HEPATITIS
| HEPATITIS C—Emmet B. Keeffe, MD, Professor of Medicine, Chief of Hepatology, and Co-Director of Liver Transplant
Program, Stanford University Medical Center, Palo Alto, California
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| Factors that increase progression of hepatitis C: >4 alcoholic beverages/day; age >40 yr; male sex; progression not linear,
ie, after 50 yr of age, rate of progression of fibrosis more rapid; active inflammation and steatosis; coinfection with
another virus
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| Diagnosis: screen high-risk groups; obtain complete blood count (CBC), paying attention to platelet count (if low, fibrosis
advanced); quantitative hepatitis C virus (HCV) ribonucleic acid (RNA; factor in predicting success of therapy); check
for high viral load (present in two thirds of US patients); viral genotype—US population ≈74% genotype 1 (biopsy indicated);
speaker does not biopsy patients with genotypes 2 and 3 because rate of treatment success high; other diagnostic
tests—obtain ultrasonography and α-fetoprotein for baseline, then repeat for screening if cirrhosis present; assess for
other viral infections that may be present based on risk behaviors
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| Evolution of therapy: little enthusiasm for interferon alfa-2b when licensed because of poor sustained virologic response
(SVR) rates; better with 1 yr of therapy; big jump forward by adding ribavirin to interferon therapy; greater advance with
current therapy, ie, pegylated interferon (peginterferon) plus ribavirin; ≈50% of patients do not respond
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| Indications for therapy based on National Institutes of Health (NIH) consensus conference: reactive antibody; confirmed
viremia with HCV RNA; compensated liver disease; elevated alanine aminotransferase (ALT); significant disease
on biopsy (stage 2 fibrosis); absence of contraindications; NIH comment that all patients with chronic HCV potential
candidates for therapy
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| Factors predicting successful treatment: genotype dominant predictor; other factors can modify outcome of antiviral therapy;
low viral load; lesser degrees of fibrosis; non-black ethnicity (reason unknown); lean body mass; young age; adherence
to therapy (80% of medication taken 80% of time); early virologic response (viral load drops ≥2 logs at week 12 of therapy);
predictors support early therapy
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| Response rates: overall rate 54% to 63% in published trials of peginterferon alfa-2a and alfa-2b; for genotype 1, range 42% to
52%, lower with high viral load (50% of US population); response rates higher for genotypes 2 and 3; optimal response rate occurs
in genotype 1 patients at 1 yr of therapy with 1000 or 1200 mg ribavirin (based on weight); for genotypes 2 and 3, equally
successful response at 800 mg of ribavirin and 24 wk of therapy
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| Predictability: at 12 wk in genotype 1 patients, if HCV RNA decreases 2 logs, patient has 72% or 65% chance of developing
SVR (depending on type of interferon); 26% and 14% of patients do not have 2-log decrease in viral load, and of
these, 0% to 3% go on to achieve SVR; so stopping therapy at 12 wk avoids extra cost and toxicity
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| Outcomes in blacks: 2 studies reported peginterferon alfa-2b plus ribavirin had 52% and 39% SVR rate vs 19% and 26%
in peginterferon alfa-2a plus ribavirin; another study shows 2-fold reduction in SVR rate in blacks; counsel patients about
lower response rate before therapy
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| Shorter therapy for genotypes 2 and 3: studies looked at 12-, 14-, and 16-wk duration of therapy; patients who are virus-
negative at 4 wk probably can get along with shorter duration of therapy, ie, 12 wk rather than 24 wk; saves toxicity, cost,
and has better compliance
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| Genotype 1 patients: study looked at treating patients for 48 vs 72 wk; showed lower relapse rate and higher SVR rate with
72 wk of therapy; second study showed lower relapse rate with longer therapy but no difference in SVR rate; retrospective
analysis shows 24-wk median time to undetectable virus in patients with genotype 1; 90% probability of SVR if
HCV RNA undetectable during 36 wk of therapy; appears total duration of therapy while virus undetectable may predict
SVR rate
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| Impact of antiviral therapy on long-term natural history: 5% have relapse within 2 yr of completion of therapy, no relapse
after 2 yr; slowed progression of fibrosis; early cirrhosis shown to be reversible; lower likelihood of liver cancer
with antiviral therapy, particularly when SVR present; increased life expectancy (all-cause as well as liver-related)
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| Special populations: normal ALT—study demonstrated that these patients do respond to antiviral therapy (52% achieved
SVR); advanced fibrosis—41% SVR rate in patients with bridging fibrosis or cirrhosis; decompensation—
controversial area; according to expert opinion, patients with Child-Pugh score A or low Model for End-stage Liver Disease
(MELD) score are potential candidates for therapy; some Child’s B patients candidates for therapy
