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Special Report on new treatments for hepatitis C.
A lot of attention has been bestowed on the topic of hepatitis C virus (HCV) lately, and rightly so. The blood-borne virus, originally referred to as "non-A, non-B hepatitis," is thought to have infected about 1.8% of the general U.S. population. Many experts believe HCV threatens to become the next major burden for the healthcare system, far greater than the impact of HIV infection.
Of the estimated four million Americans carrying antibodies to HCV, indicating current or previous infection, 2.7 million are believed to have chronic infection (60%-70%), which progresses at a slow rate, going unrecognized in most patients for decades because of the lack of obvious symptoms and eventually presenting itself as advanced liver disease in many cases.
HCV is the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in this country and the No. 1 reason for liver transplantation. HCV is responsible for 8,000-10,000 deaths annually, a number that could rise to 38,000 by the year 2010.
The past five years have produced a wealth of new information regarding the management and treatment of HCV. This prompted the National Institutes of Health to convene a consensus conference on the management of hepatitis C in June to update the statement set forth at the first NIH consensus conference on the subject, held in 1997.
Current recommendations encourage all patients at risk of contracting HCV to be tested for the virus, especially because many patients exhibit no symptoms of infection. At-risk individuals include those who received blood transfusions or organ transplants before 1992, or clotting factor concentrates prior to 1987.
Anyone who has experimented with illicit injectable drugs, even if it occurred only once 30 years ago, is at risk for HCV. Vietnam veterans appear to be at greater risk than the general population, as are healthcare and public safety workers, who may have been exposed to contaminated blood via accidental needlesticks or other methods. Pregnant women with hepatitis C have roughly a 2% risk of passing the virus on to their infants at birth. High-risk sexual behavior and multiple heterosexual partners also increase the risk of acquiring HCV.
Intranasal cocaine use; tattooing; body piercing; and sharing of razors, toothbrushes, or nail files, where there is a potential exposure to blood, are other modes of transmission that increase one's risk of contracting HCV. Prevalence is highest in the 40- to 59-year age group, African-Americans, and specific subpopulations such as the homeless, incarcerated persons, and hemophiliacs, with the highest rates at 70%-90% for injection drug users.
Acute infection with hepatitis C is characterized by the presence of HCV RNA in blood serum one to three weeks following initial exposure. Antibodies to HCV can be detected in 90% of patients after three months, and elevation in serum alanine aminotransferase (ALT) is present within two to eight weeks. Symptoms occur in only 30%-40% of acute cases, but may include malaise, weakness, abdominal pain, anorexia, and jaundice. In general, patients with jaundice have a better chance of clearing the virus from their blood than those without jaundice. Complete recovery from the acute phase will occur in 15% to 30% of individuals, while the rest will develop chronic infection, defined as the presence of HCV RNA in blood for at least six months.
The risk of progressive infection is increased by factors such as older age, male gender, immunosuppression (e.g., HIV), alcohol consumption, and hepatitis B. Liver fibrosis can develop, often leading to cirrhosis, HCC, and end-stage liver disease (ESLD) over time.
HCV is genetically diverse, with six genotypes and more than 50 subtypes that can easily mutate to avoid the immune system's surveillance. Therefore, resistance develops to HCV antibodies and results in the presence of several subspecies of HCV in one individual. This results in a high rate of chronic infection and may contribute to disappointing response rates to treatment, the inability of many patients to eliminate the virus, and difficulty in creating an effective vaccine for HCV.
Of the several different strains of HCV, genotype 1 is the most common type in the United Statesaffecting between 70%-80% of HCV patients; it is also the most difficult to treat. Genotype determination now plays a significant role in the selection of appropriate therapy. Genotypes 2 and 3, although less prevalent, respond more favorably to antiviral therapy.
According to the new NIH consensus statement, all patients with chronic hepatitis C are candidates for antiviral therapy. That's a change from the previous statement that targeted a select group of patients and suggested delaying therapy to individuals drinking significant amounts of alcohol or those actively injecting illicit drugs until their habits were discontinued for at least six months.
"There are no absolutes when it comes to offering treatment," said Stephen J. Rossi, Pharm.D., director of viral hepatitis clinical research at the San Francisco Veteran's Administration Medical Center and assistant professor of medicine at the University of California, San Francisco. "Anyone who is both HCV RNA positive and HCV antibody positive should at least be evaluated for treatment. It can then be determined whether the patient requires antiviral therapy or supportive measures," he added.
