Hepatitis B Diagnosis, Prevention, And Treatment
Content
Clinical Chemistry 43:8(B) 1500 –1506 (1997)
Beckman Conference
Hepatitis B: diagnosis, prevention, and treatment
Norman Gitlin
Hepatitis B virus (HBV) infection occurs worldwide and is an important cause of acute and chronic viral hepatitis in the US. In this review, I describe the virus, risk factors for infection, clinical features of infection, results of laboratory tests during infection, and standard and emerging treatment for chronic infection. Although 95% of adult patients recover completely from HBV infection, 90% of children <4 years of age develop chronic infection. Active vaccination is highly efficacious.
INDEXING TERMS:
chronic disease • DNA virus • risk factors
Approximately 300 000 new cases of hepatitis B are reported in the US each year [1, 2]. An estimated 300 million persons worldwide are chronic carriers of the hepatitis B virus (HBV), with 100 million carriers in China and ϳ1 million carriers in the US [1, 2].1 The annual health cost attributed to HBV in the US is $500 million. The natural history of acute HBV infection varies according to the patient’s age at the time of infection. In adults, 95% of cases resolve spontaneously with varying degrees of severity of the acute illness; the remaining 5% of adults develop chronic hepatitis B. In contrast, 90% of infected neonates develop chronic hepatitis B.
HBV
The HBV is a partially double-stranded circular DNA virus of the class Hepadnaviridae. The viral particle is 42 nm in size and consists of an outer lipoprotein coat and hepatitis B surface antigen (HBsAg), which circulates in the blood in two forms: as a viral particle-bound protein form or as a free, noninfectious protein presenting as 22-nm spherical and tubular particles [3] (see Fig. 1). The latter free forms predominate. The detection of HBsAg in serum alone does not always imply infectivity or viral
replication, since HBsAg may exist in the blood only as free forms that are noninfectious and are not associated with viral particles. The HBsAg is the component of the HBV vaccine that induces a protective, neutralizing antibody with a long-term action against HBV infection. The inner viral core of the HBV particle contains hepatitis B core antigen (HBcAg), a double-stranded DNA molecule, and hepatitis B e antigen (HBeAg), a soluble, nonparticulate substance that is often present with core antigen. The detection of HBeAg is also a useful marker of viral replication. Finally, the inner core also contains a DNAdependent polymerase. The inner viral core does not exist independently in the blood; it can be detected and measured only after digestion of the HBsAg off the circulating viral particle. The HBcAg is a marker of the infectious viral material and it is the most accurate index of viral replication. The genome of HBV consists of the S gene, which codes for HBsAg; two pre-S region genes (pre-S1, pre-S2) that code for the hepatocyte receptor binding site; the C gene, which codes for HBcAg and HBeAg; the P gene, which codes for a DNA polymerase; and an X gene that activates viral and cellular promoters [4]. Although HBV is a DNA virus, it replicates in a way similar to retroviruses, making an intermediate RNA transcript. Mutations of the HBV genome have been recognized [5–7]. A precore mutant strain manifests as an infection with high concentrations of HBsAg and of HBV DNA, yet an absence of HBeAg and presence of antibody to HBeAg (anti-HBe). Patients infected with this mutant often manifest with severe chronic hepatitis, early progression to cirrhosis, and a variable response to interferon therapy. It may have an association with fulminant hepatic failure.
risk factors
The major routes of transmission of HBV are intravenous drug use (also needlesticks and tattoos), sexual transmission, and maternal/infant transmission at birth. The maternal transmission of HBV to her infant is almost inevitable if the mother is both HBsAg and HBeAg positive at the time of the baby’s birth. Because mandatory blood bank screening of donor blood for HBV came into effect in 1972, the current risk of posttransfusion transmission of HBV is extremely low. The HBV is found
Division of Digestive Diseases, Emory University School of Medicine, 2101 WMB, Atlanta, GA 30322. Fax 404-778-4715. 1 Nonstandard abbreviations: HBV, hepatitis B virus; HBsAg, HB surface antigen; HBcAg, HB core antigen; HBeAg, HB e (early) antigen; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HBIG, hepatitis B immune globulin; and FIAU, fialuridine. Received February 24, 1997; revised and accepted June 2, 1997.
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sponse to the HBV. Necrosis of hepatocytes results from the host’s immune attack on HBV-infected hepatocytes in which viral replication is occurring. Immunologic activity involves host cytotoxic T cells directed against HBcAg on the hepatocyte surface membrane. Concurrent infection with hepatitis delta (HDV) in patients with preexisting HBV infection can result in an accelerated deterioration of the hepatitis and the complications of cirrhosis and death [21].
serologic and biochemical features
The serological markers of HBV infection vary depending on whether the infection is acute or chronic. A summary of the serologic findings that occur in acute HBV is given in Fig. 2 [22]. The first serologic marker of HBV infection is HBsAg, which can be detected from 2 to 12 weeks after infection with HBV. The presence of HBsAg often antedates symptoms or abnormalities of hepatic biochemistry by 6 – 8 weeks. In patients who recover, HBsAg disappears from the serum 12–20 weeks after the onset of symptoms or increase in concentrations of aminotransferases. The detection of IgM antibody to hepatitis B core antigen (antiHBc IgM) usually occurs 2 weeks after the detection of HBsAg, and it remains detectable for up to 6 months after the onset of the acute hepatitis. Before the disappearance of this antibody, another antibody to the hepatitis core antigen of the IgG class (anti-HBc IgG) appears and remains detectable indefinitely. The detection of the antiHBc IgM is of assistance in diagnosing an acute infection in patients with HBsAg concentrations that are below the sensitivity threshold of the diagnostic assay. HBeAg is detectable in acute HBV infection if the titer of the viral infection is high. The presence of HBeAg implies infectivity, and the persistence of HBeAg for Ͼ20 weeks increases the potential risk of the acute HBV progressing to chronicity. A quantitative assay of HBV involving a molecular hybridization technique is now available. A dot-blot or
Fig. 1. HBV.
in blood, saliva, breast milk, vaginal secretions, semen, and ascitic fluid [8 –10]. Homosexual transmission has been declining as a consequence of awareness and actions taken to stem the AIDS epidemic. Heterosexual transmission accounts for over a third of the new cases in the US. The HBV carrier rate varies greatly in the world. The overall rate in the US is 0.3%; in parts of Africa, the Philippines, and Asia, carrier rates are as high as 20% [11, 12]. The risk of acquiring HBV after an accidental stick from a needle recently used on a patient with HBV varies from 20% if the patient was only HBsAg positive to 66% if the patient was both HBsAg and HBeAg positive.
