The Management of Viral Hepatitis

Canadian Association for Study of the Liver

Proceedings of a consensus conference held in
Montreal, Quebec in March 1999

HEPATITIS C VIRUS

Hepatitis C virus (HCV) is a heterogeneous, single-stranded, positive-sense RNA virus belonging to the Flaviviridae family. Like many other RNA viruses, HCV has an inherently high mutation rate, resulting in considerable genetic heterogeneity throughout the genome. This genetic heterogeneity subdivides the hepatitis C virus into six major genotypes that vary in distribution worldwide⁽⁴⁷⁾. Genotype 1 appears to be the predominant type in Canada^(46-49). Quasispecies are closely related variants of a single genotype within a single individual, which arise from mutations that occur during viral replication. Quasispecies diversity may increase with time and contribute to interferon resistance and viral persistence.

Information on the rates of development of chronicity after an initial HCV infection comes largely from studies of post-transfusion hepatitis. In these studies viral clearance from serum occurred in about 20-30% of patients initially infected with hepatitis C. It is not known whether this is also true for hepatitis C acquired through other routes. To be confident that viral clearance has been achieved PCR-based assays must be used. Negative HCV RNA by PCR assays indicate viral clearance from serum, but give no information about the state of HCV in the liver or in other privileged niches (e.g., lymphocytes). Thus, given the current state of knowledge complete viral clearance cannot be ascertained with certainty. Therefore, patients who are anti-HCV-positive who have spontaneously developed negative HCV RNA by PCR should continue to be monitored at intervals for the presence of liver disease.

The outcome of chronic hepatitis C virus infection is not well defined. A proportion of patients will ultimately develop cirrhosis and hepatocellular carcinoma^(50-52). However, the proportion of patients at risk for this outcome has not been accurately determined. Various reports have suggested that the lifetime risk of cirrhosis in HCV carriers is between 20-50%. Although several factors have been identified which increase this risk, e.g., alcohol consumption^(53-55), the magnitude of increase in risk has not been well defined. Furthermore, the rate at which disease progresses has also not been completely defined^(56-58). Some studies have indicated that after 17 years of infection the prevalence of cirrhosis is no more than 2%⁽⁶⁰⁾. Other studies have indicated that the mean duration between infection and the first diagnosis of cirrhosis is about 20 years⁽⁵⁰⁾. The differences in these studies are accounted for by referral bias. As a result there is considerable uncertainty about the rate of disease progression.

Factors that increase the risk of progression to cirrhosis include age over 40, consumption of even moderate amounts of alcohol^(53-55), and increased age of acquisition of infection. Patients infected by transfusion are also thought to have more aggressive disease, but in this cohort having a transfusion may be a surrogate marker for increased age at acquisition of disease, since the transfused population is considerably older than the average population. The risk of progression to cirrhosis also appears related to the degree of liver inflammation and fibrosis seen at the time of a biopsy. Patients with persistently normal ALT have a lower likelihood of progression to cirrhosis^(56,60,61). There is no clear association of disease progression with genotype or viral load. Co-infection with HIV is associated with higher viral loads, and a more rapid progression to cirrhosis (see later). Co-infection with hepatitis B is associated with a greater risk of HCC than either disease alone (see later).

Predictions of disease progression depend on the assumption that the rate of disease progression is linear, and that it takes an equal amount of time to progress from e.g., stage 1 fibrosis to stage 2 fibrosis as from stage 3 to stage 4 fibrosis. This assumption may not be correct.

Once cirrhosis has developed the 10 year survival is about 80%. However, the rate of development of complications of cirrhosis over the same time period is about 40%⁽⁶²⁾.

Over the next 10-20 years chronic hepatitis C is predicted to become a major burden on the health care system in Canada as patients who are currently asymptomatic with relatively mild disease progress to end-stage liver disease and develop hepatocellular carcinoma. Predictions in the USA indicate that there will be a 60% increase in the incidence of cirrhosis, a 68% increase in hepatoma incidence, a 279% increment in incidence of hepatic decompensation, a 528% increase in the need for transplantation, and a 223% increase in liver death rate. There are no comparable studies to assess the future health burden in Canada, but since the demographics in the US and Canada are similar, we can expect a similar increase in these disease states in Canada.

1. HEPATITIS C RNA TESTING

As with HBV DNA testing, there is a large inter-assay and intra-assay variation with HCV RNA testing. Once more the requesting physician should be familiar with the characteristics of the assay being used (table 5), and the use of a particular assay should be consistent. This variability must be considered when adapting results from the published literature to local practice.

