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© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
in the clinic
Hepatitis C
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
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© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
What factors increase the risk for HCV
infection?
 Percutaneous exposure to infected blood
 Remote or long-term injection drug
 Blood transfusion
 Tattoo or piercing with contaminated instruments
 Accidental needle-stick (health care workers)
 Reuse of needles and syringes
 Hemodialysis (U.S. rate of infection: 8.9%)
 Sexual intercourse with HCV-infected person
 Mother-to-child transmission
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
How can individuals, including those who
live with an infected individual, reduce risk?
 Avoid high-risk behaviors
 Treatment programs for support
 Needle-exchange programs
 Use condoms
 Advised for patients with multiple sex partners
 Don’t share razors, toothbrushes, nail clippers
 Follow infection control practices in health care setting
 Always use new needle and new syringe to access
medication from multidose vials
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
CLINICAL BOTTOM LINE: Prevention…
 Main risk factor for infection: percutaneous exposure
 Transfusion of blood products
 Injection drug use
 Hemodialysis
 Other risk factors: sexual transmission, mother-child
transmission
 To prevent infection, avoid high-risk behaviors
 Don’t share or reuse needles
 Use condoms
 Use infection control practices in health care settings
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
Who should clinicians screen for HCV infection?
 Those with risk factors
 Injection drug use (past or present)
 Receipt of clotting factor concentrates before 1987; or of
blood or blood components or solid-organ transplantation
before July 1992; or of blood from HCV-positive donor
 Long-term hemodialysis treatment
 Repeatedly elevated serum alanine transaminase levels
 Specific high-risk exposure to known HCV-positive blood
 Needle-sticks or other sharp exposure; mucosal exposure
 HIV infection
 Being the child of HCV-positive woman
 History of multiple sex partners or STDs
 Being born between 1945-1965 (new CDC recommendation)
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
What test should clinicians use for screening?
 Use ELISA to test for antibody to HCV
 Sensitivity 98.9%-100%
 Specificity 99.3%-100%
 (When performed with second- or third-generation assays)
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
CLINICAL BOTTOM LINE: Screening…
 Screen all persons with risk factors for HCV antibody
 Including anyone born from 1945 to 1965
 Use ELISA test for HCV antibody
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
What is the clinical spectrum of HCV infection?
 Acute infection
 Often asymptomatic or nonspecific: fatigue, nausea,
abdominal pain, flu-like
 Jaundice
 Acute liver failure uncommon
 Chronic infection (develops in 74%-86% over time)
 Symptoms: Fatigue, jaundice, lower-extremity edema,
ascites, altered mental status, GI bleeding
 Abnormal liver tests
 Cirrhosis, portal hypertension
 Hepatocellular carcinoma
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
Extrahepatic Manifestations
 Arthritis
 Porphyria cutanea tarda
 Leukocytoclastic vasculitis
 Lichen planus
 Raynaud phenomenon
 The sicca syndrome
 Idiopathic thrombocytopenic purpura
 Membranoproliferative glomerulonephritis
 Membranous nephropathy
 Hypo/hyperthyroidism
 Diabetes mellitus
 Essential mixed cryoglobulinemia
 Monoclonal gammopathy
 Non-Hodgkin lymphoma
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
What laboratory tests should clinicians use?
 Positive antibody to HCV on ELISA ?
 Measure HCV RNA by PCR to confirm chronic infection
 Note: quantitative viral load doesn’t predict HCV severity
(correlates poorly with hepatic histology)
 Considering therapy ?
 Obtain HCV genotype (affects Rx response, regimen, duration
 Most other liver function studies lack specificity
 Reserve other lab tests for those with evidence of cirrhosis or
extrahepatic manifestations of HCV
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
When should clinicians consider liver biopsy?
 Once infection confirmed with HCV RNA testing
 Identifies those most at risk for disease progression
 Moderate-to-severe fibrosis ? Consider treatment
 Minimal or no fibrosis ? May defer treatment
 Biopsy may show significant fibrosis even if alanine
aminotransferase levels normal
 Helps assess risk vs. benefit of treatment
 Limitations: sampling error + interobserver variability
 Repeatedly test hepatic histology over time (to lower
error rate and variability + estimate progression)
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
What other liver conditions have similar
clinical presentations?
 Differential diagnosis is broad
 Because symptoms & lab abnormalities nonspecific
 Consider HCV when any liver disease causes mild-tomoderate transaminase level elevations or cirrhosis
 Infection can occur in patients with other liver diseases
 Testing for hepatitis C may be warranted even when
alternative diagnosis seems secure
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
CLINICAL BOTTOM LINE: Diagnosis…
 Chronic HCV infection usually asymptomatic
 Liver function tests often abnormal
 Extrahepatic manifestations or portal hypertension or
hepatocellular carcinoma may be present
 To diagnose: Use ELISA to test for antibody to HCV
 To confirm: use PCR to measure HCV RNA
 Consider liver biopsy
 Evaluates degree of fibrosis
 Guides treatment decisions
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
Are lifestyle interventions helpful in the
management of hepatitis C infection?
 Abstain from alcohol
 Increased alcohol hastens development of cirrhosis in
HCV-infected individuals
 Avoid hepatotoxic drugs
 Normal doses of acetaminophen: not contraindicated
 Beware overdose thru heavy acetaminophen use
 Use care with NSAIDs, which are risky in cirrhosis
 Follow low-sodium diet (if cirrhosis and ascites present)
 Don’t restrict protein with cirrhosis (malnutrition risk)
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
Are complementary-alternative therapies
useful?
