eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease
Hepatitis B: Treatment & Medication
Updated: May 1, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
Until recently, no specific treatment has been available for persons with acute hepatitis B virus (HBV) infection. Supportive and symptomatic care used to be the mainstay of therapy for most patients. However, the recent advent of nucleoside analogues such as lamivudine and adefovir dipivoxil has had a major impact on treatment of chronic hepatitis B. Nucleoside analogues achieve viral suppression (as measured by loss of Hb e Ag and suppression of HBV DNA), and recombinant interferon alfa aims at immunomodulation.
New nucleosides that are not yet approved by the US Food and Drug Administration (FDA) for hepatitis B include tenofovir, emtricitabine, and clevudine (not approved in the United States for any indication as of January 2008). Entecavir is now approved and has the advantage of developing very little resistance and is effective against mutants resistant to lamivudine. Telbuvidine is an L -nucleoside with specific anti-HBV activity that was approved by the FDA in 2006. It seems to achieve significantly better viral suppression than lamivudine monotherapy, although resistance and cross-resistance is common. Combination therapy in the future may have additive or synergistic effects, reduction of adverse effects, and reduction of resistance with achievement of better viral suppression.
Surgical Care
- Liver transplantation for decompensated liver disease
- Surgical resection of hepatocellular carcinoma
Consultations
- Infectious disease specialists for placement in therapeutic protocols
- Gastroenterologist for biopsy assessment and therapy
Diet
A high-energy diet is desirable, and because many patients may have nausea late in the day, they best tolerate their major caloric intake in the morning. Intravenous feeding is necessary in the acute stage if the patient has persistent vomiting and cannot eat.
Activity
Although forced and prolonged bed rest is not essential for full recovery, many patients feel better with restricted physical activity.
Medication
Interferon alfa has been the mainstay of treatment for chronic hepatitis B since its introduction in the mid 1980s; however, only 30-40% of patients respond to this therapy. Lamivudine and the newer nucleoside analogues (ie, famciclovir, lobucavir, and adefovir dipivoxil) directly block the replication of hepatitis B virus (HBV); they are highly effective, bioavailable, and extremely well tolerated. To date, interferon alfa-2b, peginterferon alfa-2a, lamivudine, adefovir, entecavir, and telbivudine are FDA approved for hepatitis B. For more information, see Guidelines from the American Association for the Study of Liver Diseases (AASLD) for Chronic Hepatitis B.
Antiviral agents
Interferon may prevent the progression of acute hepatitis to the chronic stage and may promote more rapid resolution of viremia and normalization of serum aminotransferase levels. Several nucleoside analogues are active against HBV. The most widely used and studied is lamivudine, which has produced promising responses. However, relapse rates tend to be high after treatment is discontinued.
Interferon alfa-2b (Intron A)
Biologic interferons are proteins produced by host cells in response to viral infection. Three interferons have been identified, and each has antiviral and immunoregulatory actions: interferon-a is produced by B lymphocytes and monocytes; interferon-b is produced by fibroblasts; and interferon -g is produced by T-helper and NK cells. Immunomodulatory effects of interferons are mediated by an increase in HLA class I antigen and FC receptor expression, an increased CD4/CD8 ratio, and activation of NK cell pathways.
Ideally, candidates for interferon therapy have evidence of ongoing viral replication (presence of HBe Ag or HBV DNA) for at least 6 mo and either persistently increased serum aminotransferase activity or evidence of chronic hepatitis B infection on liver biopsy findings. Before recombinant interferon therapy, screening patients for at least 4-6 mo to identify those who may be entering a period of spontaneous seroconversion to HBe Ab is often beneficial.
Clinical variables associated with a favorable response to therapy are high pretherapy aminotransferase levels, low HBV DNA levels, and active disease at liver biopsy. Other, less useful, variables include female sex, acquisition of infection in adulthood, heterosexuality, HIV antibody negativity, and history of acute hepatitis. Responses to interferon alfa-2b, is defined as a sustained loss of HBe Ag and HBV DNA, with a normalization or near normalization of ALT levels for at least 6 mo after therapy; this is observed in 25-40% of patients.
