hepatitis b diagnosis, prevention, and treatment

Hepatitis B: diagnosis, prevention, and treatmentNorman Gitlin

Hepatitis B virus (HBV) infection occurs worldwide andis an important cause of acute and chronic viral hepatitisin the US. In this review, I describe the virus, riskfactors for infection, clinical features of infection, re-sults of laboratory tests during infection, and standardand emerging treatment for chronic infection. Although95% of adult patients recover completely from HBVinfection, 90% of children <4 years of age developchronic infection. Active vaccination is highly effica-cious.

INDEXING TERMS: chronic disease • DNA virus • risk factors

Approximately 300 000 new cases of hepatitis B are re-ported in the US each year [1, 2]. An estimated 300 millionpersons worldwide are chronic carriers of the hepatitis Bvirus (HBV), with 100 million carriers in China and ;1million carriers in the US [1, 2].1 The annual health costattributed to HBV in the US is $500 million. The naturalhistory of acute HBV infection varies according to thepatient’s age at the time of infection. In adults, 95% ofcases resolve spontaneously with varying degrees ofseverity of the acute illness; the remaining 5% of adultsdevelop chronic hepatitis B. In contrast, 90% of infectedneonates develop chronic hepatitis B.

HBVThe HBV is a partially double-stranded circular DNAvirus of the class Hepadnaviridae. The viral particle is 42nm in size and consists of an outer lipoprotein coat andhepatitis B surface antigen (HBsAg), which circulates inthe blood in two forms: as a viral particle-bound proteinform or as a free, noninfectious protein presenting as22-nm spherical and tubular particles [3] (see Fig. 1). Thelatter free forms predominate. The detection of HBsAg inserum alone does not always imply infectivity or viral

replication, since HBsAg may exist in the blood only asfree forms that are noninfectious and are not associatedwith viral particles. The HBsAg is the component of theHBV vaccine that induces a protective, neutralizing anti-body with a long-term action against HBV infection. Theinner viral core of the HBV particle contains hepatitis Bcore antigen (HBcAg), a double-stranded DNA molecule,and hepatitis B e antigen (HBeAg), a soluble, nonparticu-late substance that is often present with core antigen. Thedetection of HBeAg is also a useful marker of viralreplication. Finally, the inner core also contains a DNA-dependent polymerase. The inner viral core does not existindependently in the blood; it can be detected and mea-sured only after digestion of the HBsAg off the circulatingviral particle. The HBcAg is a marker of the infectiousviral material and it is the most accurate index of viralreplication.

The genome of HBV consists of the S gene, which codesfor HBsAg; two pre-S region genes (pre-S1, pre-S2) thatcode for the hepatocyte receptor binding site; the C gene,which codes for HBcAg and HBeAg; the P gene, whichcodes for a DNA polymerase; and an X gene that activatesviral and cellular promoters [4]. Although HBV is a DNAvirus, it replicates in a way similar to retroviruses, makingan intermediate RNA transcript. Mutations of the HBVgenome have been recognized [5–7]. A precore mutantstrain manifests as an infection with high concentrationsof HBsAg and of HBV DNA, yet an absence of HBeAgand presence of antibody to HBeAg (anti-HBe). Patientsinfected with this mutant often manifest with severechronic hepatitis, early progression to cirrhosis, and avariable response to interferon therapy. It may have anassociation with fulminant hepatic failure.

risk factorsThe major routes of transmission of HBV are intravenousdrug use (also needlesticks and tattoos), sexual transmis-sion, and maternal/infant transmission at birth. Thematernal transmission of HBV to her infant is almostinevitable if the mother is both HBsAg and HBeAgpositive at the time of the baby’s birth. Because manda-tory blood bank screening of donor blood for HBV cameinto effect in 1972, the current risk of posttransfusiontransmission of HBV is extremely low. The HBV is found

Division of Digestive Diseases, Emory University School of Medicine, 2101WMB, Atlanta, GA 30322. Fax 404-778-4715.

1 Nonstandard abbreviations: HBV, hepatitis B virus; HBsAg, HB surfaceantigen; HBcAg, HB core antigen; HBeAg, HB e (early) antigen; ALT, alanineaminotransferase; AST, aspartate aminotransferase; HBIG, hepatitis B immuneglobulin; and FIAU, fialuridine.

