HEPATITIS B
| HBV THERAPY (IN ADULTS): PEGINTERFERON AND NUCLEOSIDE/NUCLEOTIDE ANALOGUES —Kris V.
Kowdley, MD, Professor of Medicine, University of Washington Medical Center, Seattle
|
| Options for therapy: interferon (Intron-A, Roferon A)—5 million U daily, or 10 million U 3 times weekly, for 16
wk; for patients with hepatitis B e antigen (HBeAg)-negative disease, or precore variant form of disease (HBcAg), 5
million U daily or 10 million U 3 times weekly, for 12 to 18 mo; pegylated-interferon alfa-2a—long-acting; 180 µg/
wk subcutaneously for 12 mo; lamivudine—first oral nucleoside agent; approved in 1998 at dose of 100 mg daily for
12 mo; adefovir—10 mg daily for 12 mo; entecavir (Baraclude)—0.5 mg daily for 12 mo, 1.0 mg daily for 12 mo
for lamivudine-resistant hepatitis B virus (HBV)
|
| Whom to treat: target therapy for those with active disease (somewhat of a “moving target”); clear trend to view
HBV as chronic viral disease, especially with new data suggesting level of viral replication associated with risk for
liver cancer; patients with highest risk for progressive disease (ie, significant histologic damage) most likely to benefit;
tailor therapy to those most likely to respond, eg, HBeAg-positive patients with higher likelihood of seroconversion
after therapy
|
 | Definition of active disease: traditionally targeted patients with highest level of necroinflammatory changes or fibrosis
on liver biopsy; however, in contrast to Hepatits C virus (HCV), American Association for the Study of Liver Diseases
(AASLD) treatment guidelines do not require liver biopsy to initiate treatment; elevated serum alanine aminotransferase
(ALT; more than twice upper limit of normal), when associated with active viral replication (HBV
DNA in serum >105 copies/mL), sufficient indication for treatment
|
| AASLD treatment guidelines: HBeAg-positive patients with serum HBV DNA >105 copies/mL via polymerase chain
reaction (PCR) assay and serum ALT more than twice upper limit of normal; HBeAg-negative patients with ALT
more than twice upper limit of normal and serum HBV DNA >105 copies/mL; no differentiation in viral-load
threshold for starting treatment between HBeAg-positive and HBeAg-negative patients, but this changing; HBeAg-
negative patients with HBV DNA lower than threshold and ALT less than twice upper limit of normal should be followed;
cirrhotic patients—if compensated, treatment recommended at same levels of viremia; if decompensated,
liver transplantation indicated, and threshold for treating somewhat lower (interferon not good)
|
| US treatment algorithm (because clinical guidelines often do not reflect clinical reality): in HBeAg-positive patients
with viral load >105 copies/mL and normal ALT, consider liver biopsy and treat if significant disease evident; in
HBeAg-positive patients with high viral load and any elevation of ALT, treatment indicated; in HBeAg-negative
patients, viral-load threshold for initiating treatment >104 copies/mL with any elevation of ALT; in HBeAg-negative
or HBeAg-positive patients with normal ALT and viral load greater than thresholds, biopsy recommended to
determine treatment
|
| Typical case: medical student, 28 yr of age, born in China; previously HBeAg positive; received no prior treatment;
asymptomatic; family history positive for HBV in sibling and mother, but not for hepatocellular carcinoma (HCC);
oral contraceptives only medication; body mass index (BMI) 26; vital signs normal; no chronic liver disease, and no
organomegaly; pathology normal; ALT elevated; patient likely HBeAg positive
|
| Initial work-up: characterize HBV disease; obtain e-antigen status, viral load; delta antibody probably not needed
(consider if from Mediterranean region); exclude other causes
|
| Radiology: baseline ultrasonography important to assess for subtle signs of cirrhosis or portal hypertension; keep
HCC in mind, especially in early-onset disease and in Asian patients
|
| Liver biopsy: controversial in patients with elevated ALT; helpful in patients without significant elevation of ALT or
in HBeAg-negative patients with marginal viremia and those on fence
|
| Lifestyle issues: caution against alcohol; educate on BMI (ie, in patient with baseline risk, obesity strong and independent
risk factor for HCC)
|
| Indications for HBV vaccination: men who have sex with men; intravenous drug users; heterosexuals with multiple
sexual partners; health care workers; inmates and staff in correctional institutions; recipients of pooled blood