Treatment is emphasized for those at increased risk for progression to cirrhosis. This includes those with positive HCV RNA, a liver biopsy showing fibrosis, at least moderate liver inflammation and necrosis, and elevated serum ALT levels. In other patients, the decision to treat is less clear and should be determined on an individual basis.
Response to treatment is measured by elimination of all detectable traces of HCV RNA that is sustained for 24 weeks following the completion of treatment. This sustained virologic response (SVR) is difficult to attain for many patients but is nonetheless the primary goal of therapy. In general, patients with low viral load are more likely to respond to treatment, while high viral load is associated with higher rates of treatment failure.
Early viral response (EVR), a two-log decrease in HCV RNA levels during the first 12-24 weeks of treatment, is predictive of SVR. Even if treatment is continued for a year, patients who do not achieve an EVR have only a small chance of achieving SVR. But treatment can offer other benefits to the patient, even if failure occurs, such as decreasing viral load, reducing liver inflammation, slowing the progression of HCV, and reducing the risk of HCC.
Standard interferon (IFN) products, such as Intron A (IFN alfa-2b, Schering-Plough) and Roferon-A (IFN alfa-2a, Roche), once the mainstay of HCV therapy, are modeled after naturally occurring IFN, an important component of the immune system, produced in response to a viral infection. The addition of Rebetol (ribavirin, Schering-Plough) to IFN was the first major advance in HCV therapy. Ribavirin inhibits the inosine monophosphate dehydrogenase (IMPDH) enzyme system, which in turn blocks the synthesis of RNA and DNA. Although ribavirin itself has only weak antiviral actions, it works to complement the actions of IFN.
Since the last NIH consensus conference, there have been significant improvements in the treatment of HCV infection, the most profound being the introduction of pegylated (polyethylene glycol [PEG]) interferon and ribavirin combination therapy. Peginterferon (PEG-IFN) products, currently available as PEG-Intron (PEG-IFN alfa-2b, Schering-Plough), which is dosed by weight, and Pegasys (PEG-IFN alfa-2a, Roche), with fixed dosing and pending Food & Drug Administration approval for later this year, have one or more chains of polyethylene glycol attached to the IFN molecule. This provides a much longer half-life than standard IFN, allowing for once-weekly dosing, improved efficacy, and better adherence to therapy.
The efficacy of the two PEG-IFN forms + ribavirin combinations were examined in several large clinical trials and found to be superior to both standard IFN + ribavirin combination and PEG-IFN monotherapy. Results showed an average SVR rate of 42%-46% for patients with genotype 1 treated with PEG-IFN + ribavirin for 48 weeks. Response rates were approximately 76%-82% for genotypes 2 and 3 treated for 24 weeks. Because genotype 1 is harder to treat, higher doses and longer duration of therapy are necessary.
"The SVR rates appear to be similar with both PEG-IFN products; however, there are no clinical trials comparing the two forms directly," said Rossi. When treating genotype 1, PEG-IFN alfa-2b was shown to be effective for patients with low viral load. But PEG-IFN alfa-2a had a slightly better SVR rate for high-viral-load patients. Since high viral load is associated with difficult-to-treat cases, PEG-IFN alfa-2a may offer some advantage in these patients, he added. But with a longer half-life than its counterpart, side effects caused by PEG-IFN alfa-2a may take longer to subside following discontinuation of treatment.
A large-scale, multicenter, U.S. trial known as the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) is currently evaluating the efficacy of PEG-IFN alfa-2a, given as maintenance therapy over several years, for the prevention of progression of HCV infection to cirrhosis and HCC, and reducing the need for liver transplantation. According to the new NIH consensus statement, until the results of this four-year study are available, use of PEG-IFN as long-term continuous therapy should be considered experimental.
Coinfection with HIV increases the risk of progression to liver fibrosis, cirrhosis, and HCC in patients with HCV. Preliminary data show treatment with PEG-IFN + ribavirin is superior to standard IFN + ribavirin in this population, and although control of the HIV infection (CD4 count) did not appear to be affected by the HCV treatment, more studies are needed.