Received February 24, 1997; revised and accepted June 2, 1997.

Clinical Chemistry 43:8(B)1500–1506 (1997) Beckman Conference

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in blood, saliva, breast milk, vaginal secretions, semen,and ascitic fluid [8–10]. Homosexual transmission hasbeen declining as a consequence of awareness and actionstaken to stem the AIDS epidemic. Heterosexual transmis-sion accounts for over a third of the new cases in the US.The HBV carrier rate varies greatly in the world. Theoverall rate in the US is 0.3%; in parts of Africa, thePhilippines, and Asia, carrier rates are as high as 20%[11, 12]. The risk of acquiring HBV after an accidentalstick from a needle recently used on a patient with HBVvaries from 20% if the patient was only HBsAg positive to66% if the patient was both HBsAg and HBeAg positive.

clinical featuresThe incubation period for HBV ranges from 45 to 180days. Clinical features of the disease vary considerably.Jaundice occurs in ,10% of children ,5 years of age.However, jaundice manifests in 50% of older children andadults. No specific clinical manifestations occur with anacute HBV infection. The presentation is no different fromother causes of acute viral hepatitis. Symptoms includeanorexia, nausea, vomiting, flu-like complaints, fatigue,and malaise. Physical findings range from minimal non-specific abnormalities to jaundice and hepatomegaly (of-ten tender), and occasionally extend to extrahepaticfeatures reflecting immune-complex phenomena such asvasculitis, immune complex nephritis, arthritis, a serum-sickness-like illness, and polyarteritis nodosa [13–17]. Themajority of adults with acute HBV make a full and totalrecovery; only ;5% of adults, especially men, develop achronic HBV infection that is often asymptomatic. About10–20% of these adult patients may deteriorate andprogress to cirrhosis or liver cancer [18–20]. The remain-ing 80–90% of patients with chronic HBV infectionultimately resolve and totally recover from their HBVinfection over 2–5 years. The risk of developing a chronicHBV infection is as high as 90% if the acute HBV occurs inneonates or infants ,4 years of age. The fatality rate dueto fulminant hepatic failure as a consequence of acuteHBV in the US is ;0.2% (1 in 2000). The outcome of acuteHBV infection is determined by the host’s immune re-

sponse to the HBV. Necrosis of hepatocytes results fromthe host’s immune attack on HBV-infected hepatocytes inwhich viral replication is occurring. Immunologic activityinvolves host cytotoxic T cells directed against HBcAg onthe hepatocyte surface membrane. Concurrent infectionwith hepatitis delta (HDV) in patients with preexistingHBV infection can result in an accelerated deterioration ofthe hepatitis and the complications of cirrhosis and death[21].

serologic and biochemical featuresThe serological markers of HBV infection vary dependingon whether the infection is acute or chronic. A summaryof the serologic findings that occur in acute HBV is givenin Fig. 2 [22].

The first serologic marker of HBV infection is HBsAg,which can be detected from 2 to 12 weeks after infectionwith HBV. The presence of HBsAg often antedates symp-toms or abnormalities of hepatic biochemistry by 6–8weeks. In patients who recover, HBsAg disappears fromthe serum 12–20 weeks after the onset of symptoms orincrease in concentrations of aminotransferases. The de-tection of IgM antibody to hepatitis B core antigen (anti-HBc IgM) usually occurs 2 weeks after the detection ofHBsAg, and it remains detectable for up to 6 months afterthe onset of the acute hepatitis. Before the disappearanceof this antibody, another antibody to the hepatitis coreantigen of the IgG class (anti-HBc IgG) appears andremains detectable indefinitely. The detection of the anti-HBc IgM is of assistance in diagnosing an acute infectionin patients with HBsAg concentrations that are below thesensitivity threshold of the diagnostic assay. HBeAg isdetectable in acute HBV infection if the titer of the viralinfection is high. The presence of HBeAg implies infectiv-ity, and the persistence of HBeAg for .20 weeks increasesthe potential risk of the acute HBV progressing to chro-nicity.

