Treatment of chronic hepatitis B

Treatment of Chronic Hepatitis BStephanie D. Straley, PA-C, MSNorah A. Terrault, MD, MPH

AddressDepartment of Medicine, Division of Gastroenterology, University of California, S357, 513 Parnassus Avenue, San Francisco, CA 94143-0538, USA.E-mail: [email protected]: [email protected] Hepatitis Reports 2003, 2:49–59Current Science Inc. ISSN 1540-3416Copyright © 2003 by Current Science Inc.

IntroductionHepatitis B virus (HBV) is a parenterally transmittedvirus that is acquired from exposure to infected bloodor body secretions. Adolescents and adults account forthe majority of new cases of hepatitis B reported in theUnited States (US). Sexual contact and injection druguse are the most common routes of transmission. Peri-natal and early childhood infections are much less fre-quent in the US, but this is the most common mode oftransmission in countries in which HBV is endemic. Theincidence of hepatitis B is declining owing to the imple-mentation of vaccination programs and preventionmeasures to reduce transmission of both HIV and HBVinfections. However, there remains a large reservoir ofchronically infected individuals [1]. Hepatitis B surfaceantigen (HBsAg) carrier rates are higher among AsianAmericans and African Americans than whites [1]. Thehighest rates of chronic HBV infection are among indi-viduals who have immigrated to the US from areas ofhigh HBV endemicity such as Southeast Asia, Africa,and the Mediterranean area [1,2]. Chronic hepatitis B

affects 1.25 million Americans and accounts for 5% to10% of chronic liver disease cases in the US.

NATURAL HISTORY OF CHRONIC HEPATITIS B INFECTIONThe frequency of the chronic carriage of HBV followingacute infection depends on the age of the individual atthe time of infection. Only 2% to 5% of immunocom-petent adults become chronic carriers following expo-sure, whereas the frequency of chronic disease is over90% in infants exposed at the time of birth. Amongindividuals who become chronic carriers of HBV infec-tion, those with evidence of active viral replication(defined by HBV DNA levels ≥ 105 copies/mL with orwithout hepatitis B early antigen [HBeAg] and abnor-mal liver enzymes) are at highest risk of liver-relatedcomplications, including cirrhosis and hepatocellularcarcinoma (HCC). Cirrhosis is estimated to occur inabout 20% of chronically infected individuals. The riskof cirrhosis and other liver complications increases with

Opinion statementInterferon (IFN) alpha, lamivudine, and adefovir are the three antiviral therapies currently approved for the treatment of chronic hepatitis B virus (HBV). Initiation of treatment is indicated in patients with abnormal liver enzymes and markers of active viral replication (ie, HBV DNA positive). Hepatitis B early antigen seroconversion rates are higher and treatment duration is shorter with IFN than with lamivudine or adefovir. However, treatment results in frequent side effects and many patients have contra-indications to therapy. Lamivudine and adefovir are better tolerated, but have lower seroconversion rates after 12 months of treatment. Resistance develops in 20% of lamivudine patients after 12 months; adefovir resistance has not been identified to date. Individualization of therapy, based on factors such as patient comorbidities, response to prior therapies, and stage of disease (ie, presence of cirrhosis), is recommended. All patients over the age of 40 or with advanced liver disease should be continually screened for hepatocellular carcinoma with serum alpha-fetoprotein and abdominal imaging every 6 months.

50 Current Treatment Options

the duration of disease and is higher in men, those withexcessive alcohol intake, and coinfection with hepatitisC virus (HCV) or HIV. In case-control studies, the risk ofHCC is increased five- to 15-fold in HBV-infectedpersons compared with the general population. Patientswith cirrhosis are at higher risk of cancer than thosewithout cirrhosis; 70% to 90% of cases of HBV-associated cancers occur in persons with cirrhosis [3].

In terms of treatment, patients with chronic HBVinfection can be divided into two categories: those with“active” liver disease (ie, abnormal serum aminotrans-ferase levels, HBV DNA levels ≥ 105 copies/mL, orHBeAg positive) and those without “active” liver disease(ie, normal serum aminotransferase levels, HBeAg nega-tive, and HBV DNA levels < 105 copies/mL) [4]. Thosepatients with active disease are at greatest risk of liver-related complications and are the target group for treat-ment [5••]. Seroconversion from HBeAg to anti-HBe istypically accompanied by a decline in HBV DNA levelsto low levels (< 105 copies/mL), normalization of liverenzymes (aspartate aminotransferase [AST], alanineaminotransferase [ALT]), and resolution of necroin-flammatory activity on liver histology. The rate ofspontaneous resolution of active replication and sero-conversion from HBeAg to anti-HBe is 5% to 20% peryear. The outcome of chronic HBV infection is largelydependent on the severity and stage of disease at thetime that active HBV replication ceases, either spontane-ously or with the aid of antiviral treatment. Patientswith a prolonged phase of active viral replication are atgreater risk of liver-related complications than patientswith shorter duration of active viral replication.

