Hepatitis C Treatment Reduces the Virus but Serious Liver Problems May Progress

Patients with chronic hepatitis C and advanced liver disease who did not respond to previous standard therapy experienced significant decreases in their liver enzymes, viral levels, and liver inflammation following treatment with long-term pegylated interferon. However, the treatment did not slow or prevent the progression of serious liver disease. These findings come from the clinical trial, Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) and were reported at the annual meeting of the American Association for the Study of Liver Disease in Boston on November 5, 2007. HALT-C is funded by the National Institutes of Health (NIH) with additional support from Hoffmann-La Roche Inc.

"The HALT-C trial unequivocally demonstrated that maintenance therapy with peginterferon does not prevent progression of liver disease among patients who have failed prior treatments," said James Everhart, M.D., project scientist for HALT-C and a program director for the Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the principal sponsor of HALT-C at NIH. "These results add to the incentive to develop more effective drugs that will benefit patients with severe liver disease due to hepatitis C."

HALT-C, a randomized multicenter trial of 1,050 patients with chronic hepatitis C who had failed prior treatment to eradicate the infection, assessed whether long-term treatment with peginterferon alfa-2a reduced the development of cirrhosis, liver failure, or liver cancer. The 517 patients randomized to the treatment arm received 90 micrograms of peginterferon in weekly injections for 3.5 years. The 533 patients in the control arm underwent the same follow-up and care as the treated patients including liver biopsies, quarterly clinic visits, and blood tests. All patients had advanced liver fibrosis, a gradual scarring of the liver that puts patients at risk for progressive liver disease.

The outcomes assessed in HALT-C were death, liver cancer, ascites (excess fluid in the abdomen), or encephalopathy (brain and nervous system damage), and for those who did not have cirrhosis initially, the development of cirrhosis. At the end of the study, 34.1 percent of the patients in the treated group and 33.8 percent of the patients in the control group had experienced at least one outcome. Patients in the treated group had significantly lower blood levels of the hepatitis C virus and less liver inflammation. However, there was no major difference in rates of any of the primary outcomes between groups.

Among treated patients, 17 percent stopped peginterferon by one year and six months and 30 percent stopped the drug two years later. Adverse events such as infections, musculoskeletal or digestive problems were the most common reasons patients stopped taking the drug.

Viral hepatitis C infects more than 100 million persons worldwide and as many as 4 million persons in the United States. Hepatitis C ranks with alcohol abuse as the most common cause of chronic liver disease and leads to about 1,000 liver transplants in the United States each year. The best current antiviral therapy consists of pegylated interferon given by injection in combination with oral ribavirin prescribed for about 6 months to a year. This therapy eliminates the virus in about 50 percent of infected patients.

Side Effects of Treatment

Common side effects of alpha interferon and peginterferon (occurring in more than 10 percent of patients) include

• fatigue
• muscle aches
• headaches
• nausea and vomiting
• skin irritation at the injection site
• low-grade fever
• weight loss
• irritability
• depression
• mild bone marrow suppression
• hair loss (reversible)

Most of these side effects are mild to moderate in severity and can be managed. They are worse during the first few weeks of treatment, especially with the first injection. Thereafter, side effects diminish. Acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID) such as ibuprofen or naproxen may be helpful for the muscle aches and low-grade fever. Fatigue and depression are occasionally so troublesome that the dose of peginterferon should be decreased or therapy stopped early. Depression and personality changes can occur on peginterferon therapy and be quite subtle and not readily admitted by the patient. These side effects need careful monitoring. Patients with depression may benefit from antidepressant therapy using selective serotonin reuptake inhibitors. Generally, the psychiatric side effects resolve within 2 to 4 weeks of stopping combination therapy.

Ribavirin also causes side effects, and the combination is generally less well tolerated than peginterferon monotherapy. The most common side effects of ribavirin are

• anemia
• fatigue and irritability
• itching
• skin rash
• nasal stuffiness, sinusitis, and cough

Ribavirin causes a dose-related hemolysis of red cells; with combination therapy, hemoglobin usually decreases by 2 to 3 g/dL and the hematocrit by 5 to 10 percent. The amount of decrease in hemoglobin is highly variable. The decrease starts between weeks 1 and 4 of therapy and can be precipitous. Some patients develop symptoms of anemia, including fatigue, shortness of breath, palpitations, and headache.

The sudden drop in hemoglobin can precipitate angina pectoris in susceptible people, and fatalities from acute myocardial infarction and stroke have been reported in patients receiving combination therapy for hepatitis C. For these important reasons, ribavirin should not be used in patients with pre-existing anemia or with significant coronary or cerebral vascular disease. If such patients require therapy for hepatitis C, they should receive peginterferon monotherapy.

Ribavirin has also been found to cause itching and nasal stuffiness. These are histamine-like side effects; they occur in 10 to 20 percent of patients and are usually mild to moderate in severity. In some patients, however, sinusitis, recurrent bronchitis, or asthma-like symptoms become prominent. It is important that these symptoms be recognized as attributable to ribavirin, because dose modification (by 200 mg per day) or early discontinuation of treatment may be necessary.