A quantitative assay of HBV involving a molecularhybridization technique is now available. A dot-blot or

Fig. 1. HBV.

Fig. 2. Time sequence of serologic indicators of acute hepatitis B.

Clinical Chemistry 43, No. 8(B), 1997 1501

liquid hybridization technique detects HBV DNA concen-trations of $104 genome-equivalents/mL. The HBV DNAassay is useful in determining ongoing viral replication,even when HBeAg is not detectable. HBV DNA assay isalso useful as a prognostic index regarding response tointerferon therapy. Patients with HBV DNA concentra-tions ,200 ng/L are more likely to have a successfultherapeutic outcome than those with higher HBV DNAconcentrations. Antibody to hepatitis B surface antigen(anti-HBs) becomes detectable during the recovery fromacute HBV infection in patients who do not progress to achronic infection. The disappearance of the HBsAg occursa few weeks before the advent of the anti-HBs. Thepresence of anti-HBs after acute infection indicates recov-ery from the infection and generally lifelong immunityfrom reinfection. The interpretation of the above HBVmarkers are summarized in Table 1.

Three phases of viral replication occur during thecourse of HBV infection, especially in patients withchronic hepatitis B.

High replicative phase. Associated with the presence ofHBsAg, HBeAg, and HBV DNA detectable in the sera.Increases in the aminotransferases occur, histologic evi-dence of moderate inflammatory activity is evident, andthe 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, theappearance of anti-HBe, and histologic evidence of adecrease in inflammatory activity. These serologicchanges (loss of HBV DNA and HBeAg) are referred to as“seroconversion.”

Nonreplicative phase. Associated with either the absence ofmarkers of viral replication (or they are detectable only byhighly sensitive techniques), diminished inflammation,and inactivity of the histologic findings. However, ifcirrhosis has already developed, it persists indefinitely.

The increase in aminotransferases [especially alanineaminotransferase (ALT)] during acute hepatitis B variesfrom a mild/moderate increase of 3- to 10-fold to astriking increase of .100-fold. The latter does not neces-

sarily imply a poor prognosis. The ALT concentrations areusually higher than the aspartate aminotransferase (AST)concentrations. The bilirubin concentration rises in mostpatients with acute HBV infection. Clinical jaundice man-ifests in 50% of adults with bilirubin concentrations of.51.3 mmol/L (3.0 mg/dL). Concentrations up to 513mmol/L (30.0 mg/dL) can occur. A slight rise in alkalinephosphatase is also evident. In patients who developfulminant hepatic failure, a rapid fall in ALT and ASTmay mislead one into concluding that the hepatic infec-tion is resolving when in fact loss of hepatocytes isoccurring. Sustained increases in the concentrations of theaminotransferases for .6 months is regarded as indica-tive of chronic hepatitis.

TreatmentprophylaxisActive prophylaxis against HBV infection is available in theform of a recombinant HBV vaccine. The commercialproducts available are Recombivax HB (Merck, WestPoint, PA) and Engerix-B (Smith Kline Beecham, Philadel-phia, PA). The recommended dosage for these products isgiven in Table 2. Recombivax HB is given as threeintramuscular injections at 0, 1, and 6 months and En-gerix-B is given as three intramuscular injections at 0, 1and 2 months. Both are highly effective in producingantibodies. The seroconversion rates associated with thedevelopment of anti-HB varies. It is in the range of95–98% in females and 85% in males [23]. Lower ratesoccur if vaccination is given after age 40 years, or inpatients who are immunocompromised, malnourished,alcoholic, obese, or who have chronic renal disease. Thecurrent recommendation is to vaccinate all newborn in-fants, and all adolescents and adults in high-risk groups.The interval for booster vaccinations against HBV is stillundecided. A 10-year booster injection has been sug-gested. However, patients who initially responded to thevaccine and subsequently lost their anti-HB titers stillappear immune to subsequent exposure to HBV [24–26].Reexposure to HBV leads to an anamnestic response andrarely to a subclinical infection.