clinical features
The incubation period for HBV ranges from 45 to 180 days. Clinical features of the disease vary considerably. Jaundice occurs in Ͻ10% of children Ͻ5 years of age. However, jaundice manifests in 50% of older children and adults. No specific clinical manifestations occur with an acute HBV infection. The presentation is no different from other causes of acute viral hepatitis. Symptoms include anorexia, nausea, vomiting, flu-like complaints, fatigue, and malaise. Physical findings range from minimal nonspecific abnormalities to jaundice and hepatomegaly (often tender), and occasionally extend to extrahepatic features reflecting immune-complex phenomena such as vasculitis, immune complex nephritis, arthritis, a serumsickness-like illness, and polyarteritis nodosa [13–17]. The majority of adults with acute HBV make a full and total recovery; only ϳ5% of adults, especially men, develop a chronic HBV infection that is often asymptomatic. About 10 –20% of these adult patients may deteriorate and progress to cirrhosis or liver cancer [18 –20]. The remaining 80 –90% of patients with chronic HBV infection ultimately resolve and totally recover from their HBV infection over 2–5 years. The risk of developing a chronic HBV infection is as high as 90% if the acute HBV occurs in neonates or infants Ͻ4 years of age. The fatality rate due to fulminant hepatic failure as a consequence of acute HBV in the US is ϳ0.2% (1 in 2000). The outcome of acute HBV infection is determined by the host’s immune re-
Fig. 2. Time sequence of serologic indicators of acute hepatitis B.
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liquid hybridization technique detects HBV DNA concentrations of Ն104 genome-equivalents/mL. The HBV DNA assay is useful in determining ongoing viral replication, even when HBeAg is not detectable. HBV DNA assay is also useful as a prognostic index regarding response to interferon therapy. Patients with HBV DNA concentrations Ͻ200 ng/L are more likely to have a successful therapeutic outcome than those with higher HBV DNA concentrations. Antibody to hepatitis B surface antigen (anti-HBs) becomes detectable during the recovery from acute HBV infection in patients who do not progress to a chronic infection. The disappearance of the HBsAg occurs a few weeks before the advent of the anti-HBs. The presence of anti-HBs after acute infection indicates recovery from the infection and generally lifelong immunity from reinfection. The interpretation of the above HBV markers are summarized in Table 1. Three phases of viral replication occur during the course of HBV infection, especially in patients with chronic hepatitis B. High replicative phase. Associated with the presence of HBsAg, HBeAg, and HBV DNA detectable in the sera. Increases in the aminotransferases occur, histologic evidence of moderate inflammatory activity is evident, and the risk of evolving to cirrhosis is high. Low replicative phase. Associated with the loss of HBeAg, or a fall or loss of the HBV DNA concentrations, the appearance of anti-HBe, and histologic evidence of a decrease in inflammatory activity. These serologic changes (loss of HBV DNA and HBeAg) are referred to as “seroconversion.” Nonreplicative phase. Associated with either the absence of markers of viral replication (or they are detectable only by highly sensitive techniques), diminished inflammation, and inactivity of the histologic findings. However, if cirrhosis has already developed, it persists indefinitely. The increase in aminotransferases [especially alanine aminotransferase (ALT)] during acute hepatitis B varies from a mild/moderate increase of 3- to 10-fold to a striking increase of Ͼ100-fold. The latter does not neces-
sarily imply a poor prognosis. The ALT concentrations are usually higher than the aspartate aminotransferase (AST) concentrations. The bilirubin concentration rises in most patients with acute HBV infection. Clinical jaundice manifests in 50% of adults with bilirubin concentrations of Ͼ51.3 mol/L (3.0 mg/dL). Concentrations up to 513 mol/L (30.0 mg/dL) can occur. A slight rise in alkaline phosphatase is also evident. In patients who develop fulminant hepatic failure, a rapid fall in ALT and AST may mislead one into concluding that the hepatic infection is resolving when in fact loss of hepatocytes is occurring. Sustained increases in the concentrations of the aminotransferases for Ͼ6 months is regarded as indicative of chronic hepatitis.
Treatment prophylaxis
Active prophylaxis against HBV infection is available in the form of a recombinant HBV vaccine. The commercial products available are Recombivax HB (Merck, West Point, PA) and Engerix-B (Smith Kline Beecham, Philadelphia, PA). The recommended dosage for these products is given in Table 2. Recombivax HB is given as three intramuscular injections at 0, 1, and 6 months and Engerix-B is given as three intramuscular injections at 0, 1 and 2 months. Both are highly effective in producing antibodies. The seroconversion rates associated with the development of anti-HB varies. It is in the range of 95–98% in females and 85% in males [23]. Lower rates occur if vaccination is given after age 40 years, or in patients who are immunocompromised, malnourished, alcoholic, obese, or who have chronic renal disease. The current recommendation is to vaccinate all newborn infants, and all adolescents and adults in high-risk groups. The interval for booster vaccinations against HBV is still undecided. A 10-year booster injection has been suggested. However, patients who initially responded to the vaccine and subsequently lost their anti-HB titers still appear immune to subsequent exposure to HBV [24 –26]. Reexposure to HBV leads to an anamnestic response and rarely to a subclinical infection. Passive immunization is available by using pooled serum from patients who have recovered spontaneously from acute HBV and who have significant anti-HBs concentrations. The product, hepatitis B immune globulin (HBIG), is given simultaneously with HBV vaccine to newborn infants whose mothers are HBsAg positive, or postneedle stick or after sexual exposure in adults who are not immune to HBV [27]. The vaccine and globulin are given into opposite deltoid muscles (or for newborns, into opposite thigh muscles). Administration of HBIG vaccine therapy is most effective if given within 12 h of birth or exposure to HBV. Follow-up HBV vaccination schedules must be completed at 1 and 6 months to obtain active immunization and to provide the individual with longterm (Ͼ10 years) immunity.
Table 1. Interpretation of hepatitis B markers.