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| Nonresponders: treat with different/more effective regimen; base decision to treat on presence of advanced fibrosis, favorable
response, and whether patient tolerated therapy in past; largest study showed all factors predicting success for first
course of therapy also predicted success for second course; current studies looking at how to treat patients who have
failed peginterferon plus ribavirin
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| Maintenance therapy: studies looking at treating patients with smaller doses of peginterferon alone for 3.5 to 4 yr; subject
of debate; some think maintenance therapy remains experimental, others think it can be incorporated into routine practice;
if used, patient should have advanced fibrosis, no decompensation, decrease in viral load (ideally, patient has tolerated
peginterferon before); do not know dose or how long to use it
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 | Three coinfection trials: treated with peginterferon 2a or 2b; overall SVR rates 27% to 40%; genotypes predictive; genotypes
2 and 3 responded favorably; acceptable toxicity, including patients on antiretroviral therapy
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| Hepatocellular carcinoma (HCC) and hepatitis B: new data on risk based on active replication of hepatitis B virus
(HBV); 60-fold relative risk in patients who are HBV e antigen (HBeAg) positive compared to those that were HBeAg
negative; found relationship between HBV DNA level and development of liver cancer; hypothesis that we can prevent
long-term outcomes of hepatitis B by suppressing HBV DNA; preliminary reports looking at single baseline HBV DNA
level and liver disease progression; those with high levels of HBV DNA at baseline and follow-up had highest risk for
progression to cirrhosis or liver cancer
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| Variants of virus: wild type—HBeAg positive early in course of disease; spontaneous mutations—pre-core (27%) and
core-promoter mutation (44%); these abolish HBeAg production; referred to as HBeAg-negative chronic hepatitis B; treatment-induced
mutations—YMDD mutations occur with lamivudine (20%/yr), N236T and A181V point mutations occur
with adefovir (0% at yr 1, 2% at yr 2, 7% yr 3, 15% at yr 4); genotypes—in United States, see mostly genotypes A, B, C, and
D; B and C more common in Americans of Asian descent; A and D more common in Americans from western and southern
Europe; in Asian population, genotype B favorable because it produces less active disease, slower progression, and lower incidence
of HCC; genotypes can predict response to antiviral therapy with interferon or peginterferon, not with oral agents;
genotype A responds most favorably to peginterferon; tests to determine genotype now comercially available
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| Phases of infection: early immune tolerance—body does not recognize virus as foreign; HBeAg positive; have high
HBV DNA, but ALT levels persistently normal; on biopsy, patients have normal histology or very mild nonspecific
changes; chronic hepatitis B or immune active or immune clearance phase—may be HBeAg positive for wild type or
HBeAg negative with either pre-core or core-promoter mutant; have elevated ALT level; may have brief immune active
phase and proceed to inactive carrier state (characterized by low HBV DNA [<104 and normal ALT level]); candidates
for therapy have high HBV DNA level and high ALT
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| Goals of treatment: prevent long-term outcomes (ie, cirrhosis, liver cancer, and death) by durable suppression of HBV
DNA; monitor HBV DNA, ALT, and look for HBeAg loss and hepatitis B surface antigen (HBsAg) loss; HBsAg loss
occurs with low frequency with oral agents (1.5%-3.0%), higher frequency (4%-7%) with interferon therapy
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| For HBeAg-positive patients: goal to achieve HBeAg loss (seroconversion); reduce DNA to low level; normalize ALT; if
these goals achieved and therapy stopped, durability ≈80%
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| For HBeAg-negative patients: keep DNA low; normalize ALT; relapse common; long-term therapy has become rule
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| Licensed drugs in United States: interferon alfa-2b (Intron A), lamivudine (Epivir), adefovir (Hepsera), entecavir (Baraclude),
peginterferon alfa-2a (Pegasys)
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| One-year data: HBeAg-positive patients—seroconversion 12% with adefovir, ≈18% with interferon and lamivudine (increases
to 20%-40% response rate when treated with oral agents for 2 and 3 yr); HBeAg-negative patients —loss of
HBV DNA in 50% to 70%; best results achieved with 1 yr of therapy with interferon alfa-2b; when therapy
stopped—80% to 90% have durable response with interferon, 50% to 80% with lamivudine; 91% of patients on adefovir
have durable response when therapy discontinued; drug resistance absent with interferon, high with lamivudine,
and relatively low with adefovir
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| Entecavir and peginterferon alfa-2a: at 1 yr, 21% response rate for entecavir for HBeAg seroconversion, 27% with
peginterferon; durability of response 82% 24 wk after discontinuing entecavair, ≈80% after stopping Pegasys; no drug
resistance with entecavir after 2 yr of monotherapy, however, 7% likelihood of developing new novel mutations using
entecavir in lamivudine-resistant patients (none using peginterferon)