Passive immunization is available by using pooled serumfrom patients who have recovered spontaneously fromacute HBV and who have significant anti-HBs concentra-tions. The product, hepatitis B immune globulin (HBIG),is given simultaneously with HBV vaccine to newborninfants whose mothers are HBsAg positive, or postneedlestick or after sexual exposure in adults who are notimmune to HBV [27]. The vaccine and globulin are giveninto opposite deltoid muscles (or for newborns, intoopposite thigh muscles). Administration of HBIG vaccinetherapy is most effective if given within 12 h of birth orexposure to HBV. Follow-up HBV vaccination schedulesmust be completed at 1 and 6 months to obtain activeimmunization and to provide the individual with long-term (.10 years) immunity.

Table 1. Interpretation of hepatitis B markers.

Marker Acute infection Chronic infectionPast

infection

HBsAg 1 1 2

HBeAg 1 early, then 2 6 2

anti-HBs 2 2 1

anti-HBcIgM 1 2 2

anti-HBcIgG 1 1 1

anti-HBe 2 early, then 1 6 1

HBV DNA 1 early, then 2 6 2

ALT increased (marked) increased (mild–moderate)

normal

1502 Gitlin: Hepatitis B

drug therapyAcute hepatitis B does not require specific treatmentbecause .90% of adults will spontaneously clear theirinfection. Symptomatic treatment of the nausea, anorexia,vomiting, and other symptoms may be indicated. Manyagents have been evaluated for the treatment of chronichepatitis B. Most have been found to be ineffective or tootoxic at effective doses. Others are still under evaluation(see Table 3). In the US, the only approved therapeuticagents for treating chronic hepatitis B are interferon-a-2band interferon-a-2a. The goals of therapy are the eradica-tion of the virus, leading to a remission of the liver diseaseand an improved long-term prognosis.

Interferon. Interferon-a belongs to a family of naturaloccurring proteins that have antiviral and immunomodu-latory actions [28, 29]. They enhance T-cell helper activity,cause maturation of B lymphocytes, inhibit T-cell sup-pressors, and enhance HLA type 1 expression. The effi-cacy of interferon for the treatment of chronic hepatitis Bhas been demonstrated in a large US trial in which 37% oftreated patients receiving 5 million units per day ofinterferon for 16 weeks lost HBV DNA and HBeAg,compared with 7% of untreated controls [30]. A meta-analysis of 14 studies involving .800 patients withchronic HBV treated with interferon showed a loss ofHBV DNA in 37% and HbeAg in 33% of the interferon-treated 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 viralreplication during therapy eventually also lost HBsAgover 5 years [32].

Favorable prognostic indices for a successful outcomewith interferon therapy have been evaluated and theyinclude the following: (a) a pretreatment concentration ofHBV DNA ,200 ng/L, (b) being female, (c) heterosexualhabits, (d) concentrations of serum ALT .100 U/L (highALT concentrations may be indicative of a better hostimmune response to HBV), (e) a disease duration of ,4years, (f) absence of HIV, and (g) acquiring the HBVinfection at .6 years of age [33, 34]. These indices do notprovide an absolute guarantee of success with interferontherapy; they suggest a higher likelihood of success andthey may assist in patient selection for interferon therapy.A low concentration of HBV DNA and a raised ALT arethe best indices of predicting a successful treatmentoutcome.

Patient inclusion and exclusion criteria for interferontherapy: Patients with chronic hepatitis with an increasedserum aminotransferase for .6 months who have sero-logic evidence of active viral replication (the presence ofHBsAg, HBeAg, and an increased HBV DNA concentra-tion) should be considered for interferon therapy pro-vided they have no contraindications that exclude themfrom therapy. These contraindications are summarized inTable 4. They include the presence of hepatic decompen-sation as evidenced by biochemical variables of albumin,30 g/L, bilirubin .51.3 mmol/L (3.0 mg/dL), or a

Table 2. Recommended dosage of hepatitis B vaccines.

