A PRACTICAL APPROACH TO PATIENTS WITH HEPATITIS B AND C
INFECTIONS
From the University of Miami Miller School of Medicine’s Advances in Medicine 2008
Eugene R. Schiff, MD, Leonard Miller Professor of Medicine, and Chief, Division of Hepatology, University of
Miami Miller School of Medicine, and Director, Schiff Liver Institute, Center for Liver Diseases, Miami, FL
| HEPATITIS B: DIAGNOSIS AND MANAGEMENT OF CHRONIC INFECTION
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| Introduction: most hepatitis B virus (HBV) seen among immigrants from endemic areas; virus transmitted
perinatally; ≈400 million infected worldwide; ≈2 million in United States
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| HBV DNA level and risk: risk for cirrhosis and hepatocellular carcinoma (HCC) increases with HBV
DNA level; cirrhosis need not be present for development of HCC; monitor patients indefinitely, regardless
of treatment
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| Treatment and HBV life cycle: blocking virus from entering hepatocyte preferable; once inside cell, HBV
generates covalently closed circular (CCC) DNA that is retained in nucleus and cannot be eradicated with
existing therapies; although patient develops HBV surface antibody (HbsAb) and HBV core antibody
(HbcAb), cancer chemotherapy can reactivate disease; sustained suppression of HBV DNA over ≈14 yr
may eliminate CCC DNA through hepatocyte turnover
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| Treatment strategies: assess patients for HBV e antigen (HbeAg) and HBV e antibody (HbeAb)
|
 | Seroconversion from HBV e antigen (HbeAg)-positive to (HbeAg)-negative: does not mean virus no
longer replicating; some patients remain inactive carriers
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| Inactive disease (histologically): HBV surface antigen (HbsAg) positive; alanine aminotransferase
(ALT) level normal; HBV DNA undetectable or very low; to be labeled “inactive carrier,” patient must
be followed for years; if patient becomes HbeAb-positive during therapy, treat for ≥1 yr longer (consolidation
treatment); ≈80% of patients remain HBV DNA negative (inactive carrier)
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| Active chronic disease: if patient HbeAg-negative, aim for negative HBV DNA; when therapy stops, relapse
occurs, so must treat indefinitely; loss of HbsAg—uncommon; associated with more durable response;
relapse unlikely
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| Interferon: use long-acting (once weekly) rather than daily therapy; not effective in majority of patients;
resistant mutations do not develop; because of low efficacy and side effects, used in <5% of patients
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| Lamivudine: robust; resistant mutations likely; inexpensive; required as initial therapy by some health
maintenance organizations (HMOs)
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| Adefovir: effective in lamivudine resistance; less robust; mutations develop
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| Entecavir: robust; low mutation rate in patients naive to therapy
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| Telbivudine: highly potent, ie, reduces HBV DNA quickly; mutation problem
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| Efficacy of oral agents: HbeAg-positive patients—rate of seroconversion to HbeAb within 1 yr ≈20%;
≈66% become HBV DNA-negative within 1 yr; when HBV DNA normalized, aminotransferases normalized,
and inflammation suppressed; HbeAg-negative patients—90% rendered HBV DNA-negative
within 1 yr
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| Durability of response (remaining HBV DNA-negative after therapy stopped): HbeAg-positive patients—
≈90%; HbeAg-negative patients—“notoriously relapse”
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| Development of resistance: interferons (absent); lamivudine monotherapy (≈75% at 4 yr); adefovir
(≈30% at 5 yr); entecavir (naive patients, <1% at 4 yr; in lamivudine-resistant patients, ≈40% at 4 yr);
telbivudine (HbeAg-positive and naive, 22% at 2 yr; HbeAg-negative, ≈9%)
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| Indications for treatment
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| HbeAg positive: HBV DNA and ALT elevated—entecavir or adefovir; telbivudine possible (monitor for
mutations); ALT normal (≈19 U/L in women; ≈29 U/L in men) and lower HBV DNA—significant underlying
liver disease often present; liver biopsy indicated; follow patient; interferon—more likely to be used in
young patient (genotype A or B) with relatively high ALT level (indicating antiviral response)
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| HbeAg negative: HBV DNA >2000 IU/mL; ALT elevated—long-term treatment expected; avoid drugs likely
to cause mutation; ALT normal—biopsy helpful; follow patient
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| Sustained suppression of HBV DNA: reversal of fibrosis occurs; early cirrhosis may be reversed
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| Cirrhosis present: combination therapy indicated
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| Preventing mutations: avoid serial monotherapy; add drug, do not switch; if using drug likely to produce
mutations, assess HBV DNA level at 24 wk (if negative, low chance of resistant mutation; when positive,
75% of patients had resistance at 29 mo); if using adefovir, assess HBV DNA level at 48 wk (if negative,
mutation unlikely); poor compliance—possible cause of high HBV DNA level; patients who
become HBV DNA-negative may stop treatment
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| Tenofovir: currently used for HIV infection; highly potent and less expensive than entecavir; early approval
for HBV infection expected; efficacy—HbeAg-positive patients (6 times more potent than adefovir
at 48 wk); equally effective in lamivudine-resistant and naive patients; HbeAg-negative patients
(90% HBV DNA negative at 48 wk)