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| Log drops: mean log drop of HBV DNA 5.2 to 6.9 for entecavir, 4.6 to 5.46 for lamivudine, 3.57 to 3.65 for adefovir
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| Study of HBeAg-positive patients: hypothesis that patients would do better using interferon that operates on one mechanism
and nucleoside analogue that acts on another; used peginterferon alfa-2a alone, peginterferon alfa-2a plus lamivudine,
and lamivudine alone; no difference in outcomes in all groups after 1 yr of therapy with 24 wk follow-up;
peginterferon alfa-2a alone and peginterferon alfa-2a plus lamivudine had better DNA levels than lamivudine alone
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| Study of HBeAg-negative patients: no difference between peginterferon plus lamivudine compared to peginterferon
alone; peginterferon better than lamivudine
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| Asian long-term lamivudine trial: patients had to have compensated cirrhosis or bridging fibrosis; patients randomized
to lamivudine 100 mg/day or placebo; study discontinued in <3 yr because of favorable results in patients treated with
lamivudine
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| Adefovir data: HBeAg-negative patients given 10 mg/day and followed for 3 yr; HBV DNA <1000 copies/mL, and ALT
normalization increased each year; at 3 yr, biopsies showed improved fibrosis more likely than worsened fibrosis; same
shown with HBeAg-positive patients
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| Resistance: lower likelihood of resistance with adefovir than with lamivudine; can add adefovir when lamivudine resistance
present; patients with adefovir resistance respond to lamivudine therapy; achieve lower rate of resistance by giving
lamivudine and adefovir together, but no added efficacy; no mutations at 1 or 2 yr in nucleoside-naive patients on entecavir,
but using entecavir in previously lamivudine-resistant patients leads to induction of novel mutations
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| Guidelines for treating HBV from 3 major liver societies: check ALT and DNA levels; if ALT <2 times upper limits of
normal, monitor patient but give no treatment; if ALT slightly elevated, biopsy may help sort out who to treat; one society
recommends treating patients with high ALT and DNA >105 copies/mL, however, others say to wait 3 to 6 mo because
patient may have spontaneous seroconversion and not need treatment; for HBeAg-negative population, DNA and
ALT often fluctuate, but treat if DNA >105 copies/mL and ALT high; if levels in grey area, monitor patient or do biopsy,
or send to referral laboratory to test for pre-core mutations
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| Speaker’s algorithm: genotype should be used if any consideration for interferon therapy; peginterferon will supplant
standard interferon; adefovir and entecavir are preferred over lamivudine because of high rate of resistance; treatment criteria
similar to societies’, except 105 copies/mL adequate to treat and 104 copies/mL adequate to treat HBeAg-negative
patients; ALT does not have to be 2-fold normal; do not have to wait 3 to 6 mo to start therapy; patients with cirrhosis
should be treated with oral agent
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| UNDERSTANDING AND TREATING NONVIRAL CAUSES OF CHRONIC HEPATITIS —Sammy Saab, MD, MPH,
Assistant Professor of Medicine and Surgery, the David Geffen School of Medicine at the University of California, Los Angeles
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| Aminotransferases: must determine whether elevated aminotransferases coming from liver or somewhere else; consider nonhepatic
causes if only AST elevated; if elevations due to liver disease, exclude HBV and HCV; if patient negative for hepatitis,
consider autoantibodies, Wilson’s disease, iron overload, α1 antitrypsin deficiency, fatty liver, and medications
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| Hemochromatosis: concentrated in people of northern European origin; most common genetic disorder seen in practice;
significant cause of liver cancer; therapy is phlebotomy (can normalize life expectancy); mutation tells body to store iron
inappropriately; takes ≈4 decades to reach toxic levels; makes little sense to screen patients <20 yr of age; iron levels
must be checked in fasting state; consider other liver diseases if patient not homozygous for gene; HCV and alcoholic
disease can lead to high iron saturation levels and high ferritin; tell patients to avoid vitamin C supplements (facilitate
iron absorption)
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| Autoimmune hepatitis: inflammation of liver of unknown cause; characterized by interface hepatitis, elevated γ-globulin
levels, and autoantibodies; women affected more than men by 4:1; all ages and ethnic groups susceptible; at presentation,
80% have high γ-globulin, 50% have jaundice, and 25% have cirrhosis; elevated liver enzymes or severe damage on liver
biopsy absolute indication for treatment; symptomatic conditions with fatigue, joint pain or jaundice are relative indications;
use prednisone alone or with azathioprine
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Educational Objectives
| The goal of this program is to educate the listener about hepatitis. After hearing and assimilating this program, the clinician
will be better able to:
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| 1. State the factors that increase the progression of hepatitis C.