Age

Vaccine

Engerix-B Recombivax HB

10 mg/0.5 mL 20 mg/1.0 mL 2.5 mg/0.5 mL 5 mg/0.5 mL 10 mg/1.0 mL

Infants/HBsAgpos mothers

10 mg (0.5 mL) 5 mg (0.5 mL)

Infants/HBsAgneg mothers

10 mg (0.5 mL) 2.5 mg (0.5 mL)

1–10 yr 10 mg (0.5 mL) 2.5 mg (0.5 mL)11–19 yr 10 mg (0.5 mL) 5 mg (0.5 mL)201 yr 20 mg (1.0 mL) 10 mg (1.0 mL)

Table 3. Chronic hepatitis B: potential drug therapy.Agent Effective Ineffective Toxic Under evaluation

Interferon Interferon-a Interferon-g Interferon b

Antiviral Acyclovir Fialuridine RibavirinDideoxyinosine Adenine LamivudineAzudothymidine ArabinosideFoscarnet

Immunomodulatory Prednisone Adoptive immune transferInterleukin-2ThymosinLevamisole

Modified from Lok ASF. Therapy of Hepatitis B.In AASLD postgraduate course, November 11–12 1996, Chicago, IL.


prothrombin time .3.0 s above the control; the presenceof complications of portal hypertension (ascites, pastvariceal bleeding); leukopenia (,2 3 109/L), thrombocy-topenia (,7 3 107/L), or renal impairment [creatinine.176.8 mmol/L (2.0 mg/dL)]. Pregnancy, the presence ofan autoimmune disease, a history of severe depressionrequiring hospitalization, or a history of attempted sui-cide are also contraindications for the use of interferon.Other contraindications include a history of recent intra-venous drug abuse, alcoholism, or a severe major systemdysfunction (cardiac failure, obstructive airways disease,or uncontrolled diabetes).

The recommended dose of interferon is 5 millioninternational units, self-injected, subcutaneously daily for16 weeks with monitoring of a complete blood count,prothrombin time, total bilirubin, ALT, AST, HBsAg,anti-HBs, HBeAg, anti-HBe, and quantitative HBV DNAat 2, 4, 8, 12, and 16 weeks. A pretreatment thyrotropin(TSH) assay is also performed. A sudden, often asymp-tomatic, rise in ALT associated with a fall in HBV DNAconcentrations can occur 4 to 8 weeks into therapy. This isknown as a “flare response” and is thought to reflect theimmune-mediated clearance of HBV-infected hepato-cytes. It is followed by the disappearance of serum HBVDNA, loss of HBeAg, the appearance of anti-HBe, andnormalization of serum ALT, in that order [32]. Loss ofHBsAg occurs in 25% of patients during the 6 monthsafter seroconversion of HBeAg to anti-HBe [32]. A flareoccurs in 60–70% of responders. It can also occur in25–30% of nonresponders to interferon therapy [35, 36].The intensity of the flare seldom aggravates the underly-ing liver status. However, if there is a striking increase inALT, a rise in bilirubin, or new signs or symptoms ofhepatic decompensation, then the interferon therapyshould be reduced or withheld and the patient should be

closely followed [37, 38]. Corticosteroids given as a shortcourse concomitantly with interferon or given as a pre-treatment to interferon do not improve the results overthose of interferon alone and are not recommended [39].

Adverse profile of interferon therapy (see Table 5):Several side effects have been attributed to interferontherapy. Many are dose dependent; some resolve despitecontinued therapy; some never resolve or require cessa-tion of therapy [37, 38]. Flu-like symptoms, fevers, rigors,fatigue, myalgia, arthralgia, and headaches are verycommon immediately after injection. These symptomsrespond to analgesics (acetominophen or nonsteroidalantiinflammatory drugs). Depression of the platelets and(or) white cells also often occurs. The interferon dosagemay have to be reduced or withheld. A granulocyte countof ,7.5 3 108/L or a platelet count ,4 3 1010/L necessi-tates cessation of therapy. A reversible moderate alopeciacan manifest; depression with insomnia or an inability toconcentrate can also occur [40]. Hypnotics and mildantidepressants may be required. About 3% of patientsreceiving interferon develop a permanent hypothyroidstate requiring lifelong thyroid replacement therapy[41–43]. Weight loss, impotence and vitreous hemor-rhages have also been noted to occur. About 50% ofpatients receiving interferon therapy for 16 weeks orlonger develop antinuclear antibodies, smooth muscleantibodies, and thyroid antibodies. Autoimmune disor-ders such as thrombocytopenic purpura, hemolyticanemia, vasculitis, or type 1 diabetes can manifest[36, 38, 44, 45]. These usually resolve (apart from thehypothyroidism) after the cessation of interferon therapy.