There is a subgroup of HBV-infected individualswho are HBeAg negative but have high levels of HBVDNA and abnormal liver enzymes. These patients havean HBV variant virus that does not produce HBeAgowing to the presence of one or more mutations in theprecore region of the HBV genome. Such patients haveactive and progressive liver disease and are candidatesfor antiviral therapy despite the absence of HBeAg. Thisvariant form of HBV infection is more common inSouthern Europe and in Southeast Asia than in the US,but because many HBV-infected patients in the US haveimmigrated from these areas, HBeAg-negative variantsare not uncommon in clinical practice. Treatment ofthis subgroup of patients differs from that of HBeAg-positive patients (ie, the rate of relapse followingdiscontinuation of treatment is higher and longer treat-ment periods are required).

ASSESSING DISEASE ACTIVITY AND SEVERITYFor the individual found to be HBsAg positive, addi-tional testing is needed to determine the level of viralreplication, severity of histologic disease, and presenceof complications of chronic liver disease. Measurementof AST, ALT, total bilirubin, albumin, and prothrombin

time plus HBeAg, anti-HBe, HBV DNA levels, and anti-hepatitis D virus are recommended. An ultrasound ofthe abdomen is used to rule out HCC and to assess forradiologic signs of cirrhosis and portal hypertension. Aliver biopsy provides the most accurate means of assess-ing disease severity and can be used to determine theneed for antiviral therapy [3].

Only patients with abnormal AST and ALT levels arepotential candidates for antiviral therapy [5••,6].Patients with persistently normal liver enzymes are notrecommended for treatment with currently availableagents. Because disease activity can fluctuate over time,patients with normal liver enzymes should be moni-tored on a regular basis (eg, every 6 months at a mini-mum) for changes in disease activity. If liver enzymesbecome abnormal for a period of at least 3 months,patients should be considered for antiviral therapy.Patients with decompensated liver disease are potentialcandidates for treatment with lamivudine or adefovir,but not interferon (IFN). The presence of decompen-sated liver disease should also prompt referral for livertransplantation (Table 1).

GOALS OF TREATMENTThere are at least two potential goals of anti-HBV therapy:1) eradication of infection and reduction in the incidenceof secondary spread of infection; and 2) reduction in therate of disease progression and prevention of the compli-cations of liver disease such as decompensated cirrhosisand HCC. Currently available therapies for HBV are rela-tively ineffective in eradicating infection (ie, achievingseroconversion from HBsAg to anti-HBs). However, otherbenefits of treatment include the following: 1) reductionin inflammatory activity and fibrosis (histologicresponse); 2) normalization of aminotransferase levels(biochemical response); 3) sustained suppression ofHBV DNA replication (undetectable HBV DNA byhybridization or other assays); and 4) seroconversion ofHBeAg to anti-HBe.

Initial IFN studies used seroconversion (loss ofHBeAg and HBsAg) as the primary end point of treat-ment. In more recent clinical studies, histologic endpoints have been the primary end points of treatment.This shift in emphasis is appropriate because improve-ments in liver histology would be expected to correlatewith slower rates of disease progression, and ultimatelywith reduced rates of liver-related complications such ascirrhosis and HCC.

HBSAG-POSITIVE PATIENTS WHO ARE APPROPRIATE CANDIDATES FOR TREATMENTCurrently available therapies are targeted to patients with1) persistently abnormal liver enzymes (AST, ALT) (atleast three consecutive abnormal values over a 3-monthperiod); 2) HBV DNA levels greater than 105 copies/mL;and 3) HBeAg positive or negative. Although a liver

Current Treatment Options 51

biopsy is not essential for the initiation of treatment ofHBeAg-positive patients with abnormal ALT levels, theseverity of disease on liver biopsy may influence thetiming and choice of therapy.

PATIENTS WITH DECOMPENSATED LIVER DISEASEA decline in liver synthetic function (ie, elevated bilirubinor prothrombin time, low albumin) or symptoms ofdecompensation, such as fluid retention, encephalopathy,or variceal bleeding, should prompt referral to a transplantcenter. In patients with elevated liver enzymes and highlevels of HBV DNA (≥ 105 copies/mL), treatment withlamivudine or adefovir is an option. Studies have shownthat treatment with lamivudine or adefovir therapy is safein patients with decompensated liver disease and fre-quently associated with significant clinical improvement.The time to transplantation can by delayed by the institu-tion of lamivudine [7] or adefovir therapy. However,unlike the patient with compensated liver disease, treat-ment must be considered indefinite, because virologicrelapse after discontinuation of therapy can be associatedwith a rapid clinical deterioration. Prolonged treatmentwith lamivudine is associated with an increased rate of

lamivudine resistance, and treatment breakthrough canlead to worsening liver function and decompensation insome patients [8]. The addition of adefovir in patientswith treatment breakthrough on lamivudine results ininhibition of viral replication and improvement in syn-thetic function in most cases [9]. Thus, adefovir is the treat-ment of choice for patients with decompensated liverdisease and lamivudine-resistant HBV infection. IFN iscontraindicated in patients with decompensated liver dis-ease because serious bacterial infections and deteriorationin liver disease have occurred during treatment.

