Treatment of chronic Hepatitis C with Interferon alfa
Advantages
Inhibits hepatitis C virus replication in some patients with chronic disease
Sustained response in some patients
Important component of combined antiviral treatment
Can improve histological hepatitis
Disadvantages
Given by injection
Low sustained response rates in many patients with type 1 hepatitis and higher levels of viraemia
High relapse rates
Side effects
Neutralising antibodies in some patients
Relative expense
Treatment
Serum aminotransferase activities decline from the peaks encountered in the acute phase of the disease but remain two to eight times normal. They should be measured periodically (monthly to three monthly). If the patient remains viraemic with raised serum alanine aminotransferase activity treatment is indicated. The decision to treat patients with normal serum alanine aminotransferase activity who remain viraemic is more difficult and possibly should be based on biopsy findings as well as the likelihood of response. Several therapeutic trials of interferon alfa for acute hepatitis C have been completed. Most indicate that amelioration of the severity of the chronic hepatitis lesion or even a reduction in the rate of chronic disease is possible with at least six months of treatment. Thus if a diagnosis can be made and the patient does not seem to be convalescing two to four months after the onset of infection interferon alfa can be considered at a dose of 3-6 MU three times weekly for at least six months.
CHRONIC HEPATITIS C
Most patients with chronic hepatitis C are asymptomatic or only mildly symptomatic. Fatigue is the most common complaint. Most patients do not give a history of acute hepatitis or jaundice. There may be no abnormal physical findings. With more severe disease spider angiomas, palmar erythema, hepatomegaly, and systemic manifestations of hepatitis C - for example, cryoglobulinaemia - may be found. Serum alanine aminotransferase activity may fluctuate over time and may even be intermittently normal.
Other patients have a sustained increase in serum aminotransferase activities. With the development of cirrhosis an enlarged liver and spleen may be evident and weakness, wasting, oedema, ascites, and variceal haemorrhage become progressive problems. Older patients may present for the first time with complications of cirrhosis or even hepatocellular carcinoma.
If the serum alanine aminotransferase. activity is normal the patient should be monitored for one to three months to assess the trend in activity. However, viraemia is not uncommonly found in patients with normal enzyme activity and it is not possible to distinguish persistent from resolved infection unless hepatitis C virus RNA can be tested .
With use of this minimalist approach patients with raised serum alanine aminotransferase activity and chronic hepatitis could be considered for antiviral therapy. Serum aminotransferase activities, bilirubin concentration, alkaline phosphatase activity, and prothrombin time should be measured. In patients whose lifestyle or geographic origin suggests that they are at risk of other viral infections hepatitis B surface antigen and HIV infection should also be considered. In equivocal cases the diagnosis of chronic hepatitis C may still require confirmation and careful exclusion of all other causes of raised serum alanine aminotransferase activity, including obesity, alcoholism, inborn errors of metabolism, drug induced hepatotoxicity, and disease of the biliary tract.
Because autoimmune hepatitis is treated differently it is particularly advisable to exclude this diagnosis by excluding from treatment patients with high titres of smooth muscle or liver and kidney microsomal antibodies. The dividing line between this disease and chronic hepatitis C is not always clear, as a high proportion of patients with hepatitis C have low titres of smooth muscle and antinuclear antibodies.
Thyroid disease must be excluded by measuring thyroxine and thyroid stimulating hormone concentrations and antithyroid antibodies.
Patients can be managed or even given antiviral therapy without a liver biopsy. However, this leaves several questions unanswered, as there is currently no substitute for liver biopsy to ascertain the grade (severity and extent of hepatic inflammation) or stage (fibrosis) of the disease.
Asymptomatic cirrhosis may be present.
A characteristic histological pattern of mild chronic hepatitis with portal Iymphoid follicles and varying degrees of lobular activity is found in many patients. Serum alanine aminotransferase activity is used to assess response, and if values have not become normal in two or possibly three months, then treatment is stopped. Most responsive patients will have responded within this period. Large placebo controlled studies indicate that around half of patients have normal serum aminotransferase activities after six months of interferon alfa 3 MU three times a week.
After treatment for six months half of the initial responders will promptly relapse. Some 15-20% of unselected patient have a prolonged biochemical response to treatment and do not relapse when interferon is stopped.