There are two types of assay for hepatitis C viral RNA. Qualitative tests give a positive or negative result. Quantitative tests give the viral concentration or viral load. The only qualitative assay available is the Roche AMPLICOR^TM assay (lower limit of sensitivity 100 copies/mL). Quantitative assays available include the Chiron bDNA assay and the Roche Monitor^TM assay, which measures down to 1000 particles/mL. The most recent studies on therapy using interferon and ribavirin or PEGylated interferon use the National Genetics assay, which although commercially available requires the sample to be sent to the NGI lab. There is approximately a 10-fold difference between the Monitor and the NGI assay, so that 2x10⁶ copies/mL in the NGI assay is equivalent to about 2x10⁵ copies/mL in the Monitor assay. This becomes important when comparing viral load data between published studies and individual patients.

2. USE OF HCV RNA TESTING

Qualitative HCV-RNA testing is not essential to make the diagnosis of hepatitis C in typical patients who are anti-HCV positive. HCV RNA testing is indicated in patients who are anti-HCV-positive with normal ALT levels. Interpretation of the results of such testing is given in table 6. HCV RNA testing is also sometimes necessary in patients who are immunosuppressed, and who have unexplained elevations of the aminotransferases. In these patients there may be a false-negative anti-HCV assay. Qualitative HCV RNA may also be used to determine whether infants of infected mothers are also infected (see later), and in resolution of indeterminate serological testing. Qualitative HCV RNA monitoring is also useful in assessing the response to therapy.

Quantitative HCV RNA testing is not routinely required for all patients. There was no consensus as to the requirement for quantitative HCV-RNA testing prior to treatment. Viral load is a predictor of response to therapy, but the panel felt that viral load should not be used to assess duration of therapy (see later). High viral loads should not be a deterrent to initiating treatment.

Table 5. Manufacturer's reported dynamic ranges for HCV RNA assays

Table 6 Interpretation of hepatitis C virus RNA testing in anti-HCV-positive patients.

3. SEXUAL TRANSMISSION OF HEPATITIS C VIRUS

Direct percutaneous inoculation is the most efficient mode of transmitting HCV, although sexual, household, occupational and vertical transmission of HCV may also occur^(63-67). HCV intra-spousal transmission appears to be rare in the absence of a parenteral risk in the partner. In case-control studies sexual co-habitation with an anti-HCV-positive person was not identified as a risk for infection. Therefore HCV is not considered to be a sexually transmitted disease. Some factors, however, such as sexual promiscuity, HIV and HSV2 co-infections are associated with sexual transmission of hepatitis C^(66,67). It is not clear whether the probability of transmission between partners increases with decades of marriage and/or age^(68,69). This does not necessarily represent sexual transmission.

The infected person should inform sexual partners. Testing should be offered to the sexual partner. Patients should be advised to avoid sharing items of personal hygiene. In short-term sexual relationships condom use is advised. Unprotected sex during menstruation should be avoided. Couples should be given information about the risks of transmission, and about precautions which may reduce the risk of transmission. The committee neither recommends nor recommends against the use of condoms in stable monogamous relationships. It is up to the couple to make a decision, based upon the best information that can be provided to them.

4. MOTHER-TO-INFANT TRANSMISSION OF HEPATITIS C VIRUS

Rates of transmission of hepatitis C from mother to newborn infant vary between 0 and 3% according to different reports^(70-73). Two risk factors have been identified, HIV infection in the mother, and high maternal viral load^(70,73). It is controversial whether caesarian section prevents transmission of HCV. Results of testing breast milk for HCV RNA are conflicting. However, transmission from breast milk has not been documented. Breast feeding is considered safe and is not contraindicated.

Anti-HCV testing in the neonate is not helpful, because there is passive transfer of antibody across the placenta. This may take 12-18 months to clear. Testing for hepatitis C infection within the first 18 months of life should be by PCR assays. There is very limited information in the literature concerning the rate of chronicity after neonatal transmission. Clearance of the virus may occur more frequently than in adult infection.

5. THERAPY FOR CHRONIC HEPATITIS C

The prime indication for treatment in chronic hepatitis C is an ALT level more than 1.5 times the upper limit of normal on three consecutive occasions over more than three months.

Patients with ALT levels below 1.5 times the upper limit usually have mild disease and an excellent prognosis⁽⁶⁰⁾. Treatment may not be required. Interferon monotherapy treatment in this group is largely ineffective. There are no data on the use of interferon and ribavirin combination therapy in this group.

Although the ALT is the trigger for considering treatment, other factors may also influence the decision whether to treat or not. A liver biopsy is recommended for grading and staging of the liver disease. When treating immunosuppressed patients such as renal or bone marrow transplant recipients, a biopsy is mandatory to confirm the diagnosis. If the biopsy is normal or shows minimal disease then treatment may not be necessary. An adequate biopsy consisting of at least 3-5 portal zones is necessary for assessment. Many other factors have to be taken into consideration before deciding to treat a particular patient. Most important is to try to make an assessment of whether the patient will ever develop cirrhosis and liver failure, or particularly in patients over age 50, whether competing causes of mortality are more or less likely to cause death.