Controlled studies of interferon in children reveal comparable responses in primary non-Asian children. Chinese children respond poorly to interferon therapy. Safety and effectiveness in patients aged 1-17 years have been established.
Adult
5 million U SC qd or 10 million U SC 3 times per wk
Pediatric
<1 year: Not established
1-17 years:
High dose: 7.5-10 million U/m2 SC 3 times per wk
Low dose: 3-6 million U/m2 SC 3 times per wk; studies with both showed that the high dose was more effective
Interactions with other medications have not been fully evaluated; use caution with potentially myelosuppressive agents such as zidovudine; combination with theophylline decreases theophylline clearance, increasing theophylline levels by 100%
Documented hypersensitivity; decompensation (cirrhosis)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Interferon does not appear to protect against hepatocellular carcinoma; treatment is associated with frequent adverse events; dose reduction is required in at least 20% of patients treated with recommended regimen; discontinuation of treatment is necessary in <5% of instances; most patients have influenzalike illness with fever, chills, myalgia, and headaches 6-8 hours after first injection; symptoms improve or disappear with subsequent injections; patients benefit from premedication with acetaminophen or NSAIDs
Psychiatric adverse effects, especially depression, occur in about 15% of patients; frank delirium and suicidal ideation have been reported interferon decreases the platelet count by 30-50%, total white cell count by 20-40%, and hematocrit level slightly; changes are clinically insignificant and often return to normal after treatment is discontinued; can induce an autoimmune diathesis; associated with clinically significant worsening or unmasking of autoimmune conditions; autoantibodies, such as antinuclear, anti–smooth muscle, antithyroid, and insulin antibodies, develop in >50% of patients treated for 4 mo
Thyroid abnormalities infrequent; evaluate serum TSH levels prior to therapy; acute, serious, hypersensitivity reactions (rare) require immediate discontinuation; transient rashes have occurred after injection but have not required treatment interruption; may exacerbate preexisting psoriasis
Peginterferon alfa-2a (Pegasys)
Binds to cell surface receptors in a cascade of protein interactions resulting in gene transcription. These stimulated genes modulate inhibit viral replication in infected cells, cell proliferation, and immunomodulation. Indicated for adults with HBe Ag-positive and HBe Ag-negative chronic hepatitis B with compensated liver disease and evidence of viral replication and liver inflammation.
Adult
180 mcg SC once weekly for 48 wk; administer in abdomen or thigh
Pediatric
<18 years: Not established
Theophylline may increase toxicity by reducing clearance; cimetidine may increase the antitumor effects; zidovudine and vinblastine may increase toxicity
Documented hypersensitivity; decompensated liver disease; significant preexisting psychiatric disease; ongoing or recent alcohol use; platelet count <70,000/mcL
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
X - Contraindicated; benefit does not outweigh risk
Precautions
Insomnia; mental dysfunction (eg, mood dysfunction, depression, psychosis, aggressive behavior, hallucinations, violent behavior, suicidal ideation, suicide attempt, suicide, homicidal ideation [rare]), even without previous history of psychiatric illness; flulike symptoms; rash and pruritus; anorexia; neutropenia; thrombocytopenia; thyroid dysfunction; retinal abnormalities
Lamivudine (Epivir-HBV)
Inhibits HBV DNA polymerase. Use should be considered in patients with ongoing HBV replication, elevated aminotransferase activity, and histologic evidence of liver injury. Lamivudine is now considered first-line therapy, eclipsing interferon. Consider lamivudine in patients who fail or are unlikely to respond to interferon therapy or patients who cannot tolerate interferon. Discontinue lamivudine only when repeated assays demonstrate HBe Ag loss or seroconversion to Hbe Ab; the time for stopping treatment, however, is controversial. Results of a histologic study reported that lamivudine treatment for 3 y reduced necroinflammatory activity and reversed fibrosis (including cirrhosis) in most patients.