products; all sexual and household contacts of HBsAg-positive patients
|
| Surveillance (HCC): surveillance important in patients with cirrhosis, chronic HBV, HCV, hemochromatosis and
other metabolic diseases, and alcoholic liver disease; in patients with HBV but without cirrhosis, screening recommended
by 40 yr of age in men and 50 yr in women; for anyone with family history of HCC, speaker starts first visit
with (biannual) ultrasonography and assay for alpha fetoprotein
|
| Therapeutic decision making: citing Chinese dental student case, speaker notes liver biopsy revealed grade 2 to 3
(of 4) necroinflammatory disease and stage 2 fibrosis; patient clearly candidate for therapy; efficacy—goal with
HBeAg-positive patient is seroconversion to anti-eAg; if surface-antigen loss possible, highly desirable, but this occurs
only with prolonged therapy with oral agents (and more preferentially, interferon); stage of disease—if cirrhotic,
interferon not treatment of choice; if patient likely to need long-term treatment (eg, HBeAg negative), or patient with
modest elevation of enzymes, then resistance profile of drug becomes factor over first 2 to 3 yr; comorbidities—
peginterferon alfa-2a relative or contraindications; also consider preference and cost (peg-interferon alfa-2a more expensive)
|
| Peginterferon alfa-2a study in HBeAg-positive patients: 24-wk treatment and 24-wk follow-up—standard
dose (90/180/270 µg/wk); response defined as e-antigen loss and achieving HBV DNA of <500 copies/mL with normal
ALT; 28% of patients in 180-µg group reached end point; 72-wk data with 48-wk group—3 groups randomized
to peginterferon alfa-2a or peginterferon alfa-2a plus lamivudine vs lamivudine alone; concept of antiviral with
antiviral/immunomodulatory agent (interferon) extremely attractive in HBV, but yet to see clear evidence; nevertheless,
HBV DNA levels <100,000 copies/mL achieved in 32% and 34% of patients given peginterferon alfa-2a, with
or without lamivudine; e-antigen seroconversion achieved in 32% and 27%; normal ALT in 39% and 41%, with less
optimal responses in lamivudine monotherapy group
|
| Summary: peginterferon alfa-2a treatment benefits include finite therapy duration; good e-antigen seroconversion
rate; loss of surface antigen (now seen as equivalent sign of response to e-antigen seroconversion); weaknesses include
side effects and parenteral administration; many patients not candidates
|
| Genotype: differential responses across genotypes; however, use of genotypic testing not yet standard practice (expected
soon)
|
| Lamivudine: several studies of HBeAg-positive patients treated for 52 wk at 100 mg/day; HBeAg seroconversion in
16% to 18%, HBeAg loss in 17% to 33%; efficacy of lamivudine linked to ALT (ie, higher ALT associated with
greater likelihood of HBeAg seroconversion); resistance—Achilles’ heel of this treatment; occurs in 70% of patients,
especially in Asia, with 5 yr of treatment; after 3 yr of resistance, overall benefits of drug eliminated; after lamivudine
resistance, any subsequent agent not as effective
|
| Adefovir: prodrug converted to adefovir; in chronic HBV HBeAg-positive patients treated for 1 yr, 30% undetectable
at 1 yr, 63% normalized liver enzymes, and 14% seroconverted; in 3-yr group, seroconversion and HBV DNA suppression
achieved in ≈50% of patients and ALT normalization in majority; resistance emerging and rising at higher
rate than seen in early years; in cases of lamivudine resistance, speaker tends to add adefovir rather than switch; well
tolerated; safe in special populations; weaknesses include modest rates of seroconversion at 1 yr; nephrotoxicity possible,
but less likely with 10-mg/day dose
|
| Entecavir: newest drug approved; studies comparing to lamivudine promising; superior histologic improvement, increased
rate of ALT normalization, and slightly higher rate of seroconversion
|
| CHRONIC HBV IN CHILDREN —Maureen Jonas, MD, Associate Professor in Pediatrics, Harvard Medical School,
and Associate in Gastroenterology, Children’s Hospital, Boston, MA
|
| Early natural history of HBV: seroconversion occurs spontaneously in most children with chronic HBV without
any treatment (ie, virus stops replicating; immune system becomes active against virus; HBeAg disappears; e antibody
appears; ALT, if elevated, typically normalizes; risk for ongoing liver injury ceases)
|
| Clinical setting: most children HBeAg positive, with active viral replication and normal liver enzymes (immune-tolerant