Immunomodulators. Thymosin, containing thymic extracts,augments T-cell function and stimulates the production ofinterferons and interleukins [46, 47]. Results of a largemulticenter study were, however, unfavorable in themanagement of chronic hepatitis B. Likewise, prednisone,levamisole, and interleukin-2 have not been shown to beeffective.

Adoptive immune transfer. An isolated report of a bonemarrow transplant in a patient with leukemia and HBV

Table 4. Contraindications for interferon therapy for chronichepatitis B.

Hepatic decompensationAlbumin ,3.0 LBlirubin .51.3 mmol/L (3.0 mg/dL)Prolonged prothrombin time . 3

Portal hypertensionVariceal bleedAscitesEncephalopathy

HypersplenismLeukopenia (,2 3 1010/L)Thrombocytopenia (,7 3 1010L)

PsychiatricDepression (severe), suicide attempt

Autoimmune diseasePolyarteritis nodosa, rheumatoid arthritis

Major system impairmentPregnancyCurrent intravenous drug abuse

Table 5. Adverse profile of interferon therapy.Constitutional

Flu-like illness, fever, rigors, arthralgia, myalgia, fatigueHematologic

Leukopenia, thrombocytopeniaAlopeciaNeuropsychiatric

Depression, insomnia, irritableWeight lossOcularAutoimmune

Hypothyroidism, diabetes


resulted in clearance of HBsAg and HBV DNA [48]. Thelimitations of the potential therapy are obvious.

Nucleoside analogs. Nucleoside analogs undergo phos-phorylation and then compete with substrates for incor-poration into the viral DNA sequence. The reaction iscatalyzed by host cell kinases. Fialuridine (FIAU) had adisastrous effect when used to treat chronic HBV. After 12weeks of therapy, study patients developed hepatic fail-ure, lactic acidosis, hypoglycemia, neuropathy, coagu-lopathy, and renal failure [49]. Death occurred because ofan irreversible effect on mitochondrial DNA in the cells ofthe liver, heart, muscle, and pancreas. Liver biopsiesshowed microvascular steatosis and abnormal mitochon-dria. The drug produced toxicity by its incorporation intothe cells’ mitochondrial genome in place of thymidine.

Lamivudine, an orally administered nucleoside analoggiven as a single daily dosage of 100 mg, suppresses HBVDNA in nearly all patients with chronic HBV. However,HBV DNA concentrations rebound after the cessation ofshort-term therapy [50]. After 12 months of continuousoral therapy, some mutant HBV escape was reported;however, long suppression of HBV replication was seenin most patients [51]. The drug appears to hold consider-able promise; it will probably be administered in combi-nation drug therapy with interferon. Side effects havebeen mild, with headache, nausea, fatigue, and slightincrease of serum amylase noted. The lack of toxicity withlamivudine favors its long-term administration. Lamivu-dine is especially effective in treating viruses that dependon reverse transcriptase for their replication [52, 53]. Itwas recently approved by the FDA at a higher dose rangefor the treatment of HIV infection. Other agents, ganciclo-vir and famciclovir, have shown antiviral activity againstHCV [54]. They are currently undergoing evaluation.

The prognosis in patients with chronic hepatitis B andthe recognized association between HBV infection andhepatocellular cancer are well established. This latterassociation in part reflects the vertical transmission ofhepatitis B from mother to infant, with a high incidence ofchronic hepatitis in neonates ultimately progressing overa few decades to cirrhosis and possibly hepatocellularcancer. An effective universal infant vaccination programand a vigorous therapeutic program probably involving acombination of interferon and lamivudine may offer aneffective approach to the enormous problem of HBVinfection worldwide. Studies recently published showthat compared with standard medical care, interferon-a-2b therapy increases the life expectancy and the quality-adjusted life expectancy and lowers the projected lifetimecosts of the liver disease caused by the HBV infection [55].

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hepatitis b diagnosis, prevention, and treatment

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