Liver transplantation is the treatment of choice forpatients with liver failure owing to chronic HBV infection.The early experience with liver transplantation of HBV-infected patients was discouraging. Recurrent and progres-sive HBV infection was common and caused graft loss in50% of patients within 5 years of transplantation. How-ever, in the past decade, effective therapies to prevent andtreat HBV infection in liver transplant recipients havebeen identified [10]. The use of therapies such as hepatitisB immunoglobulin (HBIG), lamivudine, and adefovirhave been associated with significant reductions in graftloss owing to recurrent HBV disease.

Treatment

• Patients need to be counseled regarding prevention of transmission to others, especially sexual partners and household contacts. All sexual partners and members of the patient’s household should be tested for HBV and vaccinated if they do not have evidence of prior HBV exposure.

• The Centers for Disease Control and Prevention recommends vaccination against hepatitis A virus for individuals with chronic liver disease owing to HBV.

Table 1. Evaluation and monitoring of the HBsAg-positive patient

TestInitial

evaluationMonitoring

disease activityAssessing

disease severity

Prior to antiviral

treatmentHCC

surveillance

AST, ALT X X X XTotal bilirubin, albumin, PT X X XHBeAg/anti-HBe X X* X Anti-HDV XHBV DNA quantitation X X* XLiver imaging study† X X XAFP X XLiver biopsy X X X‡

*Measured if changes in liver enzymes occur, suggesting spontaneous seroconversion or increased disease activity.†Ultrasound is the most common form of liver imaging study performed.‡If a liver biopsy has previously been done, repeat biopsy is not necessarily needed prior to initiation of antiviral therapy.AFP—alpha-fetoprotein; ALT—alanine aminotransferase; AST—aspartate transaminase; HBV—hepatitis B virus; HCC—hepatocellular carcinoma; HBeAg—hepatitis B early antigen; HBsAg—hepatitis B surface antigen; PT—prothrombin time.

Prevention


• The risk of HCC is increased among patients with chronic HBV infection, especially those with cirrhosis. Older age, male gender, and a family history of HCC predict higher risk of cancer. Most clinicians recommend surveillance for HCC using ultrasound plus �-fetoprotein every 6 months for patients with cirrhosis, patients older than 40 years of age, and those with a family history of HCC [3]. Whether surveillance programs reduce the mortality rates from HCC is controversial and further prospective evaluation of currently used screening strategies is needed [11].

• Heavy alcohol use (typically defined as more than 5 to 8 U/d for at least 5 years) is associated with a high frequency of cirrhosis and liver cancer [12,13]. The effects of lesser amounts of alcohol are not known, but abstinence or minimal alcohol intake is recommended.

• Smoking has been associated with an increased risk of HCC in some, but not all, studies of patients with chronic HBV disease. The effects of smoking and alcohol may be synergistic [14].

• No dietary factors have been linked to disease activity or severity. However, excess iron is associated with reduced responsiveness to IFN therapy and has been linked to increased risk of HCC [15]. Thus, iron supplements should be avoided unless iron deficiency is present. Excess vitamin A can be directly hepatotoxic, and use of supplementation is not recommended unless deficiency is documented.

• Patients who have coexistent nonalcoholic fatty liver disease (NAFLD) should be simultaneously counseled on optimizing weight, achieving and maintaining normal triglyceride levels, and controlling diabetes mellitus. NAFLD is usually diagnosed by liver biopsy.

• Use of herbal supplements should be used with caution. Many of these preparations can be hepatotoxic and cause severe liver injury. Examples of hepatotoxic herbal products associated with acute or chronic hepatitis include kava kava, chaparral, comfrey, germander, and jin bu huan. Owing to a lack of regulation of supplements, formulations and doses can vary widely. If patients are motivated to try herbal preparations, exact ingredient lists should be reviewed for known hepatotoxins, and liver tests (eg, AST, ALT, alkaline phosphatase, and bilirubin) should be monitored regularly.

• Interferon alpha, lamivudine, and adefovir are the three drugs currently approved for the treatment of chronic HBV infection. The pros and cons are listed in Table 2.

Interferon alphaInterferon alpha has both immunomodulatory and antiviral effects. IFN alpha increases the rate of sustained loss of HBeAg by 20% when compared with untreated controls. Treated patients also have a greater sustained loss of HBV DNA (37% vs 17%) and HBsAg (8% vs 1.8%) compared with controls [16]. The two factors most consistently associated with IFN responsiveness are low baseline HBV DNA (< 200 pg/mL) and high baseline aminotransferase activity (≥ five times upper limit of normal) (Note: 1 pg/mL is approximately 100,000 to 150,000 copies/mL depending on the assay). Long-term follow-up of IFN-treated patients indicates that remission is maintained in the majority, and late HBsAg seroconversion occurs at a higher rate than in untreated patients [17]. Histologic progression of disease is slowed in

Diet and lifestyle

Pharmacologic treatment


responders, and rates of HCC and liver-related death appear to be reduced [18]. Response rates differ in HBeAg-positive and HBeAg-negative patients; thus, treatment recommendations differ for these two populations. IFN alpha requires subcutaneous (SC) administration. Side effects are common, but discontinuation of treatment owing to side effects occurs in less than 10% of patients. These are the main disadvantages of IFN therapy. Advantages include the finite period of treatment (ie, 16 or 32 weeks) and the durability of HBeAg seroconversion. Additionally, treat-ment is not associated with any risk of resistant mutations.