phase); however, in some children with chronic HBV (≈25% overall), immune system tries to activate against infection,
yielding recurrent immune-mediated assaults on HBV that manifest clinically by increases in ALT (these
patients susceptible to liver damage)
|
| Therapeutic goals: hasten natural history, ie, achieve seroconversion earlier (contrary to goals in adult patient)
|
| Monitoring protocol: follow HBV immunization with surface antigen and antibody testing; provide HAV vaccination;
test family members, vaccinate susceptible members, and test again after 3 doses for antibodies; measure ALT
every 6 mo; monitor HBeAg and e antibody; yearly alpha fetoprotein test; look for cancer via liver ultrasonography
|
| Selecting patients to treat: minority of children will need treatment; document chronic HBV (surface antigen test
≥6 mo apart); ≥2 yr of age; evidence of viral replication (ruled out if patient HBeAg negative or cannot measure HBV
DNA, and treatment unnecessary); treatment considered if patient HBeAg positive and can measure HBV DNA; high
viral DNA level alone (common in children) not an indication for treatment (check ALT few times to classify into active
or inactive phase); if ALT persistently normal, put child into monitoring protocol; if ALT persistently abnormal,
consider liver biopsy
|
| Two drugs approved by Food and Drug Administration (FDA) for use in children
|
| Interferon-á: still good drug for chronic HBV in select settings; indicated for children ≥2 yr of age; still has role in
management of chronic HBV; subcutaneous injection 3 times weekly for 6 mo; need patience because seroconversion
may not occur for up to 12 mo; many side effects, but not reason to avoid; monthly blood counts recommended
(neutropenia and cytopenia); monitor for hepatitis flares (ALT and bilirubin); measure HBV DNA level
every 3 mo; monitor thyroid function tests (due to interferon; usually not symptomatic or clinically relevant); after
6 mo, monitor for seroconversion
|
| Side effects: flu-like illness; chronic fatigue; weight loss/ failure to gain weight; depression, especially with longer-
term therapy; neutropenia common (more common with longer-acting preparations); headaches, migraine exacerbation;
retinopathy (rare, but baseline eye exam indicated); hepatitis flare frightening, but not indication to stop
|
| Lamivudine: approved for children; nucleoside analogue; 3 mL/kg per day once daily to maximum of 100 mL (adult
dose); 2 liquid preparations available identical and either one viable, ie, Epivir (10-mL preparation), used for HIV,
and Epivir HBV (5-mL preparation); indicated in children with high virus level, but also in children with active
liver inflammation (ALT consistently at least twice normal [target population for seroconversion]); extremely safe
and well tolerated (side effects negligible); watch for hepatitis flare; monitor HBV DNA level (decreases); also
monitor creatinine kinase (CK) and amylase for pancreatitis and lactic acidosis; mild nonspecific CK elevations not
indication to stop drug
|
| Therapy course: ≥1 yr; treatment must be continued at least 6 mo after documented seroconversion; if no seroconversion,
can continue until HBV DNA level goes up by log of 10 (clinical definition of drug resistance); ALT flare possible
when drug stopped (careful monitoring necessary; dangerous if patient has serious liver disease); occasionally,
sero-reversion occurs (retreatment necessary)
|
| Other drugs: adefovir (Hepsera)—not same satisfaction as lamivudine in virus level reduction rate; not yet approved
for children; randomized clinical trials ongoing; much lower resistance rate (≈6% in 3 yr); peginterferon alfa-2a—
not approved in children with chronic HBV
|
| Genotyping: test not clinically available; 8 genotypes for HBV; differences in clinical disease, natural history, and
treatment; soon will drive therapy decisions
|
| Challenges for treatment: define by state of infection, not as carrier, because word implies benign state; should define
patient according to disease stage (active, inactive, latent); detect children with liver disease; cultural issues to
consider; need to decide how to do cancer surveillance; HbeAg-negative disease starting to emerge in pediatrics, too
|
Educational Objectives
| The goal of this program is to educate the listener about the management of hepatitis B virus (HBV) infection. After hearing
and assimilating this program, the clinician will be better able to:
|
| 1. List currently approved therapies for chronic HBV in adults and children.