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| Current recommendations: start with entecavir or adefovir; if using lamivudine or telbivudine, assess
HBV DNA level at 24 wk, then continue or add drug; interferon may be considered for young patient,
genotype A or B, with ALT ≥3 times upper limit of normal; for resistance to lamivudine or telbivudine,
add adefovir or tenofovir; for patients with cirrhosis, give combination therapy (tenofovir plus emtricitabine
[FTC]; Truvada)
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| HEPATITIS C: RECENT ADVANCES IN EFFECTIVE MANAGEMENT
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| Present situation: most infection acquired ≈30 yr ago; source of infection—primarily experimentation with
intravenous drugs (patients now in fifties); blood transfusion before 1992 (patients in sixties and seventies);
after 30 yr, chance of cirrhosis 30%; rate of developing cirrhosis accelerates after age 60 yr; cirrhosis confers
1.5% to 4% per year chance of HCC (epidemic now under way); monitor patients with cirrhosis
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| Goals of treatment: eradication of hepatitis C virus (HCV)—sustained viral response [SVR] equals cure; virus
undetectable 24 wk after stopping therapy; 99% of patients HCV-negative at 5-yr follow-up; if cirrhosis
has developed, risk for cancer persists (monitor twice yearly with ultrasonography and α-fetoprotein
test); HCV not eradicated—goal to suppress necroinflammation, ie, slow progression of cirrhosis
(study found maintenance interferon ineffective)
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| Treatment: combination of pegylated interferon with ribavirin; presence of steatosis leads to 50% lower
success rate; encourage weight loss before treating patients with body mass index (BMI) ≥30
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| Potential response: nonresponder (viral level remains same); partial responder (viral level reduced but
never negative); relapse after achieving negative viral level (almost always noncompliance)
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| Prevalence of HCV infection: ≈5 million in United States; 1 million diagnosed; 400,000 treated; 250,000
failed treatment; 150,000 successful; undiagnosed population—related to awareness of treatment side effects
and limited efficacy; once treatment with fewer side effects and greater success rate developed,
“they’ll come out of the woodwork”
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| Improving current therapy: achieving undetectable HCV level by wk 4 of treatment confers much better
chance of SVR; when these patients “miserable,” possible to reduce duration of therapy in genotype-1
patients normally treated 48 wk, but could be stopped after 24 wk; genotype 2 and 3 patients normally
treated 24 wk, but with rapid viral response, could be stopped after 14 wk (chance of SVR almost
same)
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| Slow responders: genotype 1; viral level reduced at 12 wk but patients remain HCV-positive; extending
treatment from 48 to 72 wk improves chance of SVR
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| Shorter-course therapy (study): genotype 2 and 3; of patients HCV-negative at wk 4, 85% achieved SVR
at 12 to 14 wk; if HCV remains positive at wk 4, treat for 24 wk (in genotype 3, only 50% attain
SVR; may require 48-wk course)
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| Genotype 1: ≈33% of patients have relatively low viral level; investigative findings—47% of patients
with viral DNA level <600,000 IU/mL became HCV-negative at 4 wk and ≈90% achieved SVR at
24 wk
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| Longer-course therapy (study): patients HCV-positive at 4 wk; negative at 24 wk; randomized to further
treatment for 48 or 72 wk; treatment for 72 wk yielded higher SVR rate than 48-wk course; ribavirin keeps
SVR rate high, primarily by reducing relapse rate
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| Newer therapies on horizon: polymerase and protease inhibitors specific for HCV expected within 5 to
10 yr; 3-drug combination may replace current therapy; protease inhibitor may also help reconstitute innate
immune response; include telaprevir and bocefovir (in phase 3 trials); desired properties—antiviral
activity against all genotypes; able to reach all infected cells (sequestered virus may explain relapse after
HCV negativity)
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| Depression: patient may be depressed about having serious illness; HCV infection itself may cause depression;
interferon therapy produces depression; spectrum of antidepressants used to treat (choice based
on whether patient hyperactive or lethargic)
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| Vaccine for HCV: currently, prospects not promising; expected to appear eventually
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| Sexual partners and risk for transmission: HBV infection—likely to be transmitted unless viral level
low; uninfected partner should be vaccinated; HCV infection—low risk for transmission; viremia much
lower than in HBV infection
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| Steatosis in HCV infection: in genotype 3 patients, eliminated when virus suppressed; obesity responsible
for nonalcoholic steatohepatitis (NASH); alcoholic steatohepatitis also possible; excessive alcohol
(“booze”) combined with NASH called BASH
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Suggested Reading
Castellares C et al: Liver cirrhosis in HIV-infected patients: prevalence, aetiology and clinical outcome. J
Viral Hepat 15:165, 2008; Chen CJ et al: Risk of hepatocellular carcinoma across a biological gradient of
serum hepatitis B virus DNA level. JAMA 295:65, 2006; Fried MW et al: HBeAg and hepatitis B virus
DNA as outcome predictors during therapy with peginterferon alfa-2a for HBeAg-positive chronic hepatitis
B. Hepatology 47:428, 2008; Fried MW et al: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus
infection. N Engl J Med 347:975, 2002; Gaeta GB et al: Therapy of chronic hepatitis B: focus on telbivudine.