Standard dosage HBeAg-positive, HBV DNA-positive adults: 10 million units (MU) SC three times weekly or 5 MU daily for 16 weeks. An additional 16 weeks of IFN treatment is recommended for those patients who remain HBeAg positive but have low HBV DNA titers (< 10 pg/mL) at the end of the initial 16 weeks of IFN therapy. The additional 16 weeks of IFN therapy increases response rates by 16% [19].HBeAg-negative, HBV DNA-positive adults (HBeAg-negative variants): 10 MU SC three times weekly or 5 MU daily for 48 weeks.HBeAg-negative, HBV DNA-positive children ≥ 2 years: 6 MU/m2 SC three times weekly for 16 weeks.

Contraindications Absolute: Decompensated liver disease (ie, elevated bilirubin or prothrombin time, low albumin, history of ascites, encephalopathy, or variceal bleeding); severe psy-chiatric disease; pregnancy (category C) or breast-feeding, leukopenia (leukocyte count < 4.0) or thrombocytopenia (platelet count < 90,000); significant comorbid diseases such as unstable coronary artery disease, uncontrolled seizure disorder, diabetes, or hypertension.Relative: Autoimmune disease (eg, psoriasis, rheumatoid arthritis); prior history of depression or psychiatric illness.

Main drug interactions Caution in patients on other myelosuppressive drugs. IFN reduces clearance of theophylline.

Table 2. FDA-approved drugs for HBV treatment

Drug Pros Cons

IFN alpha Limited duration of therapy (16 to 32 wk) Multiple, frequent side effectsHBeAg seroconversion rate is 20% to 30%;

HBsAg seroconversion rate is 10%Subcutaneous injection administrationContraindicated in patients with decompensated

liver diseaseMore costly than lamivudine

Long-term benefits, reduced rates of cirrhosis and HCC

No resistanceLamivudine Well tolerated Longer duration of therapy

Oral, once-daily dosingHistologic and virologic improvement in manyAble to use in decompensated patients

HBeAg seroconversion less frequent than IFN alpha, HBsAg loss rare

High rate of resistance (> 50% after 3 y)Cross-resistance with other nucleoside analoguesRequires dose adjustment for renal insufficiency

Adefovir Well tolerated Longer duration of therapyOral, once-daily dosing HBeAg seroconversion less frequent than IFN alpha,

HBsAg loss rareRequires dose adjustment for renal insufficiencyMore costly than lamivudine

Histologic and virologic improvement in manyAble to use in decompensated patientsEffective against lamivudine-resistant and

wild-type HBVNo resistance to date reported with treatment

periods up to 60 mo

FDA—US Food and Drug Administration; HBeAg—hepatitis B early antigen; HBsAg—hepatitis B surface antigen; HBV—hepatitis B virus; HCC—hepatocellular carcinoma; IFN—interferon.


Main side effects Flu-like symptoms, including fatigue, headache, myalgias, anorexia, nausea, and fever, are common in the first week of treatment but decrease in severity with continued administration. Alopecia, leukopenia, and thrombocytopenia are common. Less common but more serious side effects are retinopathy, neuro-psychiatric disturbances, thyroid dysfunction, bacterial infections (related to leukopenia), pulmonary fibrosis, and renal dysfunction. Approximately 20% of treated patients require dose reduction owing to adverse effects, but less than 10% of patients require treatment discontinuation owing to serious adverse effects.

Special points Administration of IFN alpha at bedtime may reduce the frequency of the flu-like symptoms. Antipyretics (eg, acetaminophen 325 to 650 mg preinjection) reduce fever, myalgias, and headaches. Adequate hydration is important during the first weeks of therapy.Perform baseline testing for the following: complete blood count (CBC) with platelets, AST, ALT, total bilirubin, alkaline phosphatase, urea, creatinine, thyroid-stimulating hormone (TSH), antinuclear antibodies, and rheumatoid factor. Electrocardiogram if older than 50 years of age. Monitor during treatment the following: CBC with differential weekly for first 2 to 4 weeks, then monthly; liver and renal function tests monthly; TSH at week 12.

Cost/cost-effectiveness Treatment of chronic HBV carriers (HBsAg and HBeAg positive) with chronic hepatitis (without cirrhosis) using IFN alpha (16-week course of 10 MU three times weekly) is associated with increased life expectancy and quality-adjusted life expectancy, as well as reduced total health care costs compared with the standard management of chronic liver disease with IFN treatment [20,21]. Cost-effectiveness analyses of lamivudine or adefovir for the treatment of chronic HBV have not been performed.