Marker Acute infection Chronic infection Past infection
HBsAg HBeAg anti-HBs anti-HBcIgM anti-HBcIgG anti-HBe HBV DNA ALT
ϩ ϩ early, then Ϫ Ϫ ϩ ϩ Ϫ early, then ϩ ϩ early, then Ϫ increased (marked)
ϩ Ϯ Ϫ Ϫ ϩ Ϯ Ϯ increased (mild– moderate)
Ϫ Ϫ ϩ Ϫ ϩ ϩ Ϫ normal
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Table 2. Recommended dosage of hepatitis B vaccines.
Vaccine Age 10 g/0.5 mL Engerix-B 20 g/1.0 mL 2.5 g/0.5 mL Recombivax HB 5 g/0.5 mL 10 g/1.0 mL
Infants/HBsAg pos mothers Infants/HBsAg neg mothers 1–10 yr 11–19 yr 20ϩ yr
10 g (0.5 mL) 10 g (0.5 mL) 10 g (0.5 mL) 10 g (0.5 mL) 20 g (1.0 mL) 2.5 g (0.5 mL) 2.5 g (0.5 mL)
5 g (0.5 mL)
5 g (0.5 mL) 10 g (1.0 mL)
drug therapy
Acute hepatitis B does not require specific treatment because Ͼ90% of adults will spontaneously clear their infection. Symptomatic treatment of the nausea, anorexia, vomiting, and other symptoms may be indicated. Many agents have been evaluated for the treatment of chronic hepatitis B. Most have been found to be ineffective or too toxic at effective doses. Others are still under evaluation (see Table 3). In the US, the only approved therapeutic agents for treating chronic hepatitis B are interferon-␣-2b and interferon-␣-2a. The goals of therapy are the eradication of the virus, leading to a remission of the liver disease and an improved long-term prognosis. Interferon. Interferon-␣ belongs to a family of natural occurring proteins that have antiviral and immunomodulatory actions [28, 29]. They enhance T-cell helper activity, cause maturation of B lymphocytes, inhibit T-cell suppressors, and enhance HLA type 1 expression. The efficacy of interferon for the treatment of chronic hepatitis B has been demonstrated in a large US trial in which 37% of treated patients receiving 5 million units per day of interferon for 16 weeks lost HBV DNA and HBeAg, compared with 7% of untreated controls [30]. A metaanalysis of 14 studies involving Ͼ800 patients with chronic HBV treated with interferon showed a loss of HBV DNA in 37% and HbeAg in 33% of the interferontreated patients compared with 17% and 13% losses, respectively, in the controls [31]. In another long-term
follow-up study, 35% of patients who lost markers of viral replication during therapy eventually also lost HBsAg over 5 years [32]. Favorable prognostic indices for a successful outcome with interferon therapy have been evaluated and they include the following: (a) a pretreatment concentration of HBV DNA Ͻ200 ng/L, (b) being female, (c) heterosexual habits, (d) concentrations of serum ALT Ͼ100 U/L (high ALT concentrations may be indicative of a better host immune response to HBV), (e) a disease duration of Ͻ4 years, (f) absence of HIV, and (g) acquiring the HBV infection at Ͼ6 years of age [33, 34]. These indices do not provide an absolute guarantee of success with interferon therapy; they suggest a higher likelihood of success and they may assist in patient selection for interferon therapy. A low concentration of HBV DNA and a raised ALT are the best indices of predicting a successful treatment outcome. Patient inclusion and exclusion criteria for interferon therapy: Patients with chronic hepatitis with an increased serum aminotransferase for Ͼ6 months who have serologic evidence of active viral replication (the presence of HBsAg, HBeAg, and an increased HBV DNA concentration) should be considered for interferon therapy provided they have no contraindications that exclude them from therapy. These contraindications are summarized in Table 4. They include the presence of hepatic decompensation as evidenced by biochemical variables of albumin Ͻ30 g/L, bilirubin Ͼ51.3 mol/L (3.0 mg/dL), or a
Table 3. Chronic hepatitis B: potential drug therapy.
Agent Effective Ineffective Toxic Under evaluation
Interferon Antiviral
Interferon-␣
Immunomodulatory
Interferon-␥ Acyclovir Dideoxyinosine Azudothymidine Foscarnet Prednisone Interleukin-2 Thymosin Levamisole
Fialuridine Adenine Arabinoside
Interferon  Ribavirin Lamivudine
Adoptive immune transfer
Modified from Lok ASF. Therapy of Hepatitis B. In AASLD postgraduate course, November 11–12 1996, Chicago, IL.
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Table 4. Contraindications for interferon therapy for chronic hepatitis B.
Hepatic decompensation Albumin Ͻ3.0 L Blirubin Ͼ51.3 mol/L (3.0 mg/dL) Prolonged prothrombin time Ͼ 3 Portal hypertension Variceal bleed Ascites Encephalopathy Hypersplenism Leukopenia (Ͻ2 ϫ 1010/L) Thrombocytopenia (Ͻ7 ϫ 1010L) Psychiatric Depression (severe), suicide attempt Autoimmune disease Polyarteritis nodosa, rheumatoid arthritis Major system impairment Pregnancy Current intravenous drug abuse
prothrombin time Ͼ3.0 s above the control; the presence of complications of portal hypertension (ascites, past variceal bleeding); leukopenia (Ͻ2 ϫ 109/L), thrombocytopenia (Ͻ7 ϫ 107/L), or renal impairment [creatinine Ͼ176.8 mol/L (2.0 mg/dL)]. Pregnancy, the presence of an autoimmune disease, a history of severe depression requiring hospitalization, or a history of attempted suicide are also contraindications for the use of interferon. Other contraindications include a history of recent intravenous drug abuse, alcoholism, or a severe major system dysfunction (cardiac failure, obstructive airways disease, or uncontrolled diabetes). The recommended dose of interferon is 5 million international units, self-injected, subcutaneously daily for 16 weeks with monitoring of a complete blood count, prothrombin time, total bilirubin, ALT, AST, HBsAg, anti-HBs, HBeAg, anti-HBe, and quantitative HBV DNA at 2, 4, 8, 12, and 16 weeks. A pretreatment thyrotropin (TSH) assay is also performed. A sudden, often asymptomatic, rise in ALT associated with a fall in HBV DNA concentrations can occur 4 to 8 weeks into therapy. This is known as a “flare response” and is thought to reflect the immune-mediated clearance of HBV-infected hepatocytes. It is followed by the disappearance of serum HBV DNA, loss of HBeAg, the appearance of anti-HBe, and normalization of serum ALT, in that order [32]. Loss of HBsAg occurs in 25% of patients during the 6 months after seroconversion of HBeAg to anti-HBe [32]. A flare occurs in 60 –70% of responders. It can also occur in 25–30% of nonresponders to interferon therapy [35, 36]. The intensity of the flare seldom aggravates the underlying liver status. However, if there is a striking increase in ALT, a rise in bilirubin, or new signs or symptoms of hepatic decompensation, then the interferon therapy should be reduced or withheld and the patient should be
