Special Feature
Hepatitis C: Advances in Understanding and Treatment
By Hal B. Jenson, MD, FAAP
A distinct form of human hepatitis (non-a, non-B hepatitis) that differed from classic infectious hepatitis (hepatitis A) and blood-borne hepatitis (hepatitis B) has been recognized since the 1970s. However, the agent that was responsible for most cases of non-A, non-B hepatitis, now known as hepatitis C virus (HCV), was not discovered until 1988, by molecular cloning.1-3 The escalating prevalence of HCV-related disease, the epidemiology of HCV infections, and an "alarming increase in morbidity and mortality due to HCV related disease" makes this infection (and attempts to treat it) an important public health problem in the United States and, indeed, a worldwide issue.4
It is estimated that there are about 4 million people in the United States infected with HCV. Almost all of these individuals have been infected by exposure to contaminated blood or blood products or by use of intravenous drugs. As many as 40-50% of adolescent and young adult patients with thalassemia major are seropositive for anti-HCV. A high prevalence of HCV infection is also found in hemophiliacs.5 The overall rate of vertical transmission of HCV to infants from HCV-infected mothers is only about 5% but may be much higher (36%) with high maternal HCV burden. Transmission by breast-feeding apparently does not appear to occur,6,7 so maternal HCV infection is not a contraindication to breast-feeding.
HCV is an RNA virus with marked genetic heterogeneity, with six major genotypes and numerous subtypes and quasi-species, which may permit it to escape host immune surveillance. Genetic variation may partially explain the differences in clinical course.
HCV infection, both acute and chronic, is usually asymptomatic. A positive enzyme immunoassay (EIA), which becomes positive within four weeks of exposure, establishes the diagnosis of HCV infection. A recombinant immunoblot assay (RIBA) is used if the diagnosis is in doubt, such as a positive EIA test in a person with no risk factors. The presence of antibodies indicates exposure to HCV but provides no information about persistent infection or active liver disease. Active infection is best determined by quantitation of copies of HCV RNA in the patient’s blood using reverse transcription polymerase chain reaction (RT-PCR) amplification. RT-PCR is not currently licensed for use in the United States but is used for research studies. The presence of HCV-associated liver disease is indicated by an elevated serum alanine transaminase (ALT) and confirmed by histologic examination of liver biopsy. Chronic HCV hepatitis in patients with anti-HCV is defined by persistently elevated levels of ALT in the presence of hepatic fibrosis, and in research studies also by the presence of HCV RNA in the blood. Most patients with chronic HCV hepatitis have 105-7 genome copies/mL of HCV RNA in their serum.1
Recent studies of the natural history of HCV hepatitis show that many adult patients with chronic HCV hepatitis have relatively mild clinical disease with slow progression. There are really no significant, long-term data about chronic HCV hepatitis in pediatric patients. The experience in adults suggests that about 85% of patients with HCV infection develop chronic hepatitis, and, after approximately 20-30 years, about 25% will ultimately progress to cirrhosis, liver failure, and occasionally hepatocellular carcinoma. Risk factors for progression to hepatic fibrosis include older age, male sex, and even moderate alcohol ingestion (two 1-oz drinks per day). Currently, there is no means to identify patients who will have progressive disease; a liver biopsy is the only means to assess the presence and extent of hepatic fibrosis.
Until recently, the only available therapy was interferon alfa-2a (since 1991) and interferon alfa-2b (since 1996), but the results of treatment have been disappointing. When interferon was administered three times a week for 12 months, about 40% of patients had normalization of serum ALT levels and clearance of HCV RNA from the serum, but the response was transient in most patients with rapid return to pretreatment levels. Overall, only 10-15% of patients are "sustained responders," defined as normal ALT and negative RT-PCR six months after therapy. "Relapsers" initially show a response but virus is again detectable six months after therapy is discontinued. "Nonresponders" never lose detectable virus.
