have normal serum ALT levels.140 They usually have very mild liver disease,21,141 and many are asymptomatic 142. Response to interferon is poor in these patients and there is usually not an appreciable improvement of liver tissue.143,144 In some cases, interferon induces a reactivation of liver disease.145

In general, responsiveness to interferon is diminished when cirrhosis is present, although there is more than a 50% probability of sustained response in those who are able to maintain a virological response during treatment.146,147 In two large well-controlled studies, treatment with interferon decreased the incidence of hepatocellular carcinoma. However, analysis failed to show a significant independent effect of interferon on survival. The beneficial effects of interferon are not convincingly documented for most cirrhotic patients, but interferon does provide an important reduction in complications of cirrhosis for those with a sustained response to therapy.148

Although it might take decades to appear, CHC is a major risk factor for hepatocellular carcinoma. After 20 years of infection, about 8% of patients can be expected to have hepatocellular carcinoma.149,150 Risk factors for developing hepatocellular carcinoma are older age, male gender, and severe liver disease. Most cases of HCV-related hepatocellular carcinoma occur in the people who already have cirrhosis, suggesting that liver disease is the risk factor for hepatocellular carcinoma not HCV infection.149 In fact, Japanese studies demonstrated that the risk of hepatocellular carcinoma is lower in patients with HCV-related cirrhosis who have been treated with interferon whether they had a good response or not.151

Continued . . .


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