Emergence of resistance is the major drawback of nucleoside analogue monotherapy (incidence of resistance rises from 15-32% in the first year to 67-69% by the fifth year of treatment). The proper management of viral breakthrough in patients treated with lamivudine is not yet defined. Continuation of lamivudine appears to be warranted in most cases because the resistant strains of HBV seem to be attenuated and are associated with only mild liver injury. Combination therapy with 2-3 nucleoside analogues may delay or prevent emergence of viral resistance, but clinical trials are needed.
Safe and effective in children aged 2-17 y. Note that the available dosage forms differ between Epivir and Epivir-HBV (formula specific for hepatitis B virus). Epivir-HVB is available as a 100 mg tab or PO solution 5 mg/mL, whereas Epivir contains 150 mg/tab or 10 mg/mL in PO solution.
Adult
CrCl >50 mL/min: 100 mg PO qd
CrCl 30-49 mL/min: 100 mg PO for first dose, then 50 mg qd
CrCl 15-29 mL/min: 35 mg PO for first dose, then 25 mg qd
CrCl 5-14: 35 mg PO for first dose, then 15 mg qd
CrCl <5 mL/min: 35 mg PO first dose, then 10 mg qd
Pediatric
<2 years: Not established
2-17 years: 3 mg/kg/d PO; not to exceed 100 mg daily
>17 years: Administer as in adults
Trimethoprim/sulfamethoxazole increases bioavailability of lamivudine; lamivudine increases concentration of zidovudine when administered concurrently
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in pediatric patients with history of prior antiretroviral nucleoside exposure, pancreatitis, or other significant risk factors for pancreatitis; new-generation nucleoside analogues appear to be remarkably free of adverse effects; mild constitutional symptoms (eg, malaise, fatigue, headache, nausea, abdominal discomfort) have been reported; aminotransferase levels increase in 30-40% of patients; lactic acidosis/severe hepatomegaly with steatosis, including fatal cases, have been reported (mostly in women); obesity and prolonged exposure to nucleosides may be risk factors; physician experienced in managing chronic hepatitis B should assess patients before treatment; safety and efficacy is not established in patients with decompensated liver disease or organ transplants, in pediatric patients, and in patients dually infected with HBV, HCV, hepatitis delta, or HIV; reduced dose recommended in impaired renal function
Adefovir dipivoxil (Hepsera)
Indicated for chronic hepatitis B. An acyclic analogue of deoxyadenoside monophosphate and inhibits amplification of circular DNA in HBV-infected hepatocytes. When given daily for 48 wk, was associated with significant improvement of histologic results, higher rate of Hbe Ag seroconversion, reduction of HBV DNA by 3 logs, and higher normalization rate of ALT when compared with placebo. Has low chance of adefovir-resistance development; however, a new adefovir-resistant mutant has been detected in 1.6% of patients at 96 weeks follow-up.
Adult
CrCl >50 mL/min: 10 mg PO qd
CrCl 20-49 mL/min: 10 mg PO q48h
CrCl 10-19 mL/min: 10 mg PO q72h
Hemodialysis: 10 mg PO qwk following hemodialysis
Pediatric
Not established
Coadministration with drugs excreted renally or known to affect renal function may affect adefovir renal elimination; ibuprofen 800 mg PO tid increased adefovir exposure by approximately 23%; however, the clinical significance of this is unknown
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Overall, a safe medication; no renal toxic effects recorded in clinical trials with the dose used for chronic hepatitis B, but renal function must be monitored closely; higher doses may have renal adverse effects, including renal tubular dysfunction
Entecavir (Baraclude)
Guanosine nucleoside analogue with activity against HBV polymerase. Competes with natural substrate deoxyguanosine triphosphate to inhibit HBV polymerase activity (ie, reverse transcriptase). Less effective for lamivudine-refractory HBV infection. Indicated for treatment of chronic hepatitis B infection. Available as tab and PO solution (0.05 mg/mL; 0.5 mg = 10 mL).