LamivudineLamivudine, a cytosine analogue, is orally administered and well tolerated even in patients with advanced liver disease. With treatment periods of 12 months, sero-conversion from HBeAg to anti-HBe occurs in 16% to 18%, and treatment response correlates with reduced inflammatory indices on liver biopsy and decreased rates of cirrhosis [22•]. The duration of lamivudine treatment may be important in deter-mining the durability of the response when treatment is stopped. The most impor-tant predictor of response is high baseline aminotransferase levels (≥ five times the upper limits of normal) [23]. The rate of HBeAg seroconversion increases with duration of therapy, with rates of 27% and 40% after 2 and 3 years of lamivudine treatment. Reemergence of HBV DNA while on drug therapy (treatment break-through) occurs in approximately 15% to 20% of treated patients after 12 months of treatment. The risk of treatment breakthrough increases with time, reaching 55% after 3 years of lamivudine therapy [24]. Treatment breakthrough among compliant patients is associated with mutations in the YMDD locus of domain C of the polymerase and decreased sensitivity to lamivudine in vitro [25]. Clinically, treatment breakthrough is characterized by increasing HBV DNA levels and abnormal AST and ALT. Deterioration in liver function and worsening clinical status are rare with treatment breakthrough [24], unless the patient has under-lying cirrhosis or advanced liver disease [26].

As with IFN, sustained response rates differ in HBeAg-positive and HBeAg-negative patients. The rate of relapse after discontinuation of lamivudine at 12 months is much higher in HBeAg-negative patients (90%) compared with HBeAg-positive patients (20% to 30%) [27,28•]. Continued treatment beyond 12 months is limited by an increasing rate of HBV resistance and virologic breakthrough in both groups. These data suggest that lamivudine monotherapy may not be the optimal therapy for patients with the HBeAg-negative variant form of chronic active HBV infection. The advantages of lamivudine include an oral route of administration and excellent tolerability. The disadvantages of lamivudine are lower rates of HBeAg and HBsAg seroconversion (with 12 months’ treatment) than with IFN, the need for long-term therapy to increase seroconversion rates, and the risk of viral resistance, which accompanies prolonged therapy. Although there may be few serious clinical consequences associated with the development of resistant HBV infection in the short term, the long-term consequences are largely unknown.


Standard dosage 100 mg orally once daily for 12 months.Contraindications Pregnancy (category C). Dose reduction for renal insufficiency (creatinine clearance

[CrCl] < 50 cm3/min): if CrCl is 30 to 49 mL/min, then first dose should be 100 mg, then 50 mg every day; if CrCl is 15 to 29 mL/min, then first dose should be 100 mg, then 25 mg every day; if CrCl is 5 to 14 mL/min, then first dose should be 35 mg, then 15 mg every day; if CrCl is less than 10 mL/min, then first dose should be 35 mg, then 10 mg every day.

Main drug interactions Zalcitabine can inhibit intracellular phosphorylation of lamivudine; therefore, concurrent use is not recommended. Trimethoprim/sulfamethoxazole has been shown to increase levels of lamivudine. However, no dose adjustments of either drug are recommended.

Main side effects Fatigue, nausea, and headache most commonly reported. Elevated serum aminotransferase levels are seen in 25% of patients during treatment or in the 6 months following discontinuation of therapy. This ”flare” of disease activity may be indicative of seroconversion from HBeAg to anti-HBe. Asymptomatic elevations of serum amylase levels are seen, but pancreatitis is exceedingly rare.

Special points Patients should undergo HIV testing pretreatment to avoid the inadvertent induction of lamivudine-resistant HIV. HIV- or HBV-coinfected patients should be on antiretroviral therapy prior to initiation of anti-HBV therapy with lamivudine. A higher dose of lamivudine (150 mg twice daily) is used in HIV- or HBV-coinfected patients.

Cost/cost-effectiveness The cost of lamivudine for 12 months is less than IFN alpha for 16 weeks, but there is lower rate of seroconversion (16% vs 33% after 12 months of therapy) and the durability of the response appears to be less. Formal cost-effectiveness analyses have not been conducted. Lamivudine 100 mg daily for 12 months is less expensive than adefovir 10 mg daily for 12 months.

AdefovirAdefovir, an adenosine analogue, is orally administered and well tolerated in patients with compensated and decompensated disease. Adefovir is approved for the treatment of patients with wild-type and lamivudine-resistant chronic HBV infection. Adefovir, 10 mg daily for 12 months, results in histologic improvement in 53% to 64% of patients compared with 25% to 35% of placebo-treated patients and normalization of liver enzymes in 48% to 72% versus 16% to 29% of controls. As seen with lamivudine, pretreatment ALT level was the best predictor of treat-ment response. Patients with high ALT levels and low HBV DNA levels were most likely to respond. Adefovir is nephrotoxic at higher doses (60 and 120 mg) as shown in prior HIV clinical trials. However, at the lower dose of 10 mg used in HBV treatment, no significant changes in serum creatinine have been observed. There have been no reports of adefovir resistance with treatment periods up to 60 weeks.

Standard dosage 10 mg orally once daily for 12 months. The optimal duration of therapy is still under study.