Patients should be monitored every one to four weeks during treatment and have their blood counts and serum aminotransferase activities measured at these intervals. Thyroid function values should be measured before, during, and at the end of treatment.
The patterns of response vary. Some patients may have a partial response with improvement but not return to normal of serum aminotransferase activities. A proportion of patients may show a good initial response to treatment but then have an increase in serum alanine aminotransferase activity again despite continuing treatment. Possibly some of these patients develop neutralising interferon antibodies or interferon resistance. A proportion of patients with chronic hepatitis C have chronic disease with features of autoimmune hepatitis which is provoked by interferon alfa. This phenomenon is unusual and not common enough to suggest that hepatitis C is an autoimmune disease or that corticosteroids are a first line treatment for hepatitis C. HLA typing may indicate this predisposition.
Approach when hepatitis C virus RNA testing is available
A more comprehensive approach to treatment should use hepatitis C virus RNA to define patients with normal serum alanine aminotransferase activity who are none the less viraemic to monitor antiviral therapy and measure virological response. Thus liver biopsy should be considered in patients with raised serum aminotransferase activity or a positive hepatitis C virus RNA test result; this second group of patients may have accrued appreciable liver damage but have intermittently abnormal alanine aminotransferase values. Liver biopsy may help to optimise the dose and judge a virological response to treatment.
Serum hepatitis C virus RNA may become undetectable in patients who have normal aminotransferase activities after four to eight weeks of interferon alfa. Serum aminotransferase activities usually relapse in patients who remain hepatitis C virus RNA positive at the end of treatment - but some patients may remain positive for a period despite normal serum aminotransferase values. Undetectable hepatitis C virus RNA at the end of treatment does not preclude a relapse in serum aminotransferase activity in patients after stopping interferon, but it lessens this probability.
The sensitivity of tests for hepatitis C virus RNA is an issue which requires more careful standardisation than is applied at present. There are inadequate data to indicate (a) whether patients with normal aminotransferase activities and negative for hepatitis C virus RNA at six months should continue treatment to prevent relapse (probably) and (b) whether patients with normal aminotransferase activities and posit*e for hepatitis C virus RNA at six months will become negative for hepatitis C virus RNA if treatment is extended beyond six months (unlikely). The logic of individually tailoring the antiviral dose to the level of viraemia or adapting the dose of interferon to hepatitis C virus RNA status after eight weeks is being tested.
Measures to improve responsiveness to interferon alfa need consideration. It is not certain whether initiating treatment with 3 MU is optimal. Longer treatments or induction with a higher dose (5-6 MU) may be more effective, as there is evidence for dose responsiveness. Prolonging treatment for a year or longer results in lower relapse rates. However, relapses still occur after higher doses and patients have more side effects at higher doses.
Giving a second course of treatment with a different interferon may be usefulin some patients.
Approach when hepatitis C virus RNA measurement and genotyping or serotyping are available
Because long term response rates to treatment have been disappointing, a third approach could be to improve response rates by categorising patients as "good" or "poor" responders according to the known host and viral determinants of response to interferon.
Several workers have suggested that patients with types 2 and 3 infection are more likely to have a sustained response to treatment than patients with type I (and possibly type 4). Types 1a and 1b infection are equally resistant to interferon. Long term responses are also higher in patients with lower circulating levels of virus measured by branched chain DNA assay or competitive polymerase chain reaction.Patients with fewer than 10 to power six copies of hepatitis C virus RNA per ml are more likely to sustain responses (though the precise cut off has not been determined). Within genotypes response rates may be higher for patients with lower virus concentrations and less advanced disease. Younger patients and patients without fibrosis or cirrhosis are also more responsive to treatment.The mechanisms by which different genotypes might differ in responsiveness to treatment remain obscure.
With this approach the patient's genotype or serotype and level of viraemia should be measured before considering treatment. As subtypes are not important, serotyping will suffice for most patients. Patients in the good response group could be offered interferon alfa. Treatment for one year should be considered to reduce relapse rates. Patients in the poor response group require a different or additional treatment - for example, within a trial of combination antiviral agents. Though emerging evidence implies that genotyping or serotyping and measurement of viraemia may become a necessary part of the pretreatment assessment of patients, we are not yet at a point at which interferon can be proscribed for patients with type 1 infection, except possibly in older patients with advanced cirrhosis.