Dig Liver Dis 39 Suppl 3:S372, 2007; Ganem D et al: Hepatitis B virus infection--natural history
and clinical consequences. N Engl J Med 350:1118, 2004; Hadziyannis SJ et al: Peginterferon-alpha2a and
ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin
dose. Ann Intern Med 140:346, 2004; Hui CK et al: Treatment of Hepatitis B e Antigen-negative Patients.
Curr Treat Options Gastroenterol 10:474, 2007; in: N Engl J Med 351:3512, 2004; Lai CL et al: Telbivudine
versus lamivudine in patients with chronic hepatitis B. N Engl J Med 357:2576, 2007; Loomba R et al:
Treatment of chronic hepatitis B. Antivir Ther12 Suppl 3:H33, 2007; Marcellin P et al: Peginterferon alfa-
2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis
B. N Engl J Med 351:1206, 2004; Matthews SJ: Telbivudine for the management of chronic hepatitis B virus
infection. Clin Ther 29:2635, 2007; Poynard T et al: Biochemical surrogate markers of liver fibrosis
and activity in a randomized trial of peginterferon alfa-2b and ribavirin. Hepatology 38:481, 2003; Poynard
T et al: Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected
with hepatitis C. Hepatology 38:75, 2003; Sangiovanni A et al: The natural history of compensated
cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 patients. Hepatology 43:1303, 2006; Yoo
BC et al: Clevudine is highly efficacious in hepatitis B e antigen-negative chronic hepatitis B with durable
off-therapy viral suppression. Hepatology 46:1041, 2007; Yoo BC et al: Twenty-four-week clevudine therapy
showed potent and sustained antiviral activity in HBeAg-positive chronic hepatitis B. Hepatology
45:1172, 2007; Yuen MF et al: Long-term lamivudine therapy reduces the risk of long-term complications
of chronic hepatitis B infection even in patients without advanced disease. Antivir Ther 12:1295, 2007;
Zeuzem S et al: Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with
chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol 44:97, 2006.
Educational Objectives
| The goal of this program is to enable internists to adopt new strategies for diagnosing and treating infection
with hepatitis B virus (HBV) and hepatitis C virus (HCV). After hearing and assimilating this program, the
clinician will be better able to:
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| 1. Determine the viral status of patients infected with HBV.
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| 2. Adopt the optimal treatment strategy for each stage of HBV infection.
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| 3. Identify the goals of therapy for HCV infection.
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| 4. Improve the implementation of current strategies for treating patients infected with HCV.
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| 5. Anticipate new therapies for more effectively managing HCV infection.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee
to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the following has been disclosed: Dr. Schiff—Boehringer Ingelheim (grant; research
support); Merck (scientific advisory board; grant; research support); Pfizer (scientific advisory board; data safety monitoring
board; grant; research support); Roche Molecular (scientific advisory board; grant; research support); Schering-Plough (data
safety monitoring board; grant; research support). The planning committee reported nothing to disclose.
Acknowledgements
Dr. Schiff was recorded at Advances in Medicine 2008, sponsored by the University of Miami Miller School of Medicine, and
held January 13-18, 2008, in Miami, FL. The Audio-Digest Foundation thanks Dr. Schiff and the sponsor for their cooperation in
the production of this program.
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