closely followed [37, 38]. Corticosteroids given as a short course concomitantly with interferon or given as a pretreatment to interferon do not improve the results over those of interferon alone and are not recommended [39]. Adverse profile of interferon therapy (see Table 5): Several side effects have been attributed to interferon therapy. Many are dose dependent; some resolve despite continued therapy; some never resolve or require cessation of therapy [37, 38]. Flu-like symptoms, fevers, rigors, fatigue, myalgia, arthralgia, and headaches are very common immediately after injection. These symptoms respond to analgesics (acetominophen or nonsteroidal antiinflammatory drugs). Depression of the platelets and (or) white cells also often occurs. The interferon dosage may have to be reduced or withheld. A granulocyte count of Ͻ7.5 ϫ 108/L or a platelet count Ͻ4 ϫ 1010/L necessitates cessation of therapy. A reversible moderate alopecia can manifest; depression with insomnia or an inability to concentrate can also occur [40]. Hypnotics and mild antidepressants may be required. About 3% of patients receiving interferon develop a permanent hypothyroid state requiring lifelong thyroid replacement therapy [41– 43]. Weight loss, impotence and vitreous hemorrhages have also been noted to occur. About 50% of patients receiving interferon therapy for 16 weeks or longer develop antinuclear antibodies, smooth muscle antibodies, and thyroid antibodies. Autoimmune disorders such as thrombocytopenic purpura, hemolytic anemia, vasculitis, or type 1 diabetes can manifest [36, 38, 44, 45]. These usually resolve (apart from the hypothyroidism) after the cessation of interferon therapy. Immunomodulators. Thymosin, containing thymic extracts, augments T-cell function and stimulates the production of interferons and interleukins [46, 47]. Results of a large multicenter study were, however, unfavorable in the management of chronic hepatitis B. Likewise, prednisone, levamisole, and interleukin-2 have not been shown to be effective. Adoptive immune transfer. An isolated report of a bone marrow transplant in a patient with leukemia and HBV
Table 5. Adverse profile of interferon therapy.
Constitutional Flu-like illness, fever, rigors, arthralgia, myalgia, fatigue Hematologic Leukopenia, thrombocytopenia Alopecia Neuropsychiatric Depression, insomnia, irritable Weight loss Ocular Autoimmune Hypothyroidism, diabetes
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resulted in clearance of HBsAg and HBV DNA [48]. The limitations of the potential therapy are obvious. Nucleoside analogs. Nucleoside analogs undergo phosphorylation and then compete with substrates for incorporation into the viral DNA sequence. The reaction is catalyzed by host cell kinases. Fialuridine (FIAU) had a disastrous effect when used to treat chronic HBV. After 12 weeks of therapy, study patients developed hepatic failure, lactic acidosis, hypoglycemia, neuropathy, coagulopathy, and renal failure [49]. Death occurred because of an irreversible effect on mitochondrial DNA in the cells of the liver, heart, muscle, and pancreas. Liver biopsies showed microvascular steatosis and abnormal mitochondria. The drug produced toxicity by its incorporation into the cells’ mitochondrial genome in place of thymidine. Lamivudine, an orally administered nucleoside analog given as a single daily dosage of 100 mg, suppresses HBV DNA in nearly all patients with chronic HBV. However, HBV DNA concentrations rebound after the cessation of short-term therapy [50]. After 12 months of continuous oral therapy, some mutant HBV escape was reported; however, long suppression of HBV replication was seen in most patients [51]. The drug appears to hold considerable promise; it will probably be administered in combination drug therapy with interferon. Side effects have been mild, with headache, nausea, fatigue, and slight increase of serum amylase noted. The lack of toxicity with lamivudine favors its long-term administration. Lamivudine is especially effective in treating viruses that depend on reverse transcriptase for their replication [52, 53]. It was recently approved by the FDA at a higher dose range for the treatment of HIV infection. Other agents, ganciclovir and famciclovir, have shown antiviral activity against HCV [54]. They are currently undergoing evaluation. The prognosis in patients with chronic hepatitis B and the recognized association between HBV infection and hepatocellular cancer are well established. This latter association in part reflects the vertical transmission of hepatitis B from mother to infant, with a high incidence of chronic hepatitis in neonates ultimately progressing over a few decades to cirrhosis and possibly hepatocellular cancer. An effective universal infant vaccination program and a vigorous therapeutic program probably involving a combination of interferon and lamivudine may offer an effective approach to the enormous problem of HBV infection worldwide. Studies recently published show that compared with standard medical care, interferon␣-2b therapy increases the life expectancy and the qualityadjusted life expectancy and lowers the projected lifetime costs of the liver disease caused by the HBV infection [55].