These relatively poor results have led to study of combination antiviral therapy, based on the model of other viral infections such as HIV, where combination therapy is much more effective than monotherapy. A recent randomized study by McHutchison and colleagues and the Hepatitis Interventional Therapy Group studied the effectiveness of 48 weeks of interferon alfa-2b vs. a combination of interferon alfa-2b and ribavirin in more than 900 adult HCV-infected patients.8 Efficacy was assessed by measurements of the level of serum HCV RNA and serum ALT, and serial liver biopsies. Combination therapy with interferon alfa-2b and ribavirin resulted in higher frequency of sustained response (38% vs 13%) and in histologic improvement (61% vs 41%). However, individuals with HCV genotype 1, the most prevalent in the United States, had only a 28% response rate compared to 66% for those with genotypes 2 and 3. It appears that 24 weeks of combination therapy provides maximal response for patients with genotypes 2 and 3, and 48 weeks of therapy is optimal for patients with genotype 1. Retreatment of nonresponders with combination therapy may result in a sustained response of up to 50%. Both interferon alfa-2b and ribavirin have significant side effects. Discontinuation of treatment is necessary in 8-21% of patients. The major adverse effect is emotional disturbance, mainly depression. Other adverse effects include headache, fatigue, and arthralgia, myalgia, and diarrhea in 30-60% of patients.
Where do we stand with respect to therapy for HCV infection in children? There have been only a few pediatric studies using interferon-alfa. The results in most but not all of these have been similar to the adult studies.9-12 It is likely that combination therapy would result in better outcomes, but we really do not have a good understanding of the natural history of HCV infection in children. The next steps in therapy will be modification of combination therapy including induction and maintenance regimens, new once-a-week formulations, and incorporation of helicase or protease inhibitors in combination therapy. Similar to HIV, the goal will be to reduce viral replication and associated cell death; it is unlikely that the virus will be completely eradicated from the body.
Individuals with HCV risk factors should be screened for the following: any use (even if only once) of illegal drugs; recipients of clotting factors made before 1987 (when inactivation procedures were introduced); hemodialysis patients; persons with persistently abnormal (even slightly) ALT levels; recipients who have been notified that they received blood from an HCV-positive donor; and recipients of any blood transfusion, blood component, or organ transplant before 1992.1-3 Persons with clinical hepatitis not due to hepatitis A or hepatitis B should be tested for anti-HCV. Routine screening of all pregnant women is not recommended. Children born to HCV-infected women should be tested for anti-HCV after 12 months of age; RT-PCR testing is not generally available. Neither national nor international adoptees are at increased risk, although adoptees should be tested if the mother was known to be at high risk.3
Persons infected with HCV should be immunized with hepatitis A and hepatitis B vaccines to minimize further hepatic injury. To minimize transmission, they should use condoms, not share toothbrushes or razors, and not donate blood or organs.
Pediatric HCV infections should become progressively more unusual, at least in the United States, because it is now possible to nearly completely exclude HCV contamination from blood and blood products, and because of the low rate of vertical transmission. The situation in adults is much different. HCV-related liver disease is currently the most common indication for liver transplantation in the United States.1,2 The approximately 8000-10,000 deaths annually in the United States is expected to triple by the year 2015—higher than the annual death rate from AIDS.
References
1. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 1998;47(RR-19):1-39.
2. National Institutes of Health Consensus Development Conference Panel Statement. Hepatology 1997; 26(Suppl 1):2S-10S.
3. American Academy of Pediatrics, Committee on Infectious Diseases. Pediatrics 1998;101:481-485.
4. Liang TJ. N Engl J Med 1998;339:1547-1548.
5. Darby SC, et al. Lancet 1997;350:1425-1431.
6. Lam JP, et al. J Infect Dis 1993;167:572-576.
7. Lin HH, et al. J Pediatr 1995;126:589-591.
8. McHutchison JG, et al. N Engl J Med 1998;339: 1485-1492.
9. Rosenthal P. J Pediatr Gastroenterol Nutr 1997;24:363-364.
10. Iorio R, et al. Arch Dis Child 1996;74:152-156.
11. Bortolotti F, et al. Hepatology 1995;22:1623-1627.
12. Zwiener RJ, et al. Pediatr Infect Dis J 1996;15:906-908.
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