|
| 2. Discuss challenges of selection of adult patients to treat for HBV.
|
| 3. Site guidelines for HBV treatment.
|
| 4. Describe differences in management of chronic HBV in children and adults.
|
| 5. Detail a monitoring protocol for the case of a child with HBV.
|
Discussed on This Program
Adefovir dipivoxil [Hepsera]
Entecavir [Bariclude]
Emcitrabine and tenofovir disoproxil fumarate [Truvada]
Emtricitabine [Emtriva]
Interferon (several trade names and formations)
Lamivudine [Epivir]
Peginterferon alfa-2a [Pegasys]
Pradefovir (investigational)
Tenofovir disoproxil fumarate[Viread]
Suggested Reading
Ayaz C et al: Comparison of lamivudine and alpha-interferon combination with alpha-interferon alone in the treatment
of HBeAg-positive chronic hepatitis B. Indian J Gastroenterol 25:71, 2006; Braga EL et al: Clinical and epidemiological
features of patients with chronic hepatitis C co-infected with HIV. Braz J Infect Dis 10:17, 2006; [Epub] 2006 Jun 2.
Chan HL et al: Long-term lamivudine treatment is associated with a good maintained response in severe acute exacerbation
of chronic HBeAg-negative hepatitis B. Antivir Ther 11:465, 2006; Freed GL et al: Use of a new combined vaccine
in pediatric practices. Pediatrics 118:e251, 2006; [Epub] 2006 Jul 10. Hwang S et al: Lessons learned from 1,000
living donor liver transplantations in a single center: how to make living donations safe. Liver Transpl 12:920, 2006; Jonas
MM: Treatment of chronic hepatitis B in children. J Pediatr Gastroenterol Nutr 43 Suppl 1:S56, 2006;
Karaoglan M et al: Immunomodulation therapy in children with chronic hepatitis B. J Natl Med Assoc 98:143, 2006;
Lee YS et al: Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48
weeks of adefovir dipivoxil monotherapy. Hepatology 43:1385, 2006; Mieli-Vergani G et al: Treatment of hepatitis B
virus in children: why, whom, how? Indian J Gastroenterol 25:121, 2006; Prakoso E et al: Long-term lamivudine
monotherapy prevents development of hepatitis B virus infection in hepatitis B surface-antigen negative liver transplant recipients
from hepatitis B core-antibody-positive donors. Clin Transplant 20:369, 2006; Ribeiro NR et al: Distribution
of hepatitis B virus genotypes among patients with chronic infection. Liver Int 26:636, 2006; Shepherd J et al: Adefovir
dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic
evaluation. Health Technol Assess 10:1, 2006; Sherman M et al: Entecavir for treatment of lamivudine-refractory,
HBeAg-positive chronic hepatitis B. Gastroenterology 130:2039, 2006; Sokucu S et al: Comparison of interferon
monotherapy with interferon-lamivudine combination treatment in children with chronic hepatitis B. Indian J Gastroenterol
25:136, 2006; Suzuki F et al: Changes in viral loads of lamivudine-resistant mutants and evolution of HBV sequences
during adefovir dipivoxil therapy. J Med Virol 78:1025, 2006; van Bommel F et al: Tenofovir for patients
with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy. Hepatology
44:318, 2006
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue, Dr. Jonas reported
relationships with Bristol Myers Squibb and Gilead Sciences. Dr. Kowdley reported nothing to disclose.
Dr. Kowdley spoke at New Treatments in Chronic Liver Disease, held April 1-2, 2006, at La Jolla, CA, and sponsored by
Scripps Clinic. Dr Jonas spoke at the 11th Annual Postgraduate Course of the North American Society for Pediatric Gastroenterology,
Hepatology, and Nutrition, held October 20, 2005, in Salt Lake City, UT, and sponsored by The North American
Society for Pediatric Gastroenterology, Hepatology and Nutrition. The Audio-Digest Foundation thanks the speakers
and the sponsors for their cooperation in the production of this program.
|