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42. Watanabe U, Hashimoto E, Hisamitsu T, et al. The risk factor for development of thyroid disease during interferon-␣ therapy for chronic hepatitis C. Am J Gastroenterol 1994;89:399 – 403. 43. Baudine E, Marcellin P, Pouteau M, et al. Reversibility of thyroid dysfunction induced by recombinant alpha interferon in chronic hepatitis C. Clin Endocrinol 1993;39:657– 61. 44. Lisker-Melman M, Di Bisceglie AM, Usala SJ, et al. Development of thyroid disease during therapy of chronic viral hepatitis with alpha interferon. Gastroenterology 1992;102:2155– 60. 45. Mayet W-J, Hess G, Gerken G, et al. Treatment of chronic type-B hepatitis with recombinant alpha-interferon induces autoantibodies not specific for autoimmune chronic hepatitis. Hepatology 1989;10:24 – 8. 46. Mutchnick MG, Appelman HD, Chung HT, et al. Thymosin treatment of chronic hepatitis B: a placebo-controlled pilot trial. Hepatology 1991;14:409 –15. 47. Fattovich G, Guistina G, Brollo L, et al. Therapy for chronic hepatitis B with lymphoblastoid interferon-␣ and levamisole. Hepatology 1992;16:1115–9. 48. Ilan Y, Nagler A, Adler R, Tur-Kaspa R, Slavin S, Shouval D. Ablation of persistent hepatitis B by bone marrow transplantation from a hepatitis B-immune donor. Gastroenterology 1993;104: 1818 –21. 49. McKenzie R, Fried MR, Sallie R, et al. Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. N Engl J Med 1995;333:1099 – 105. 50. Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, Vicary C, Rubin M. A preliminary trial of lamivudine for chronic hepatitis B infection. N Engl J Med 1995;333:1657– 61. 51. Dienstag JL, Schiff ER, Mitchell M, Gitlin N, et al. Extended lamivudine retreatment for chronic hepatitis B. Hepatology 1996; 24:189A. 52. Mitsuya H, Broder S. Antiretroviral chemotherapy against human immunodeficiency virus (HIV) infection: perspective for therapy of hepatitis B virus infection. Cancer Detect Prev 1989;14:299 – 308. 53. Korba BE, Gerin JL. Use of a standardized cell culture assay to assess activities of nucleoside analogs against hepatitis B virus replication. Antiviral Res 1992;19:55–70. 54. Kruger M, Tillman HL, Trautwein C, et al. Famciclovir treatment of hepatitis B virus recurrence after orthoptic liver transplantation. A pilot study. Hepatology 1995;22:449A. 55. Wong JB, Koff RS, Tine ` F, Pauker SG. Cost-effectiveness of interferon-alpha 2b treatment for hepatitis B e antigen-positive chronic hepatitis B. Ann Intern Med 1995;122:664 –75.
Beckman Conference
Hepatitis B: diagnosis, prevention, and treatment
Norman Gitlin
Hepatitis B virus (HBV) infection occurs worldwide and is an important cause of acute and chronic viral hepatitis in the US. In this review, I describe the virus, risk factors for infection, clinical features of infection, results of laboratory tests during infection, and standard and emerging treatment for chronic infection. Although 95% of adult patients recover completely from HBV infection, 90% of children <4 years of age develop chronic infection. Active vaccination is highly efficacious.
INDEXING TERMS:
chronic disease • DNA virus • risk factors
Approximately 300 000 new cases of hepatitis B are reported in the US each year [1, 2]. An estimated 300 million persons worldwide are chronic carriers of the hepatitis B virus (HBV), with 100 million carriers in China and ϳ1 million carriers in the US [1, 2].1 The annual health cost attributed to HBV in the US is $500 million. The natural history of acute HBV infection varies according to the patient’s age at the time of infection. In adults, 95% of cases resolve spontaneously with varying degrees of severity of the acute illness; the remaining 5% of adults develop chronic hepatitis B. In contrast, 90% of infected neonates develop chronic hepatitis B.
HBV
The HBV is a partially double-stranded circular DNA virus of the class Hepadnaviridae. The viral particle is 42 nm in size and consists of an outer lipoprotein coat and hepatitis B surface antigen (HBsAg), which circulates in the blood in two forms: as a viral particle-bound protein form or as a free, noninfectious protein presenting as 22-nm spherical and tubular particles [3] (see Fig. 1). The latter free forms predominate. The detection of HBsAg in serum alone does not always imply infectivity or viral
replication, since HBsAg may exist in the blood only as free forms that are noninfectious and are not associated with viral particles. The HBsAg is the component of the HBV vaccine that induces a protective, neutralizing antibody with a long-term action against HBV infection. The inner viral core of the HBV particle contains hepatitis B core antigen (HBcAg), a double-stranded DNA molecule, and hepatitis B e antigen (HBeAg), a soluble, nonparticulate substance that is often present with core antigen. The detection of HBeAg is also a useful marker of viral replication. Finally, the inner core also contains a DNAdependent polymerase. The inner viral core does not exist independently in the blood; it can be detected and measured only after digestion of the HBsAg off the circulating viral particle. The HBcAg is a marker of the infectious viral material and it is the most accurate index of viral replication. The genome of HBV consists of the S gene, which codes for HBsAg; two pre-S region genes (pre-S1, pre-S2) that code for the hepatocyte receptor binding site; the C gene, which codes for HBcAg and HBeAg; the P gene, which codes for a DNA polymerase; and an X gene that activates viral and cellular promoters [4]. Although HBV is a DNA virus, it replicates in a way similar to retroviruses, making an intermediate RNA transcript. Mutations of the HBV genome have been recognized [5–7]. A precore mutant strain manifests as an infection with high concentrations of HBsAg and of HBV DNA, yet an absence of HBeAg and presence of antibody to HBeAg (anti-HBe). Patients infected with this mutant often manifest with severe chronic hepatitis, early progression to cirrhosis, and a variable response to interferon therapy. It may have an association with fulminant hepatic failure.
risk factors
The major routes of transmission of HBV are intravenous drug use (also needlesticks and tattoos), sexual transmission, and maternal/infant transmission at birth. The maternal transmission of HBV to her infant is almost inevitable if the mother is both HBsAg and HBeAg positive at the time of the baby’s birth. Because mandatory blood bank screening of donor blood for HBV came into effect in 1972, the current risk of posttransfusion transmission of HBV is extremely low. The HBV is found
Division of Digestive Diseases, Emory University School of Medicine, 2101 WMB, Atlanta, GA 30322. Fax 404-778-4715. 1 Nonstandard abbreviations: HBV, hepatitis B virus; HBsAg, HB surface antigen; HBcAg, HB core antigen; HBeAg, HB e (early) antigen; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HBIG, hepatitis B immune globulin; and FIAU, fialuridine. Received February 24, 1997; revised and accepted June 2, 1997.