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| 2. List the indications for treatment of hepatitis C according to the National Institutes of Health (NIH) consensus conference.
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| 3. Describe the factors predicting the likelihood of successful treatment of a patient with hepatitis C.
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| 4. Name and describe the various virus types of hepatitis B .
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| 5. Discuss the efficacy of various agents for treatment of hepatitis B.
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Discussed on This Program
Adefovir dipivoxil [Hepsera]
Azathioprine (AZA) [Imuran]
Entecavir [Baraclude]
Interferon alfa-2a, recombinant (rIFN-A; IFLrA) [Roferon-A]
Interferon alfa-2b (recombinant) (IFN-alpha 2; rIFN-⓬ α-2-interferon) [Intron A]
Lamivudine (3TC) [Epivir, Epivir-HBV]
Peginterferon alfa-2a [Pegasys]
Peginterferon alfa-2a with ribavirin [Copegus]
Peginterferon alfa-2b [PEG-Intron, Redipen]
Prednisone (many trade names)
Ribavirin [component of Copegus; Rebetol, Virazole]
Programs of Related Interest
Angelino AF: HCV and the mind. Audio-Digest Gastroenterology 18:11(Nov 1), 2004; Chapman WG et al: Issues in
hepatobiliary disease. Audio-Digest General Surgery 51:23(Dec 7), 2004; Lee W: Topics in hepatology. Audio-Digest
Family Practice 53:06(Feb 14), 2005; Navorro VJ et al: Hepatitides. Audio-Digest Gastroenterology 18:06(Jun 1),
2004.
To Order, Contact Subscriber Service (1-800-423-2308)
Suggested Reading
Khattab E et al: Analysis of HCV co-infection with occult hepatitis B virus in patients undergoing IFN therapy. J Clin Virol
33:150, 2005; Marotta F et al: The pathogenesis of hepatocellular carcinoma is multifactorial event. Novel immunological
treatment in prospect. Clin Ter 155:187, 2004; Mo H et al: Mutations conferring resistance to a hepatitis C virus
(HCV) RNA-dependent RNA polymerase inhibitor alone or in combination with an HCV serine protease inhibitor in vitro.
Antimicrob Agents Chemother 49:4305, 2005; Peng J et al: Inhibition of hepatitis B virus replication by various RNAi
constructs and their pharmacodynamic properties. J Gen Virol 86:3227, 2005; Rivkin A: A review of entecavir in the treatment
of chronic hepatitis B infection. Curr Med Res Opin 21:1845, 2005; Sharma YR et al: A study on efficacy of lamivudine
therapy in decompensated cirrhosis of liver due to chronic hepatitis B virus infection. Nepal Med Coll J 6:106,
2004; Sominskaya I et al: Hepatitis B and C virus variants in long-term immunosuppressed renal transplant patients in
Latvia. Intervirology 48:192, 2005; Soriano V et al: Complications in treating chronic hepatitis B in patients with HIV.
Expert Opin Pharmacother 6:2831, 2005; Watashi K et al: Current approaches for developing new anti-HCV agents and
analyses of HCV replication using anti-HCV agents. Uirusu 55:105, 2005; Windisch MP et al: Dissecting the interferon-
induced inhibition of hepatitis C virus replication by using a novel host cell line. J Virol 79:13778, 2005.
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, the speakers reported
no conflict.
Dr. Keeffe was recorded September 17, 2005, in Houston, at the 30th Annual Texas Program, sponsored by the Texas Society
for Gastroenterology and Endoscopy, the American College of Gastroenterology, and the Texas Regional Societies;
Dr. Saab, February 19, 2005, in Beverly Hills, California, at Update 2005: Gastroenterology and Hepatology for the
Primary Care Physician, sponsored by the Division of Digestive Diseases and the Office of Continuing Medical Education,
the David Geffen School of Medicine at the University of California, Los Angeles. The Audio-Digest Foundation
thanks the speakers and the sponsors for their cooperation in the production of this program.
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