Liver biopsy may also be required in patients in whom treatment is not being considered, in order to assess the extent of liver injury.

It is recommended that response to treatment be defined in virologic terms. The use of ALT levels to define response to treatment is no longer recommended. Successful treatment is indicated by clearance of hepatitis C virus RNA from serum (by sensitive PCR-based assays) 6 months after the completion of therapy (sustained response). There is now evidence showing that this response is durable, in that serum HCV RNA remains negative for years⁽⁷⁴⁾. ALT levels return to normal, and the incidence of complications of cirrhosis and hepatocellular carcinoma are reduced. Survival is improved.

Dose and Duration of Treatment

The recommended treatment for chronic hepatitis C is with a combination of interferon alpha 2b and ribavirin. The dose of interferon is 3 mu TIW, and the dose of ribavirin is 1000 mg for patients weighing less that 75 kg, and 1200 mg daily for patients weighing more than 75 kg^(75-77). The use of interferon alpha 2a or other interferons in combination with ribavirin has not been reported.

Overall, about 40% of patients treated with this combination will have a sustained response. Patients with genotype 2 or 3 have about a 65% response rate^(76,77). Patients with genotype 1 have about a 30% response rate. The response rates in other genotypes are not as well defined. Response rates are also improved with lower viral loads (<2x10⁶ copies/mL by the NGI assay), age less than 40 years, absence of fibrosis and female gender⁽⁷⁷⁾.

Treatment duration with interferon and ribavirin is determined by the viral genotype. Patients who carry genotypes 2 or 3 may be treated for 24 weeks. Patients carrying any other genotype should be treated for 48 weeks^(53,54). Viral load may be used to predict response to therapy, but the data on viral load as an indicator of duration of treatment were weaker than for genotype, and viral load should not at this stage be used to determine duration of therapy. An algorithm has been developed using several of the favourable response factors listed above⁽⁷⁷⁾. However, the algorithm has not been prospectively validated, and should not be used to determine treatment duration.

Unlike interferon monotherapy, a small number of patients treated with interferon and ribavirin who ultimately become long term responders first clear HCV RNA between 12 and 24 weeks of therapy. There is as yet insufficient data to recommend whether the 12 week stop rule described for interferon monotherapy (see below) also applies to combination therapy. Approximately 14% of patients with positive HCV RNA assays at 12 weeks will become sustained responders. However, it is clear that patients who fail to clear HCV RNA by 24 weeks of treatment will not become sustained responders. Therefore, a positive HCV RNA assay after 24 weeks of therapy is an indication to stop treatment.

Interferon monotherapy should now be reserved for patients who cannot tolerate ribavirin (e.g., patients with anemia). The intended treatment duration of interferon monotherapy is 48 weeks. Response is assessed at three months using the qualitative HCV RNA test. Failure to clear HCV RNA after three months of therapy predicts inability to develop a sustained response. Treatment should be stopped if the HCV RNA is positive at three months.

Monitoring During Therapy

The addition of ribavirin to the therapy increases the likelihood of side effects. Ribavirin predictably causes hemolysis. The hemoglobin level falls within the first 2-4 weeks, then stabilizes in most patients. Ribavirin dose reduction is recommended if the hemoglobin falls below 100 gm/L. Routine monitoring for adverse effects includes a CBC weekly for the first month then CBC monthly and TSH every 3 months (there is a increased incidence of thryroiditis on interferon therapy, particularly in patients with chronic hepatitis C). Symptoms should be monitored monthly during treatment.

Treatment response is monitored by the ALT and the HCV RNA concentration. ALT is an imperfect surrogate marker for viral clearance, so that HCV RNA testing is mandatory at the appropriate time points (12 or 24 weeks of therapy, and 24 weeks after completion of therapy). Qualitative HCV RNA testing is adequate to determine response. Quantitative HCV RNA is not required.

Contraindications to therapy

In assessing whether a patient is a good candidate for therapy with interferon and ribavirin, it is essential to consider the benefits and risks for that individual. Factors that may decrease the likelihood of long term benefit from treatment include shorter life expectancy e.g. older age, co-morbid conditions, decompensated liver disease, and active alcohol abuse (abuse within previous 6 months). Ideally patients should abstain from alcohol completely while on treatment.

Factors that may predispose to a higher risk of adverse events include major psychiatric disorders, cardiovascular diseases such as significant arrhythmias, major congestive heart failure, uncontrolled hypertension or ischemic heart disease, active autoimmune diseases, poorly controlled seizure disorders, diabetic retinopathy (interferon can exacerbate diabetic retinopathy), thyroid disease (relative contraindication). Interferon can cause an autoimmune thyroiditis. However, patients who are hypothyroid cannot suffer any further harm. Other factors increasing the risk of adverse events include myelosuppression, such as thrombocytopenia and neutropenia. Therapy should not be instituted if the platelet count is less than 80x10⁹/L or the neutrophil count is less than 1.0x10⁹/L. Renal failure and anemia increase the risk of adverse effects from the ribavirin. Ribavirin is teratogenic. Patients on combination therapy and their partners must use adequate contraception.