Patients will invariably experience side effects from antiviral therapy with PEG-IFN + ribavirin and should be adequately monitored throughout the entire course of treatment. "There is no doubt it is difficult for patients," admitted Rossi of the antiviral course of treatment. And, in light of the fact that response rates are not great, it is something that must be considered in a clinician's decision to treat and manage a patient, he believes.
Common side effects associated with IFN therapy include influenza-like symptoms, fatigue, nausea, vomiting, thrombocytopenia, neutropenia, depression, mood swings, insomnia, thyroid changes, uncontrolled diabetes, and autoimmune disorders. Dosages should be reduced or eliminated if thrombocytopenia or neutropenia develop with IFN therapy.
Between 20%-30% of patients on IFN therapy will develop depression, which is usually reported early in therapy and may level out over time. Depression can be managed by early detection, questioning family members on the severity of symptoms, and dosage reduction. Patients exhibiting suicidal ideation should discontinue therapy and be referred to a mental health professional. Some physicians will recommend prophylactic use of antidepressants, such as the selective serotonin reuptake inhibitors, in an attempt to prevent depression.
Ribavirin may cause hemolytic anemia, headache, cough, shortness of breath, nausea, anorexia, dyspepsia, diarrhea, and dermatologic side effects, such as pruritus and rash. Ribavirin is taken up by the red blood cells and promotes premature removal of the cells from the blood, thereby resulting in anemia in about 10% of patients. Individuals with underlying cardiac disease should not be treated with ribavirin. Hemoglobin concentrations must be tested frequently, and the dosage of ribavirin should be reduced or eliminated if anemia develops. Treatment with erythropoietin may be useful and help alleviate the need for dosage reductions or discontinuation.
Because ribavirin is teratogenic, patients should be advised against pregnancy while being treated and for six months after treatment with ribavirin has ended. Two forms of birth control are recommended during this period of time as well as monthly pregnancy tests.
The NIH consensus statement emphasizes the need for the development of efficient, reproducible cultures of the hepatitis C virus, a necessary step for vaccine development as well as new drug discovery.
Rossi, who is also a principal investigator for several ongoing hepatitis C clinical trials at the San Francisco VAMC, predicted that interferons would most likely remain the mainstay of treatment for the next five years unless something new is fast-tracked for approval. Ribavirin analogs, such as levovirin and viramidine, currently in early clinical testing, are interesting because they capitalize on the activities of ribavirin but exhibit fewer side effects, Rossi added.
Another IMPDH inhibitor, VX-497 (merimepodib), currently being evaluated by Vertex Pharmaceuticals in a triple combination study with PEG-IFN + ribavirin, appears to have immunomodulating effects. Specific inhibitors of HCV-derived enzymes, such as the protease, helicase, and polymerase inhibitors, are also in early testing stages.
Other therapies being tested include amantadine used in combination with PEG-IFN alfa-2b + ribavirin as a "triple therapy"; histamine dihydrochloride (in phase II trials), which reduces free radicals and may protect the liver from oxidative stress; and thymalfasin (thymosin alpha 1) being tested in combination with PEG-IFN in phase III clinical trials.
"We established a clinic for hepatitis C drug treatment," Rossi said of the San Francisco VAMC. "There, our clinical pharmacists can follow patients and make changes within standard protocols based on their progress." His team may see a patient every one to two weeks for the initial few months of therapy and monthly thereafter, continually evaluating blood work and monitoring for side effects.
Pharmacists can impact patient care by providing careful monitoring and recommending adjustments to therapy for chronic HCV patientsoften alleviating certain side effects. "Providing counseling about alcohol consumption, educating injection drug users on the risks of sharing needles, and encouraging patients to remain on therapy for the long-term benefit of lowering viral load are other potential roles for pharmacists," said Rossi. Even patients achieving SVR should be aware that reinfection with HCV is possible and precautions need to be taken to prevent future infections, such as avoiding high-risk behaviors. "Pharmacists are the best healthcare professionals for providing these services to patients," he added.
"Many people will live and die with hepatitis C, but not necessarily from it," Rossi concluded. Learning to live with hepatitis C for many years is a task many chronic HCV patients must undertake. Pharmacists can play a pivotal role in helping patients maintain a reasonable quality of life during this time.