Contraindications Pregnancy (category C). Dose reduction is recommended for patients with a CrCl less than 50 cm3/min. If CrCl is 20 to 49 cm3/min, then the adefovir dose is 10 mg every 48 hours; if CrCl is 10 to 19 cm3/min, then 10 mg every 72 hours; if on hemodialysis, then 10 mg every 7 days following dialysis.

Main drug interactions Ibuprofen 800 mg three times a day increased adefovir exposure by approximately 23%. The clinical significance of this increase is not known.

Main side effects Asthenia, headache, and abdominal pain are the most common side effects reported. Hypophosphatemia and a decrease in free L-carnitine levels can occur. Supplementation should be provided if deficiencies are identified.

Special points Whenever possible, HIV- or HBV-coinfected patients should be on antiretroviral therapy prior to initiation of anti-HBV therapy with adefovir. Because adefovir has anti-HIV activity, treatment with adefovir may lead to the emergence of HIV resistance in unrecognized or untreated HIV infection. Although preliminary data on the risk of adefovir-resistant HIV in patients receiving adefovir for HBV infec-tion suggests that the dose of adefovir used in HBV treatment (10 mg daily) is too low to induce HIV resistance, the available data are limited and caution is urged.


Cost/cost-effectiveness The cost of adefovir for 12 months is less than IFN alpha, but there is a lower rate of seroconversion (12% vs 33% after 12 months of therapy) and the impact on risk of cirrhosis and HCC has not been established. Adefovir is more costly than lamivudine. Formal cost-effectiveness analyses have not been conducted.

Combination therapiesAlthough currently under study, no combination therapies have been US Food and Drug Administration approved for the treatment of HBV.

Lamivudine plus interferon alpha Despite two randomized trials showing that the efficacy of combination therapy was superior to monotherapy, the issue remains controversial because methodologic flaws plagued both studies. One study compared combination therapy to both IFN and lamivudine monotherapy [29]. The other only compared combination therapy for 24 weeks to lamivudine monotherapy for 52 weeks, but did show HBeAg seroconversion rates and histologic improvement were twice as high in the combination therapy group compared with the lamivudine monotherapy group [30].

Combination nucleoside analogues Combining two or more nucleoside analogues may increase efficacy and decrease viral resistance. Studies are underway to determine the efficacy of adefovir monotherapy versus adefovir plus lamivudine.

• Emtricitabine, the 5-fluorinated derivative of lamivudine, produces a greater than 3 log reduction in HBV DNA with short-term treatment. In a study of 98 nucleoside analogue–naive patients with chronic HBV infection, 29% achieved HBeAg seroconversion rate after 2 years of therapy with resistance developing in 19% during this same period of treatment [31]. The drug was well tolerated. Cross-resistance between emtricitabine and lamivudine has been documented.

• Entecavir, an orally administered deoxyguanosine analogue, produces a 2 to 4 log reduction of HBV DNA titers with short-term treatment. Reported side effects include headache, dizziness, and photophobia, suggesting mild neurotoxicity. Entecavir has been found to be effective in patients with lamivudine-resistant HBV and has a safety profile similar to lamivudine. No resistance has been seen in patients treated for 1 year with the 1-mg dose [32]. Phase III trials are ongoing.

• Pegylated IFNs alfa-2a and alfa-2b have been approved for the treatment of chronic HCV infection. These modified IFN molecules have polyethylene glycol molecules covalently attached, which produce more sustained absorption and reduced clearance compared with unmodified IFN alpha. Consequently, the drug’s half-life is increased allowing for once-weekly dosing. Preliminary studies have indicated the pegylated IFNs may be effective in the treatment of chronic HBV infection [33]. Additional studies using pegylated IFN as monotherapy and in combination with nucleoside analogues are underway.

• Tenofovir disoproxil is a nucleotide analogue of adenosine and is US Food and Drug Administration approved for the treatment of HIV. It has in vitro activity against lamivudine-resistant HBV [34]. In clinical studies of a small number of coinfected and HIV-negative patients with lamivudine-resistant HBV infection, tenofovir resulted in a 3 to 4 log drop in HBV DNA levels with 24 weeks of therapy [34]. Long-term data on the HBeAg seroconver-sion rates and histologic benefits, safety, and risk of resistance with tenofovir treatment are not available as yet.

• ACH-126,443, an L-nucleoside analogue, has been shown to have a 10- to 30-fold greater potency against HBV than lamivudine and adefovir. A multicenter phase I study of 36 patients demonstrated a 1.5 to 3 log decline in HBV DNA levels after 14 days [35]. Phase II studies are underway.

Emerging pharmacologic therapies


• Other nucleoside or nucleotide analogues under investigation include telbivudine (Idenix Pharmaceuticals, Cambridge, MA), clevudine (Gilead, Foster City, CA), and LY582563 (Eli Lilly Pharmaceuticals, Indianapolis, IN). Other novel therapies currently being investigated include monoclonal antibodies (XTL Biopharmaceuticals, Cambridge, MA), ribozyme therapy (Ribozyme Pharmaceuticals, Boulder, CO), and thymosin alpha-1 (SciClone Pharmaceuticals, San Mateo, CA).