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sponse to the HBV. Necrosis of hepatocytes results from the host’s immune attack on HBV-infected hepatocytes in which viral replication is occurring. Immunologic activity involves host cytotoxic T cells directed against HBcAg on the hepatocyte surface membrane. Concurrent infection with hepatitis delta (HDV) in patients with preexisting HBV infection can result in an accelerated deterioration of the hepatitis and the complications of cirrhosis and death [21].
serologic and biochemical features
The serological markers of HBV infection vary depending on whether the infection is acute or chronic. A summary of the serologic findings that occur in acute HBV is given in Fig. 2 [22]. The first serologic marker of HBV infection is HBsAg, which can be detected from 2 to 12 weeks after infection with HBV. The presence of HBsAg often antedates symptoms or abnormalities of hepatic biochemistry by 6 – 8 weeks. In patients who recover, HBsAg disappears from the serum 12–20 weeks after the onset of symptoms or increase in concentrations of aminotransferases. The detection of IgM antibody to hepatitis B core antigen (antiHBc IgM) usually occurs 2 weeks after the detection of HBsAg, and it remains detectable for up to 6 months after the onset of the acute hepatitis. Before the disappearance of this antibody, another antibody to the hepatitis core antigen of the IgG class (anti-HBc IgG) appears and remains detectable indefinitely. The detection of the antiHBc IgM is of assistance in diagnosing an acute infection in patients with HBsAg concentrations that are below the sensitivity threshold of the diagnostic assay. HBeAg is detectable in acute HBV infection if the titer of the viral infection is high. The presence of HBeAg implies infectivity, and the persistence of HBeAg for Ͼ20 weeks increases the potential risk of the acute HBV progressing to chronicity. A quantitative assay of HBV involving a molecular hybridization technique is now available. A dot-blot or
Fig. 1. HBV.
in blood, saliva, breast milk, vaginal secretions, semen, and ascitic fluid [8 –10]. Homosexual transmission has been declining as a consequence of awareness and actions taken to stem the AIDS epidemic. Heterosexual transmission accounts for over a third of the new cases in the US. The HBV carrier rate varies greatly in the world. The overall rate in the US is 0.3%; in parts of Africa, the Philippines, and Asia, carrier rates are as high as 20% [11, 12]. The risk of acquiring HBV after an accidental stick from a needle recently used on a patient with HBV varies from 20% if the patient was only HBsAg positive to 66% if the patient was both HBsAg and HBeAg positive.
clinical features
The incubation period for HBV ranges from 45 to 180 days. Clinical features of the disease vary considerably. Jaundice occurs in Ͻ10% of children Ͻ5 years of age. However, jaundice manifests in 50% of older children and adults. No specific clinical manifestations occur with an acute HBV infection. The presentation is no different from other causes of acute viral hepatitis. Symptoms include anorexia, nausea, vomiting, flu-like complaints, fatigue, and malaise. Physical findings range from minimal nonspecific abnormalities to jaundice and hepatomegaly (often tender), and occasionally extend to extrahepatic features reflecting immune-complex phenomena such as vasculitis, immune complex nephritis, arthritis, a serumsickness-like illness, and polyarteritis nodosa [13–17]. The majority of adults with acute HBV make a full and total recovery; only ϳ5% of adults, especially men, develop a chronic HBV infection that is often asymptomatic. About 10 –20% of these adult patients may deteriorate and progress to cirrhosis or liver cancer [18 –20]. The remaining 80 –90% of patients with chronic HBV infection ultimately resolve and totally recover from their HBV infection over 2–5 years. The risk of developing a chronic HBV infection is as high as 90% if the acute HBV occurs in neonates or infants Ͻ4 years of age. The fatality rate due to fulminant hepatic failure as a consequence of acute HBV in the US is ϳ0.2% (1 in 2000). The outcome of acute HBV infection is determined by the host’s immune re-
Fig. 2. Time sequence of serologic indicators of acute hepatitis B.
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liquid hybridization technique detects HBV DNA concentrations of Ն104 genome-equivalents/mL. The HBV DNA assay is useful in determining ongoing viral replication, even when HBeAg is not detectable. HBV DNA assay is also useful as a prognostic index regarding response to interferon therapy. Patients with HBV DNA concentrations Ͻ200 ng/L are more likely to have a successful therapeutic outcome than those with higher HBV DNA concentrations. Antibody to hepatitis B surface antigen (anti-HBs) becomes detectable during the recovery from acute HBV infection in patients who do not progress to a chronic infection. The disappearance of the HBsAg occurs a few weeks before the advent of the anti-HBs. The presence of anti-HBs after acute infection indicates recovery from the infection and generally lifelong immunity from reinfection. The interpretation of the above HBV markers are summarized in Table 1. Three phases of viral replication occur during the course of HBV infection, especially in patients with chronic hepatitis B. High replicative phase. Associated with the presence of HBsAg, HBeAg, and HBV DNA detectable in the sera. Increases in the aminotransferases occur, histologic evidence of moderate inflammatory activity is evident, and the risk of evolving to cirrhosis is high. Low replicative phase. Associated with the loss of HBeAg, or a fall or loss of the HBV DNA concentrations, the appearance of anti-HBe, and histologic evidence of a decrease in inflammatory activity. These serologic changes (loss of HBV DNA and HBeAg) are referred to as “seroconversion.” Nonreplicative phase. Associated with either the absence of markers of viral replication (or they are detectable only by highly sensitive techniques), diminished inflammation, and inactivity of the histologic findings. However, if cirrhosis has already developed, it persists indefinitely. The increase in aminotransferases [especially alanine aminotransferase (ALT)] during acute hepatitis B varies from a mild/moderate increase of 3- to 10-fold to a striking increase of Ͼ100-fold. The latter does not neces-
sarily imply a poor prognosis. The ALT concentrations are usually higher than the aspartate aminotransferase (AST) concentrations. The bilirubin concentration rises in most patients with acute HBV infection. Clinical jaundice manifests in 50% of adults with bilirubin concentrations of Ͼ51.3 mol/L (3.0 mg/dL). Concentrations up to 513 mol/L (30.0 mg/dL) can occur. A slight rise in alkaline phosphatase is also evident. In patients who develop fulminant hepatic failure, a rapid fall in ALT and AST may mislead one into concluding that the hepatic infection is resolving when in fact loss of hepatocytes is occurring. Sustained increases in the concentrations of the aminotransferases for Ͼ6 months is regarded as indicative of chronic hepatitis.