Patients in whom poor compliance is expected, or in whom there is a significant risk of re-infection e.g. active substance abuse may not be suitable candidates for treatment.

Other conditions, which are relative contraindications, include severe asthma, psoriasis and past history of autoimmune diseases or psychiatric disorders.

Absolute contraindications to therapy with interferon and ribavirin are decompensated liver disease, active alcohol abuse, pregnancy or lack of appropriate contraception and expected non-compliance.

Special Cases

Thalassemia

Patients with thalessemia can be offered therapy with the understanding that during treatment there is likely to be a 40 to 90% increase in their transfusion requirements. It may be possible to reduce the ribavirin dose. Data on the need to aggressively reduce hepatic iron by chelation to optimize response to treatment is controversial. Alternatively these patients may be better off waiting for the long acting interferons to become available.

Hemophilia

Patients with hemophilia can be offered therapy^(78,79). Pre-treatment assessment should include a liver biopsy that may be performed by the transjugular or by plugged percutaneous route with clotting factor coverage.

Methadone maintenance

Patients on methadone maintenance should not be excluded from treatment.

Prisoners

Therapy for incarcerated patients should be individualized based on their expected compliance and risk of re-infection.

Treatment Failures

Relapse after interferon monotherapy: - these are patients in whom the ALT normalized or in whom viral clearance occurred transiently during interferon monotherapy, but who relapsed after completion of therapy. These patients should be offered treatment with interferon and ribavirin⁽⁸⁰⁾. The expected response rate is similar to naïve patients.

Non-responder to interferon monotherapy: - These are patients in whom the ALT did not return to normal during therapy, or in whom viral clearance from serum was not achieved. There are several treatment options for these patients, each with a response rate of 10-15%. These include re-treatment with interferon and ribavirin, treatment with consensus interferon⁽⁸¹⁾, or induction therapy with interferon. There is insufficient information to make a recommendation on the effectiveness of any of the therapeutic options for patients who were non-responders to interferon monotherapy.

Failure of combination therapy: -Patients who fail to respond or who relapse after combination therapy should be managed in consultation with a centre with expertise in this area. There are no proven treatment options for these patients at present, but they may be candidates for experimental therapies.

Hepatitis C Infection in Children

In past years, hepatitis C was found with high prevalence in children who received multiple transfusions of blood derived products before testing for hepatitis C was introduced. Currently, age-related distribution of infection is likely related to different patterns of exposure. Vertical transmission in infants and body piercing, tattooing and drug abuse in adolescents are the most common routes of infection. The rate at which the initial infection becomes chronic in infants is still unknown. Up to 30% of these children appear to have spontaneous resolution of their infection.

Although progression of the disease seems to be more benign in children than in adults, some children do develop significant fibrosis. Uncontrolled trials suggest that the response rate to interferon may be as high as 33-50%^(82-84). The response to combination therapy (interferon and ribavirin) is unknown. The indications for treatment in children with hepatitis C have not been adequately defined.

Chronic hepatitis C in children should not be treated except in controlled trials.

Acute hepatitis C

Since 1991, the routine screening of blood products has decreased the prevalence of acute HCV following transfusion to negligible levels. Therefore, acute HCV infection is now seen mainly in individuals who have received an accidental needle stick injury. Although a risk for infection is relatively low at <5%, because the majority of these individuals are health care workers, every effort should be made to make an early diagnosis, and thereby minimize the risk of nosocomial transmission. There are no data to indicate which testing algorithms, using serological tests or PCR assays, are more cost effective. HCV RNA may become positive as early as 2 weeks after exposure. Anti-HCV usually becomes positive 10 weeks after exposure. There has been a suggestion that early treatment of acute hepatitis C with interferon monotherapy C may enhance the likelihood of response compared to chronic hepatitis C^(85-87). There is no information as to whether this is true for interferon and ribavirin. The possibility of an enhanced response to early therapy has to be balanced against the theoretical 20% chance of spontaneous clearance of the virus. No recommendations can be made about the timing of therapy of acute hepatitis C. The following recommendation is therefore based on expert opinion, rather than evidence from the medical literature.

Healthcare workers or others subjected to needle-stick injury or equivalent exposure should be tested by anti-HCV at the time of the injury and at 12 weeks or later to detect infection. Treatment should be with standard combination therapy of interferon and ribavirin for the standard duration despite the lack of prospective studies proving efficacy. Given the urgent need to gather data on such cases it is Bly recommended that patients with acute hepatitis C be treated in the setting of a clinical trial or a registry.

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