Liver transplantation

Standard procedure Cadaveric or living donors.Contraindications Same as other contraindications for liver transplantation. Some liver transplant

programs require that patients be HBV DNA negative (by hybridization assay) prior to transplantation. The rationale for this requirement is based on natural history data showing that the risk of recurrent HBV infection is significantly lower in those who are HBeAg negative and HBV DNA negative pretransplantation. However, with the use of agents such as lamivudine, adefovir, and HBIG, patients with and with-out active viral replication pretransplantation can be successfully transplanted.

Special points The provision of prophylactic therapy to prevent graft reinfection is essential to the success of transplantation [36]. There is variability among transplant programs as to the specific prophylactic agents used and the dose and frequency of drug administration [3,36]. The more commonly used protocols are listed next.

Lamivudine 100 mg orally pre- and post-transplantation (indefinitely). This approach is most successful with patients who are HBeAg negative and HBV DNA negative prior to starting lamivudine therapy.

Lamivudine 100 mg orally pre- and post-transplantation (indefinitely) plus HBIG 10,000 IU intraoperatively, daily for first 7 days and monthly thereafter (indefinitely). This regime is highly successful in patients with and without active viral replication prior to the start of treatment. However, the high cost of HBIG makes this an extremely expensive prophylactic protocol.

Lamivudine 100 mg orally pre- and post-transplantation (indefinitely) plus HBIG 10,000 IU intraoperatively, daily for first 7 days, then target anti-HBs titers of 100 to 500 IU/L. Other studies report use of low-dose HBIG 400 to 800 IU/L daily for the first week and monthly thereafter. These regimens also appear to be highly effective, with a failure rate of 10% or less at 1 to 3 years post-transplantation and less costly than the combination protocol detailed above.

Increasingly, patients with decompensated cirrhosis are presenting with lamivudine-resistant HBV infection. For this subgroup of patients, options for transplantation include the following: high-dose HBIG therapy (plus continuation of lamivudine, although the latter is likely of minor importance); or adefovir, which has been shown to be effective in this special population. Liver transplant patients are at higher risk of renal dysfunction; with treatment with adefovir a rise in creatinine by 0.5 mg/dL was seen in 13% of patients. It is not clear that adefovir was the cause of the elevated creatinine given the other possible causes of renal toxicity in the population, but caution is advised. Moreover, adefovir doses should be modified if renal dysfunction is present [9].

Cost/cost-effectiveness One study found that combination therapy (lamivudine plus high-dose HBIG) was more cost-effective in preventing recurrent HBV than HBIG monotherapy [37], although the analysis was limited by the assumption that all patients with recurrence would require retransplantation. An evaluation of the cost-effectiveness of combined lamivudine and high-dose HBIG versus combined lamivudine and low-dose HBIG has not been performed.

Surgery


References and Recommended ReadingPapers of particular interest, published recently, have been highlighted as:• Of importance•• Of major importance

1. McQuillan G, Coleman P, Kruszon-Moran D, et al.: Prevalence of hepatitis B virus infection in the United States: the National Health and Nutrition Examination Surveys, 1976 through 1994. Am J Public Health 1999, 89:14–18.

2. Tong MJ, Hwang S-J: Hepatitis B virus infection in Asian Americans. Gastroenterol Clin North Am 1994, 23:569–579.

3. Lok A, Heattcote E, Hoofnagle J: Management of hepatitis B: 2000—summary of a workshop. Gastroenterology 2001, 120:1828–1853.

4. Hoofnagle J, Shafritz D, Popper H: Chronic type B hepatitis and the "healthy" HBsAg carrier state. Hepatology 1987, 7:758–763.

5.•• Lok A, McMahon B: Chronic hepatitis B—AASLD practice guidelines. Hepatology 2001, 34:1225–1241.

A comprehensive review of chronic hepatitis B, including diagnosis, monitoring, and treatment guidelines.6. Canadian Association for the Study of the Liver:

Management of Viral Hepatitis: Recommended Guidelines for Physicians. Ottawa, Ontario, Canada: Canadian Association for the Study of the Liver; 1999.

7. Yao F, Terrault N, Freise C, et al.: Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation: a comparative study using a matched, untreated cohort. Hepatology 2001, 34:411–416.

8. Perrillo R, Rakela J, Dienstag J, et al.: Multicenter study of lamivudine therapy for hepatitis B after liver transplantation. Lamivudine Transplant Group. Hepatology 1999, 29:1581–1586.

9. Schiff E, Lai C, Virchow C, et al.: Adefovir dipivoxil for the treatment of chronic hepatitis B in patients pre- and post-liver transplantation with lamivudine resistant hepatitis B virus patients. Hepatology 2002, 36:371A.

10. Terrault N: Hepatitis B and liver transplantation. Clin Gastroenterol 2000, 3:389–415.

11. Sherman M, Peltekian KM: Screening for hepatocellu-lar carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population. Hepatology 1995, 22:432–438.

12. Frieden T, Ozick L, McCord C, et al.: Chronic liver disease in central Harlem: the role of alcohol and viral hepatitis. Hepatology 1999, 29:883–888.