Treatment prophylaxis
Active prophylaxis against HBV infection is available in the form of a recombinant HBV vaccine. The commercial products available are Recombivax HB (Merck, West Point, PA) and Engerix-B (Smith Kline Beecham, Philadelphia, PA). The recommended dosage for these products is given in Table 2. Recombivax HB is given as three intramuscular injections at 0, 1, and 6 months and Engerix-B is given as three intramuscular injections at 0, 1 and 2 months. Both are highly effective in producing antibodies. The seroconversion rates associated with the development of anti-HB varies. It is in the range of 95–98% in females and 85% in males [23]. Lower rates occur if vaccination is given after age 40 years, or in patients who are immunocompromised, malnourished, alcoholic, obese, or who have chronic renal disease. The current recommendation is to vaccinate all newborn infants, and all adolescents and adults in high-risk groups. The interval for booster vaccinations against HBV is still undecided. A 10-year booster injection has been suggested. However, patients who initially responded to the vaccine and subsequently lost their anti-HB titers still appear immune to subsequent exposure to HBV [24 –26]. Reexposure to HBV leads to an anamnestic response and rarely to a subclinical infection. Passive immunization is available by using pooled serum from patients who have recovered spontaneously from acute HBV and who have significant anti-HBs concentrations. The product, hepatitis B immune globulin (HBIG), is given simultaneously with HBV vaccine to newborn infants whose mothers are HBsAg positive, or postneedle stick or after sexual exposure in adults who are not immune to HBV [27]. The vaccine and globulin are given into opposite deltoid muscles (or for newborns, into opposite thigh muscles). Administration of HBIG vaccine therapy is most effective if given within 12 h of birth or exposure to HBV. Follow-up HBV vaccination schedules must be completed at 1 and 6 months to obtain active immunization and to provide the individual with longterm (Ͼ10 years) immunity.
Table 1. Interpretation of hepatitis B markers.
Marker Acute infection Chronic infection Past infection
HBsAg HBeAg anti-HBs anti-HBcIgM anti-HBcIgG anti-HBe HBV DNA ALT
ϩ ϩ early, then Ϫ Ϫ ϩ ϩ Ϫ early, then ϩ ϩ early, then Ϫ increased (marked)
ϩ Ϯ Ϫ Ϫ ϩ Ϯ Ϯ increased (mild– moderate)
Ϫ Ϫ ϩ Ϫ ϩ ϩ Ϫ normal
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Table 2. Recommended dosage of hepatitis B vaccines.
Vaccine Age 10 g/0.5 mL Engerix-B 20 g/1.0 mL 2.5 g/0.5 mL Recombivax HB 5 g/0.5 mL 10 g/1.0 mL
Infants/HBsAg pos mothers Infants/HBsAg neg mothers 1–10 yr 11–19 yr 20ϩ yr
10 g (0.5 mL) 10 g (0.5 mL) 10 g (0.5 mL) 10 g (0.5 mL) 20 g (1.0 mL) 2.5 g (0.5 mL) 2.5 g (0.5 mL)
5 g (0.5 mL)
5 g (0.5 mL) 10 g (1.0 mL)
drug therapy
Acute hepatitis B does not require specific treatment because Ͼ90% of adults will spontaneously clear their infection. Symptomatic treatment of the nausea, anorexia, vomiting, and other symptoms may be indicated. Many agents have been evaluated for the treatment of chronic hepatitis B. Most have been found to be ineffective or too toxic at effective doses. Others are still under evaluation (see Table 3). In the US, the only approved therapeutic agents for treating chronic hepatitis B are interferon-␣-2b and interferon-␣-2a. The goals of therapy are the eradication of the virus, leading to a remission of the liver disease and an improved long-term prognosis. Interferon. Interferon-␣ belongs to a family of natural occurring proteins that have antiviral and immunomodulatory actions [28, 29]. They enhance T-cell helper activity, cause maturation of B lymphocytes, inhibit T-cell suppressors, and enhance HLA type 1 expression. The efficacy of interferon for the treatment of chronic hepatitis B has been demonstrated in a large US trial in which 37% of treated patients receiving 5 million units per day of interferon for 16 weeks lost HBV DNA and HBeAg, compared with 7% of untreated controls [30]. A metaanalysis of 14 studies involving Ͼ800 patients with chronic HBV treated with interferon showed a loss of HBV DNA in 37% and HbeAg in 33% of the interferontreated patients compared with 17% and 13% losses, respectively, in the controls [31]. In another long-term
follow-up study, 35% of patients who lost markers of viral replication during therapy eventually also lost HBsAg over 5 years [32]. Favorable prognostic indices for a successful outcome with interferon therapy have been evaluated and they include the following: (a) a pretreatment concentration of HBV DNA Ͻ200 ng/L, (b) being female, (c) heterosexual habits, (d) concentrations of serum ALT Ͼ100 U/L (high ALT concentrations may be indicative of a better host immune response to HBV), (e) a disease duration of Ͻ4 years, (f) absence of HIV, and (g) acquiring the HBV infection at Ͼ6 years of age [33, 34]. These indices do not provide an absolute guarantee of success with interferon therapy; they suggest a higher likelihood of success and they may assist in patient selection for interferon therapy. A low concentration of HBV DNA and a raised ALT are the best indices of predicting a successful treatment outcome. Patient inclusion and exclusion criteria for interferon therapy: Patients with chronic hepatitis with an increased serum aminotransferase for Ͼ6 months who have serologic evidence of active viral replication (the presence of HBsAg, HBeAg, and an increased HBV DNA concentration) should be considered for interferon therapy provided they have no contraindications that exclude them from therapy. These contraindications are summarized in Table 4. They include the presence of hepatic decompensation as evidenced by biochemical variables of albumin Ͻ30 g/L, bilirubin Ͼ51.3 mol/L (3.0 mg/dL), or a
Table 3. Chronic hepatitis B: potential drug therapy.
Agent Effective Ineffective Toxic Under evaluation
Interferon Antiviral
Interferon-␣
Immunomodulatory
Interferon-␥ Acyclovir Dideoxyinosine Azudothymidine Foscarnet Prednisone Interleukin-2 Thymosin Levamisole
Fialuridine Adenine Arabinoside
Interferon  Ribavirin Lamivudine
Adoptive immune transfer
Modified from Lok ASF. Therapy of Hepatitis B. In AASLD postgraduate course, November 11–12 1996, Chicago, IL.
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Table 4. Contraindications for interferon therapy for chronic hepatitis B.
