Hepatitis B is produced by a DNA virus classified as a hepadnavirus type 1 (40-42). There are multiple serotypes. More than 300 million people suffer from chronic hepatitis B virus (HBV) infection; more than 75% of affected individuals live in Asia or are of Asian origin. The usual incubation period is 2-3 mo but may be as short as 45 d and as long as 6 mo. The frequency of clinical illness with jaundice is different at different ages. Fewer than 10% of the patients acquiring infection when younger than 5 yr of age develop jaundice, while 30-50% of those older than 5 yr of age develop this clinical sign. The death rate associated with acute HBV infection is low, from 0.5% to 1.0%, and the rate of chronic infection is quite variable depending on the age at acquisition. For example, more than 90% of neonates infected with HBV will develop chronic infection and a carrier state, compared with 50% of infants, 10% of children older than 5 yr of age, and < 5% of adults. If patients develop chronic liver disease from HBV, 15-25% will suffer early mortality.
In the United States in 1989, 83% of acute HBV infections occurred in adults, 8% in adolescents, 4% in children 1-10 yr of age, and 4% in the perinatal period. However, the age distribution of chronic HBV is quite different; 24% of patients acquired the infection in the perinatal period and 12% at 1-10 yr of age. Adult and adolescent acquisition are less represented in the chronic infection group as compared with the frequency of acute infection, with 59% of chronic HBV cases having adult acquisition and 6% acquiring the infection during adolescence.
Concentration of HBV is very high in blood, serum, and wound exudates, and is moderate in semen, vaginal fluid, and saliva. Because of its concentration in genital fluids, HBV is classified as a sexually transmitted disease; sexual transmission is highly efficient. Levels of the virus are very low in urine, stools, breast milk, tears, and sweat. The most common routes of acquisition of infection are sexual, parenteral, and vertical (perinatal from mother to child). The risk factors for acquisition of acute HBV are heterosexual activity in 41%, intravenous drug abuse in 15%, homosexual activity in 9%, household contact in 2%, health care employment in 1%, and unknown source of infection in 31% of infected subjects.
Four percent of the acute HBV infections are due to vertical transmission from mother to child in the perinatal period. The highest risk of transmission is when the mother has hepatitis B e-antigen-positive markers. In this scenario, infection of the child will occur in nearly 90% of the cases. On the other hand, when the mother is hepatitis B e-antigen-negative, the risk of transmission is closer to 15%. Depending on the age at acquisition of the infection (except in infants and toddlers), the most likely scenario is for the hepatitis B infection to be cleared with good recovery.
Patients who are chronically infected may be carriers and suffer almost no hepatic injury with minimal or nonexistent (nonreplicative phase) viral replication. Alternatively, they may have a more intense chronic hepatitis. Patients who are chronically infected and who have ongoing viral replication with elevated liver enzymes are at higher risk for progressive liver disease, and once cirrhosis develops, have a high risk for hepatocellular carcinoma. The development of cirrhosis, however, is not a prerequisite for the development of hepatocellular carcinoma.
The best marker for acute HBV infection is the hepatitis B core IgM antibody, which should always be present at the time the patient has evidence of clinical disease. For chronic infection (6 mo or longer) the most reliable marker is the presence of HBV surface antigen. It is very important to assess the degree of viral replication in chronic HBV cases, and this is usually determined by monitoring the evolution of liver enzymes, mostly alanine aminotransferase (ALT), and, most importantly, be determinations of HBV-DNA concentrations in serum by hybridization (quantitative) assays. The presence of hepatitis B e-antigen is less reliable because patients may have mutant strains of the virus and be hepatitis B e-antigen-negative, even during periods of active viral replication.
Interferon has traditionally been used as the treatment for HBV. The patients who have a better chance of response to this drug are those with well-compensated liver disease, moderately elevated liver enzymes (ALT of > 100), and only moderate elevation of HBV-DNA (< 200 pg/mL). Meta-analysis of the efficacy of interferon has shown that 33% of the patients who have chronic hepatitis B with significant viral replication may clear the hepatitis B e-antigen as compared with only 12% of the untreated controls. When treating hepatitis B, interferon is usually utilized at a dose of either 5 million units every day or 10 million units three times a week for a total of 16-24 wk. This form of therapy can be given only to patients who have no cirrhosis or who have very well compensated chronic hepatitis B with cirrhosis (bilirubin <3, absence of ascites, no previous varices bleed, serum albumin >3, and absence of hepatic encephalopathy). Interferon response, defined as loss of HB e-antigen and HBV-DNA (by hybridization or signal amplification quantitation) with normalization or near normalization of ALT where all are measured 6 mo after the end of therapy, occurs in 33% of the patients (vs 12% in controls). Loss of HBsAg occurs in 7.8% of the patients (vs 1.8% in controls).
The most recent addition to the armament against this virus is lamivudine (Epivir-HBV) at an oral dose of 100 mg a day. When Epivir-HBV was given for 52 wk to patients with chronic HBV, 15-17% of the patients responded by losing hepatitis B e-antigen, by developing hepatitis B e-antibody and by having nondetectable levels of HBV-DNA. This compared to a response rate of only 4-6% for patients receiving placebo. Importantly, when histological response was evaluated at the end of therapy, improvement was seen in 55-56% of the patients on lamivudine as compared with only 25-26% of the patients who were on placebo. Overall, the side effects of the drug were quite low and quite similar to those seen during placebo therapy.
One of the problems with lamivudine is risk of development of resistance, manifested clinically by elevation of HBV-DNA levels in all patients and elevation of ALT
in 50% of patients. The resistance mutation occurs in the YMDD locus of the virus and reduces the sensitivity of the virus to lamivudine. This resistance pattern is observed in 14% of the patients receiving this drug for 1 yr. Of importance, however, histologic improvements usually are maintained in spite of the mutation, probably because the mutant virus is less aggressive. Patients who develop lamivudine resistance could be considered for therapy with adefovir dipivoxil or with lobucavir, but the clinical experience with these drugs is very limited.
Current data suggest that long-term therapy with lamivudine is feasible but further study is needed. Patients on lamivudine therapy should be monitored at a minimum with monthly blood chemistries and with determinations of HBV-DNA quantitation at least every other month, but earlier if ALT rises. After discontinuation of lamivudine, patients should be followed with at least monthly determinations of ALT, HBV-DNA quantitation, hepatitis B e-antigen and anti-hepatitis B-e; if the disease reactivates, therapy should be restarted.
In the long term, the most effective way to prevent the occurrence of this disease is vaccination against HBV infection. Currently, vaccination is being offered to all neonates and now is starting to be given to preadolescent children and adolescents through age 18 ("catch up" vaccination). In addition to this, all health care workers and other groups at high risk should be vaccinated.
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