13. Donato F, Tagger A, Chiesa R, et al.: Hepatitis B and C virus infection, alcohol drinking, and hepatocellular carcinoma: a case-control study in Italy. Brescia HCC Study. Hepatology 1997, 26:579–584.

14. Yu M, Hsu F, Sheen I, et al.: Prospective study of hepatocellular carcinoma and liver cirrhosis in asymptomatic chronic hepatitis B virus carriers. Am J Epidemiol 1997, 145:1039–1047.

15. Mandishona E, MacPhail A, Gordeuk V, et al.: Dietary iron overload as a risk factor for hepato-cellular carcinoma in black Africans. Hepatology 1998, 27:1563–1566.

16. Wong D, Cheung A, O'Rourke K, et al.: Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann Intern Med 1993, 119:312–323.

17. Lau D, Everhart J, Kleiner D, et al.: Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa. Gastroenterology 1997, 113:1660–1667.

18. Di Marco V, Lo Iacono O, Camma C, et al.: The long-term course of chronic hepatitis B. Hepatology 1999, 30:257–264.

19. Janssen HL, Gerken G, Carreno V, et al.: Interferon alfa for chronic hepatitis B infection: increased efficacy of prolonged treatment. The European Concerted Action on Viral Hepatitis (EUROHEP). Hepatology 1999, 30:238–243.

20. Wong JB, Koff RS, Tine F, et al.: Cost-effectiveness of interferon-alpha 2b treatment for hepatitis B e antigen-positive hepatitis B. Ann Intern Med 1995, 122:664–675.

21. Dusheiko G, Roberts J: Treatment of chronic type B and C hepatitis with interferon alfa: an economic appraisal. Hepatology 1995, 22:1863–1873.

22.• Dienstag J, Schiff E, Wright T, et al.: Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999, 341:1256–1263.

Lamivudine treatment for HBeAg-positive patients.23. Perrillo R, Lai C, Liaw Y, et al.: Predictors of HBeAg

loss after lamivudine treatment for chronic hepatitis B. Hepatology 2002, 36:186–194.

24. Leung N, Lai C, Chang T, et al.: Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. Hepatology 2001, 33:1527–1532.

25. Allen M, Deslauriers M, Andrews C, et al.: Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Hepatology 1998, 27:1670–1677.

26. Perrillo R, Wright T, Rakela J, et al.: A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology 2001, 33:424–432.

27. Santantonio T, Mazzola M, Iacovazzi T, et al.: Long-term follow-up of patients with anti-HBe/HBV DNA-positive chronic hepatitis B treated for 12 months with lamivudine. Hepatology 2000, 32:300–306.

28.• Hadziyannis S, Papatheodoridis G, Dimou E, et al.: Efficacy of long-term lamivudine monotherapy in patients with hepatitis B e antigen-negative chronic hepatitis B. Hepatology 2000, 32:847–851.

Lamivudine therapy in the HBeAg-negative patient.


29. Schalm S, Heathcote J, Cianciara J, et al.: Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial. Gut 2000, 46:562–568.

30. Barbarini G, Zechini F, Pellicelli A, et al.: Long-term efficacy of interferon alpha-2b and lamivudine in combination compared to lamivudine monotherapy in patients with chronic hepatitis B. An Italian multi-center randomized trial. Hepatology 2001, 34:318A.

31. Gish R, Leung N, Wang C, et al.: Antiviral activity, safety, and incidence of resistance in chronically infected hepatitis B patients given once daily emtricitabine for 2 years. Hepatology 2002, 36(No 4, Pt 2):372A.

32. Colonno R, Rose R: Genotypic analysis following 48 week entecavir treatment of chronic HBV subjects failing lamivudine suggests sustained susceptibility and lack of resistance development. Hepatology 2002, 36(No 4, Pt 2):644A.

33. Cooksley W, Piratvisuth T, Wang Y, et al.: 40 KDA peginterferon alfa-2A (Pegasys): efficacy and safety results from a phase ii, randomized, actively con-trolled, multicenter study in the treatment of HBeAg positive chronic hepatitis B. Hepatology 2001, 34:349A.

34. Park J, Braun J, Goldman D, et al.: Co-infection with HIV and HBV: the effect of tenofovir disoproxil fumarate in lamivudine and famciclovir experienced patients. Hepatology 2002, 36(No 4, Pt 2):641A.

35. Afdhal N, O'Brien C, Oshana S, et al.: Potent anti-HBV activity of ACH-126,443 correlated with 14 day pharmacokinetics and safety: predictions for activity against YMDD mutant strains. Hepatology 2002, 36:370A.

36. Terrault N: Management of hepatitis B virus infection in liver transplant recipients: prospects and challenges. Clin Transplant 2000, 14(suppl 2):39–43.

37. Han S, Ofman J, Holt C, et al.: An efficacy and cost-effectiveness analysis of combination hepatitis B immune globulin and lamivudine to prevent recur-rent hepatitis B after orthotopic liver transplantation compared with hepatitis B immune globulin mono-therapy. Liver Transpl 2000, 6:741–748.

Treatment of chronic hepatitis B

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