Hepatic decompensation Albumin Ͻ3.0 L Blirubin Ͼ51.3 mol/L (3.0 mg/dL) Prolonged prothrombin time Ͼ 3 Portal hypertension Variceal bleed Ascites Encephalopathy Hypersplenism Leukopenia (Ͻ2 ϫ 1010/L) Thrombocytopenia (Ͻ7 ϫ 1010L) Psychiatric Depression (severe), suicide attempt Autoimmune disease Polyarteritis nodosa, rheumatoid arthritis Major system impairment Pregnancy Current intravenous drug abuse
prothrombin time Ͼ3.0 s above the control; the presence of complications of portal hypertension (ascites, past variceal bleeding); leukopenia (Ͻ2 ϫ 109/L), thrombocytopenia (Ͻ7 ϫ 107/L), or renal impairment [creatinine Ͼ176.8 mol/L (2.0 mg/dL)]. Pregnancy, the presence of an autoimmune disease, a history of severe depression requiring hospitalization, or a history of attempted suicide are also contraindications for the use of interferon. Other contraindications include a history of recent intravenous drug abuse, alcoholism, or a severe major system dysfunction (cardiac failure, obstructive airways disease, or uncontrolled diabetes). The recommended dose of interferon is 5 million international units, self-injected, subcutaneously daily for 16 weeks with monitoring of a complete blood count, prothrombin time, total bilirubin, ALT, AST, HBsAg, anti-HBs, HBeAg, anti-HBe, and quantitative HBV DNA at 2, 4, 8, 12, and 16 weeks. A pretreatment thyrotropin (TSH) assay is also performed. A sudden, often asymptomatic, rise in ALT associated with a fall in HBV DNA concentrations can occur 4 to 8 weeks into therapy. This is known as a “flare response” and is thought to reflect the immune-mediated clearance of HBV-infected hepatocytes. It is followed by the disappearance of serum HBV DNA, loss of HBeAg, the appearance of anti-HBe, and normalization of serum ALT, in that order [32]. Loss of HBsAg occurs in 25% of patients during the 6 months after seroconversion of HBeAg to anti-HBe [32]. A flare occurs in 60 –70% of responders. It can also occur in 25–30% of nonresponders to interferon therapy [35, 36]. The intensity of the flare seldom aggravates the underlying liver status. However, if there is a striking increase in ALT, a rise in bilirubin, or new signs or symptoms of hepatic decompensation, then the interferon therapy should be reduced or withheld and the patient should be
closely followed [37, 38]. Corticosteroids given as a short course concomitantly with interferon or given as a pretreatment to interferon do not improve the results over those of interferon alone and are not recommended [39]. Adverse profile of interferon therapy (see Table 5): Several side effects have been attributed to interferon therapy. Many are dose dependent; some resolve despite continued therapy; some never resolve or require cessation of therapy [37, 38]. Flu-like symptoms, fevers, rigors, fatigue, myalgia, arthralgia, and headaches are very common immediately after injection. These symptoms respond to analgesics (acetominophen or nonsteroidal antiinflammatory drugs). Depression of the platelets and (or) white cells also often occurs. The interferon dosage may have to be reduced or withheld. A granulocyte count of Ͻ7.5 ϫ 108/L or a platelet count Ͻ4 ϫ 1010/L necessitates cessation of therapy. A reversible moderate alopecia can manifest; depression with insomnia or an inability to concentrate can also occur [40]. Hypnotics and mild antidepressants may be required. About 3% of patients receiving interferon develop a permanent hypothyroid state requiring lifelong thyroid replacement therapy [41– 43]. Weight loss, impotence and vitreous hemorrhages have also been noted to occur. About 50% of patients receiving interferon therapy for 16 weeks or longer develop antinuclear antibodies, smooth muscle antibodies, and thyroid antibodies. Autoimmune disorders such as thrombocytopenic purpura, hemolytic anemia, vasculitis, or type 1 diabetes can manifest [36, 38, 44, 45]. These usually resolve (apart from the hypothyroidism) after the cessation of interferon therapy. Immunomodulators. Thymosin, containing thymic extracts, augments T-cell function and stimulates the production of interferons and interleukins [46, 47]. Results of a large multicenter study were, however, unfavorable in the management of chronic hepatitis B. Likewise, prednisone, levamisole, and interleukin-2 have not been shown to be effective. Adoptive immune transfer. An isolated report of a bone marrow transplant in a patient with leukemia and HBV
Table 5. Adverse profile of interferon therapy.
Constitutional Flu-like illness, fever, rigors, arthralgia, myalgia, fatigue Hematologic Leukopenia, thrombocytopenia Alopecia Neuropsychiatric Depression, insomnia, irritable Weight loss Ocular Autoimmune Hypothyroidism, diabetes
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resulted in clearance of HBsAg and HBV DNA [48]. The limitations of the potential therapy are obvious. Nucleoside analogs. Nucleoside analogs undergo phosphorylation and then compete with substrates for incorporation into the viral DNA sequence. The reaction is catalyzed by host cell kinases. Fialuridine (FIAU) had a disastrous effect when used to treat chronic HBV. After 12 weeks of therapy, study patients developed hepatic failure, lactic acidosis, hypoglycemia, neuropathy, coagulopathy, and renal failure [49]. Death occurred because of an irreversible effect on mitochondrial DNA in the cells of the liver, heart, muscle, and pancreas. Liver biopsies showed microvascular steatosis and abnormal mitochondria. The drug produced toxicity by its incorporation into the cells’ mitochondrial genome in place of thymidine. Lamivudine, an orally administered nucleoside analog given as a single daily dosage of 100 mg, suppresses HBV DNA in nearly all patients with chronic HBV. However, HBV DNA concentrations rebound after the cessation of short-term therapy [50]. After 12 months of continuous oral therapy, some mutant HBV escape was reported; however, long suppression of HBV replication was seen in most patients [51]. The drug appears to hold considerable promise; it will probably be administered in combination drug therapy with interferon. Side effects have been mild, with headache, nausea, fatigue, and slight increase of serum amylase noted. The lack of toxicity with lamivudine favors its long-term administration. Lamivudine is especially effective in treating viruses that depend on reverse transcriptase for their replication [52, 53]. It was recently approved by the FDA at a higher dose range for the treatment of HIV infection. Other agents, ganciclovir and famciclovir, have shown antiviral activity against HCV [54]. They are currently undergoing evaluation. The prognosis in patients with chronic hepatitis B and the recognized association between HBV infection and hepatocellular cancer are well established. This latter association in part reflects the vertical transmission of hepatitis B from mother to infant, with a high incidence of chronic hepatitis in neonates ultimately progressing over a few decades to cirrhosis and possibly hepatocellular cancer. An effective universal infant vaccination program and a vigorous therapeutic program probably involving a combination of interferon and lamivudine may offer an effective approach to the enormous problem of HBV infection worldwide. Studies recently published show that compared with standard medical care, interferon␣-2b therapy increases the life expectancy and the qualityadjusted life expectancy and lowers the projected lifetime costs of the liver disease caused by the HBV infection [55].
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