Adult
Treatment for nucleoside naive: 0.5 mg PO qd 2 h ac or 2 h pc
CrCl 30-49 mL/min: 0.25 mg PO qd
CrCl 10-29 mL/min: 0.15 mg PO qd
CrCl <10 mL/min: 0.05 mg PO qd
Receiving lamivudine or lamivudine resistance: 1 mg PO qd 2 h ac or 2 h pc
CrCl 30-49 mL/min: 0.5 mg PO qd
CrCl 10-29 mL/min: 0.3 mg PO qd
CrCl <10 mL/min or hemodialysis or CAPD: 0.1 mg PO qd
Pediatric
<16 years: Not established
>16 years: Administer as in adults
Not a substrate, inhibitor, or inducer of cytochrome P450; coadministration with drugs that reduce renal function (eg, aminoglycosides, cidofovir, cyclosporine) or that compete for active tubular secretion (eg, probenecid, salicylates) may increase serum concentration of either entecavir or coadministered drug
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Reduce dose with renal impairment; if on hemodialysis, administer afterwards; common adverse effects include headache, tiredness, dizziness, and nausea; may elevate liver enzyme levels; may cause lactic acidosis; severe acute exacerbations of hepatitis B may occur in patients who discontinue antihepatitis B therapy
Telbivudine (Tyzeka)
Nucleoside analogue approved by FDA for chronic hepatitis B treatment. Inhibits hepatitis B viral DNA polymerase. Indicated in patients with evidence of ongoing hepatitis B viral replication and either persistent elevated aminotransferase activity or histologic evidence of active liver disease. Consider in patients who did not or are unlikely to respond to interferon or for patients who cannot tolerate interferon. Emergence of resistance is major drawback of nucleoside analogue monotherapy.
Adult
CrCl >50 mL/min: 600 mg PO qd
CrCl 30-49 mL/min: 600 mg PO q48h
CrCl <30 mL/min (not requiring dialysis): 600 mg PO q72h
ESRD: 600 mg PO q96h
Optimal treatment duration not established
Pediatric
<16 years: Not established
>16 years: Administer as in adults
Toxicity may increase when concurrently administered with drugs that decrease renal excretion (eg, acyclovir, aminoglycosides, amphotericin B, cisplatin, cyclosporine, metformin, tacrolimus); may increase risk of myopathy when coadministered with HMG-CoA reductase inhibitors (statins)
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, reported with use of nucleoside analogs alone or in combination with antiretrovirals; severe acute hepatitis B exacerbations reported when antihepatitis B therapy (including telbivudine) is discontinued (closely monitor hepatic function with both clinical and laboratory follow-up for at least several months following discontinuation of antihepatitis B therapy and resume therapy if necessary); myopathy has been reported; common adverse effects include upper respiratory tract infection, fatigue, malaise, abdominal pain, nasopharyngitis, headache, increased CK level, cough, nausea, vomiting, flulike symptoms, diarrhea, pyrexia, arthralgia, rash, back pain, dizziness, and dyspepsia
More on Hepatitis B |
| Overview: Hepatitis B |
| Differential Diagnoses & Workup: Hepatitis B |
 Treatment & Medication: Hepatitis B |
| Follow-up: Hepatitis B |
| References |
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References
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Further Reading
Keywords
hepatitis B, hepatitis B virus, HBV, infectious hepatitis, hepatitis B infection, acute liver disease, chronic liver disease, fulminant hepatic failure, viral hepatitis, viral hepatitis type B, cirrhosis, hepatocellular carcinoma, urticarial rashes, arthralgia, arthritis, Gianotti-Crosti syndrome, papular acrodermatitis, necrotizing vasculitis, hypocomplementemic glomerulonephritis, Essential mixed cryoglobulinemia, pulmonary hemorrhage, vasculitis, acute pericarditis, polyserositis, Henoch-Schönlein purpura, anorexia, nausea, malaise, vomiting, arthralgias, myalgias, headache, photophobia, pharyngitis, coryza, jaundice, dark urine, abdominal pain, splenomegaly, cervical adenopathy, spider angioma, encephalopathy, fetor hepaticus, coagulopathy, renal failure, adult respiratory distress syndrome, pancreatitis, myocarditis, atypical pneumonia, aplastic anemia, transverse myelitis, peripheral neuropathy