Uncommon side effects of alpha interferon, peginterferon, and combination therapy (occurring in less than 2 percent of patients) include

• autoimmune disease (especially thyroid disease)
• severe bacterial infections
• marked thrombocytopenia
• marked neutropenia
• seizures
• depression and suicidal ideation or attempts
• retinopathy (microhemorrhages)
• hearing loss and tinnitus

Rare side effects include acute congestive heart failure, renal failure, vision loss, pulmonary fibrosis or pneumonitis, and sepsis. Deaths have been reported from acute myocardial infarction, stroke, suicide, and sepsis.

A unique but rare side effect is paradoxical worsening of the disease. This effect is assumed to be caused by induction of autoimmune hepatitis, but its cause is really unknown. Because of this possibility, aminotransferases should be monitored. If ALT levels rise to greater than twice the baseline values, therapy should be stopped and the patient monitored. Some patients with this complication have required corticosteroid therapy to control the hepatitis.

Who should be treated?

Patients with anti-HCV, HCV RNA, elevated serum aminotransferase levels, and evidence of chronic hepatitis on liver biopsy, and with no contraindications, should be offered therapy with the combination of peginterferon and ribavirin. The National Institutes of Health Consensus Development Conference Panel recommended that therapy for hepatitis C be limited to those patients who have histological evidence of progressive disease. Thus, the panel recommended that all patients with fibrosis or moderate to severe degrees of inflammation and necrosis on liver biopsy should be treated and that patients with less severe histological disease be managed on an individual basis. Patient selection should not be based on the presence or absence of symptoms, the mode of acquisition, the genotype of HCV RNA, or serum HCV RNA levels.

Between 30 and 40 percent of patients with chronic hepatitis C have normal serum aminotransferase levels. These patients usually have mild disease that is unlikely to progress. Nevertheless, such patients may wish to be treated and, indeed, response rates to peginterferon and ribavirin appear to be independent of serum aminotransferase levels. Patients who prefer not to be treated at present should be monitored as advances in the field may ultimately lead to more effective and better tolerated therapies. When questions arise regarding treatment, liver biopsy can be helpful in documenting the level of disease activity and liver fibrosis and thus the advisability of waiting for future improvements in therapy.

Patients with cirrhosis can be offered therapy if they do not have signs of decompensation, such as ascites, persistent jaundice, wasting, variceal hemorrhage, or hepatic encephalopathy. However, combination therapy has not been shown to improve survival or the ultimate outcome in patients with pre-existing cirrhosis.

The role of peginterferon and ribavirin therapy in children with hepatitis C remains uncertain. Ribavirin has yet to be evaluated adequately in children, and pediatric doses and safety have not been established. Thus, if children with hepatitis C are treated, monotherapy is recommended, and ribavirin should not be used outside of controlled clinical trials.

People with both HCV and HIV infection should be offered therapy for hepatitis C as long as there are no contraindications. Indeed, hepatitis C tends to be more rapidly progressive in patients with HIV co-infection, and end-stage liver disease has become an increasingly common cause of death in HIV-positive persons. For these reasons, therapy for hepatitis C should be recommended even in HIV-infected patients with early and mild disease. Once HIV infection becomes advanced, complications of therapy are more difficult and response rates are less. The decision to treat people co-infected with HIV must take into consideration the concurrent medications and medical conditions. In particular, ribavirin may have significant interactions with anti-retroviral drugs used to treat HIV infection. In patients with co-infection, control of the HIV infection should be the first priority; in persons who are inadequately treated for HIV or who have low CD4 counts, therapy of concurrent HCV is unlikely to be successful and may have serious complications.

In many of these indefinite situations, the indications for therapy should be reassessed at regular intervals. In view of the rapid developments in hepatitis C today, better therapies may become available within the next few years, at which point expanded indications for therapy would be appropriate.

Patients with chronic hepatitis C should be advised on the likelihood of a beneficial outcome to antiviral therapy. For patients with genotypes 2 and 3, the likelihood of a sustained virological response is 70 to 80 percent. In patients with genotype 1, the likelihood of a sustained virological response is between 40 and 55 percent, but the individual likelihood correlates with several viral and patient factors. The major predictive factor for a response is the level of HCV RNA in serum: response rates being higher if HCV RNA levels are lower—levels less than 800,000 IU/ml generally being considered low. Furthermore, response rates are higher in women than men, in younger than older persons, in persons with normal body weight compared with those who are overweight or obese, and in persons with lesser degrees of fibrosis on liver biopsy. Strikingly, response rates are also higher among Caucasian Americans and Asian Americans than among African American patients. Thus, average overall response rates in persons with HCV genotype 1 infection are 50 to 60 percent among Caucasian Americans, but only 25 to 30 percent among African American patients. The reasons for these racial differences are not known.

Patients with acute hepatitis C are a major challenge to management and therapy. Because such a high proportion of patients with acute infection develop chronic hepatitis C, prevention of chronicity has become a focus of attention. In small studies, 83 to 100 percent of persons treated within 1 to 4 months of onset have had resolution of the infection. What is unclear is when to initiate treatment, at what dose, for what duration, and with which regimen. A practical but rigorous approach is to start peginterferon (in usual doses) and ribavirin (800 mg daily) for 24 weeks if HCV RNA is still detected 3 months after onset of infection. The role of ribavirin and the use of shorter courses of therapy are currently under evaluation.