However, patients should at least be forewarned that response rates in this group in previous trials have been low.
Higher sustained response rates should be the objective, and selection of patients will improve treatment results. This approach thereby applies evidence based treatment to obviate future disease and prioritise the provision of interferon alfa. The known data have significant microeconomic and macroeconomic consequences. The issue remains complex, as the improved responsiveness in patients with lower viral loads begs the question of whether these patients ultimately have less severe disease. This cannot be answered now, but it is correct to point out that the prevalence of cirrhosis is not significantly different in patients with types 1 and 4 versus types 2 and 3 hepatitis C and there are no completely non-pathogenic genotypes of hepatitis C.
New research is needed to concentrate on bettering responsiveness in demonstrably unresponsive patients.
Importantly, patients with normal serum alanine aminotransferase activities before treatment may develop an exacerbation after failed interferon treatment. The mechanism is unknown but could be a result of displacement of interferon sensitive clones. There is thus good reason for selecting responsive patients if patients with normal serum alanine aminotransferase activity (but who are hepatitis C virus RNA positive with chronic hepatitis) are to be considered for treatment.
Patients with homogenous circulating quasispecies are also more likely to respond to treatment. Though this has been incompletely studied, in some cases it mirrors a shorter duration of infection. Recent molecular evidence indicates that an interferon sensitive region can be defined in the NS5a region in patients with type 1b infection. Patients with more amino acid mutations in the NS5a gene (region 2209-2248) were more likely to have a complete response than patients with wild type 1b.
When can treatment be considered successful?
Accepted criteria have not been established, but it is reasonable to infer that patients with normal serum alanine aminotransferase activity and negative for hepatitis C virus RNA a year after stopping interferon, with histologically improved disease activity, have had a meaningful response. Responsive patients usually exhibit histological improvement, and sustained clearance of hepatitis C virus RNA is the most likely outcome to have tangible benefit in patients who have not developed cirrhosis. The potential benefit of maintenance treatment for patients who respond but relapse after stopping treatment is being examined.
A recent report has suggested that histological improvement can be observed in treated patients in the absence of a biochemical response.This effect could be the result of a separate anti-inflammatory and antifibrogenic effectof interferon alfa but requires confirmation of long term benefit before it could be considered an objective of interferon treatment.
Interferon for cirrhosis
Patients are at risk of sequelae once cirrhosis has developed. Hence treatment with interferon alfa should be targeted to patients before cirrhosis occurs. Recently, several small trials have suggested that interferon improves liver function and reduces the incidence of hepatocellular carcinoma in patients with cirrhosis due to hepatitis B or C. There are reservations about the conclusions drawn from this limited experience. There is little information regarding potentially injurious exacerbations of the hepatitis C (or B) after transient suppression in patients given intermittent treatment. There is also little information regarding the toxicity of interferon in patients with advanced liver disease; dose-response studies have not been completed. None the less, this could be a potentially important treatment if the antiproliferative, antifibrogenic, and immunomodulatory properties of interferon alfa can be proved to play a part in preventing malignant transformation. Though these data are interesting, further trials are necessary before advising this measure.
Treatment of other special groups
The treatment of special groups, including children, patients with systemic manifestations, patients having renal dialysis, HIV positive patients, and patients with transplants, is beyond the scope of this article. These patients are often difficult to treat, but sustained responses can occur. Cirrhosis due to hepatitis C has become an important indication for liver transplantation, and the number of patients given transplants for decompensated hepatic disease has increased in the past five years. It has become apparent that recurrence of hepatitis C virus infection is almost universal. Thus though the recurrence is usually associated with comparatively mild disease, follow up of these patients has been short, and severe sequelae, including cirrhosis, may become more common with time. The most promising treatments are ribavirin and interferon used together.
Side effects of interferon alfa
Early
Flu-like illness, chills, fever, malaise, muscle aches, headache
Poor appetite
Later - common
Weight loss
Increased need for sleep
Psychological side effects (irritability, anxiety, depression)
Hair loss
Thrombocytopenia,leucopenia
Unusual or severe
Seizures
Acute psychosis
Bacterial infections
Autoimmune reactions
Hyperthyroidism or hypothyroidism or transient thyroiditis
Rare
Proteinuria
Myocardiopathy
Rashes
Interstitial lung disease
Retinal changes
Ototoxicity