In patients with clinically significant extrahepatic manifestations, such as cryoglobulinemia and glomerulonephritis, therapy with interferon can result in remission of the clinical symptoms and signs. However, relapse after stopping therapy is common. In some patients, long-term or maintenance peginterferon therapy can be used despite persistence of HCV RNA in serum if clinical symptoms and signs resolve on therapy.

Who should not be treated?

Therapy is inadvisable outside of controlled trials for patients who have

• clinically decompensated cirrhosis because of hepatitis C

• kidney, liver, heart, or other solid-organ transplant

• specific contraindications to either monotherapy or combination therapy

Contraindications to peginterferon therapy include severe depression or other neuropsychiatric syndromes, active substance or alcohol abuse, autoimmune disease (such as rheumatoid arthritis, lupus erythematosus, or psoriasis) that is not well controlled, bone marrow compromise, and inability to practice birth control. Contraindications to ribavirin and thus combination therapy include marked anemia, renal dysfunction, and coronary artery or cerebrovascular disease, and inability to practice birth control.

Peginterferon has multiple neuropsychiatric effects. Prolonged therapy can cause marked irritability, anxiety, personality changes, depression, and even suicide or acute psychosis. Patients particularly susceptible to these side effects are those with pre-existing serious psychiatric conditions and patients with neurological disease.

Strict abstinence from alcohol is recommended during therapy of hepatitis C. Peginterferon therapy can be associated with relapse in people with a previous history of drug or alcohol abuse. Therefore, interferon should be given with caution to a patient who has only recently stopped alcohol or substance abuse. Typically, a 6-month abstinence is recommended before starting therapy, but this should be applied only to patients with a history of alcohol abuse, not to social drinkers. Patients with continuing alcohol or substance abuse problems should only be treated in collaboration with alcohol or substance abuse specialists or counselors. Patients can be successfully treated while on methadone or in an active substance abuse program. Indeed, the rigor and regular monitoring that accompany methadone treatment provide a structured format for combination therapy. The dose of methadone may need to be modified during peginterferon-based therapy for hepatitis.

Peginterferon therapy can induce autoantibodies, and a 24- to 48-week course triggers an autoimmune condition in about 2 percent of patients, particularly if they have an underlying susceptibility to autoimmunity (high titers of antinuclear or antithyroid antibodies, for instance). Exacerbation of a known autoimmune disease (such as rheumatoid arthritis or psoriasis) occurs commonly during peginterferon therapy.

Peginterferon has bone marrow suppressive effects. Therefore, patients with bone marrow compromise or cytopenias, such as a low platelet count (< 75,000 cells/mm3) or neutropenia (< 1,000 cells/mm3), should be treated cautiously and with frequent monitoring of cell counts. These side effects appear to be more common with peginterferon than standard interferon.

Ribavirin causes red cell hemolysis to a variable degree in almost all patients. Therefore, patients with a pre-existing hemolysis or anemia (hemoglobin < 11 grams [g] or hematocrit < 33 percent) should not receive ribavirin. Similarly, patients who have significant coronary or cerebral vascular disease should not receive ribavirin, as the anemia caused by treatment can trigger significant ischemia. Fatal myocardial infarctions and strokes have been reported during combination therapy with alpha interferon and ribavirin.

Growth factors such as erythropoietin to raise red blood cell counts or granulocyte stimulating factor to raise neutrophil counts have been used successfully to treat patients with cytopenias during combination therapy. The proper role, dose, and side effects of these adjunctive therapies have yet to be defined.

Ribavirin is excreted largely by the kidneys. Patients with renal disease can develop hemolysis that is severe and even life-threatening. Patients who have elevations in serum creatinine above 2.0 mg per deciliter (dL) should not be treated with ribavirin.

Finally, ribavirin causes birth defects in animal studies and should not be used in women or men who are not practicing adequate means of birth control. Peginterferon also should not be used in pregnant women, as it has direct antigrowth and antiproliferative effects.

Combination therapy should therefore be used with caution. Patients should be fully informed of the potential side effects before starting therapy.

A common question is whether liver biopsy is necessary before starting treatment of hepatitis C. The answer is that it is not necessary but is prudent and provides rationale for whether therapy is critical. Nevertheless, the major use of liver biopsy is to help in the decision of whether to initiate treatment or to delay until there are further advances in the field. In some situations, liver biopsy may not be very helpful. Patients with genotype 2 and 3, for instance, have a high rate of response and might be offered therapy regardless of the severity of hepatitis shown by liver biopsy. Furthermore, patients with genotype 1 who have laboratory or clinical evidence of advanced fibrosis can be assumed to have progressive liver disease, and therapy can be recommended without biopsy documentation. Finally, some patients wish to be treated regardless of severity of the underlying hepatitis and the liver biopsy results will not alter medical care. As response rates to therapy of hepatitis C improve, liver biopsy will play a lesser role in management.