 Herbal remedies don’t improve the outcome of infection
 Avoid herbal remedies known to be hepatotoxic
 Chaparral
 Leaf germander
 Jin bu huan
 Mistletoe
 Pennyroyal
 Traditional Chinese herbs
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
When should clinicians consider drug therapy?
 If patient has no contraindications (see next slide) and…
 Compensated liver disease and
 Detectable serum HCV RNA
 Alternate strategy: track liver disease progression
 Biopsy every 3 to 5 years
 Both strategies have merit
 Given substantial side effects of drug treatment
 Weigh risk for decompensation of liver disease against
decreased Rx response in advanced fibrosis or cirrhosis
 Discuss risks & benefits of each strategy with patients
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
Contraindications to pegIFN and ribavirin Rx
 Uncontrolled major depression, particularly suicide attempts
 Autoimmune hepatitis or other autoimmune disorders
 Bone marrow, lung, heart, or kidney transplantation
 Severe hypertension, CHD, CHF, CVD, or other serious
nonliver disorders likely to reduce life expectancy
 Renal insufficiency
 Noncompliance with office visits or medications
 Decompensated cirrhosis or hepatocellular carcinoma
 Pregnancy or inability to practice birth control methods
 Severe anemia, thrombocytopenia, or granulocytopenia
Controversial contraindications: Active alcohol use, illicit drug use
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
How should clinicians choose from among
available treatment regimens?
 Backbone treatment for chronic HCV: pegIFN + ribavirin
 pegIFN: subcutaneous injections 1x/wk
 Ribavirin: by mouth in divided doses 2x/d
 Genotype determines regimen, duration, likely response
 Genotype 1
 Standard care now includes boceprevir / telaprevir
 Regimen improves response rate, reduces treatment time
 Genotypes 2 – 6
 PegIFN + ribavirin: 24 – 48 wks (depending on genotype)
 HIV co-infection
 Treat HCV if HIV status is stable (pegIFN-ribavirin only)
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
Which vaccinations should patients receive?
 Hepatitis A vaccine
 Ask about prior vaccination / exposure to hepatitis A
 Vaccinating empirically may be more cost-effective than
measuring for antibodies
 Hepatitis B vaccine
 Ask about prior vaccination / exposure to hepatitis B
 If no vaccination / exposure: measure anti-HBs
 If negative: administer HBV series
 Annual influenza vaccine
 Pneumococcal vaccine
 For all patients with cirrhosis, regardless treatment for HCV
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
What is appropriate clinical management for
patients with suboptimal response to therapy?
 Null response: <2-log reduction in HCV RNA by week 12 when
treated with interferon-α–based regimen
 Partial response: >2-log reduction by week 12, but detectable
 Relapse: undetectable at treatment end; detectable in follow-up
 Evaluate therapy
 Perform histologic examination of liver to guide treatment
 Genotype 1: if pegIFN-ribavirin regimen failed, retreat with
addition of protease inhibitor
if protease inhibitor failed, don’t try different one
(refer to hepatologist for alternative approaches)
 Genotype 2-6: if patient nonadherent, can try a 2nd course
re-treat if previous dosing was incorrect of if
inappropriate dose reductions occurred
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
What are the side effects of hepatitis C drugs?
Interferon
 Fatigue
 Flu-like syndrome
 Nausea and vomiting
 Headaches
 Low-grade fever
 Weight loss
 Irritability
 Depression
 Hair thinning
Ribavirin
 Hemolytic
anemia
 Fatigue
 Pruritus
 Rashes
 Cough, dyspnea,
bronchospasm
Boceprevir
 Anemia
 Dysgeuesia
 Injection site Irritation
 Bone marrow
suppression
Telaprevir
 Anemia
 Rash
 GI side effects
Uncommon side
effects: interferon
combination
 Autoimmune
thyroiditis
 Seizures
 Suicidal ideation
or attempts
 Retinopathy
 Sepsis
 Myocardial
infarction
 Pulmonary
fibrosis
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
How can the side effects be managed?
 Anemia: reduce ribavirin dose
 Thrombocytopenia: try thrombopoietin-receptor
agonists
 Be alert to possible hepatotoxity, thromboembolic
complications
 Don’t reduce or interrupt protease inhibitors
 Risk for viral resistance
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
How should clinicians evaluate the
response to therapy?
 Baseline: Assess HCV RNA titers at initiation of therapy
 Goal: Undetectable viral load for 6 mos after therapy end (SVR)
Genotype 1
 Boceprevir + pegIFN-ribavirin: assess titers @ 8, 12, 24 weeks
 >100 IU/mL at week 12 or detectable at week 24: stop Rx
 Undetectable at week 8 & 24: ? shorten course of therapy
 Prior null responders: treat 48 weeks regardless response
 Telaprevir + pegIFN-ribavirin: assess titers @ 4, 12, 24 weeks
 >1000 IU/mL at week 4 & 12 or detectable at 24: stop Rx
 Undetectable at week 4 & 12: treat 24 weeks if no cirrhosis
and treatment-naïve, or if patient previously relapsed
 With cirrhosis, prior partial responders or nonresponders:
treat for full 48 weeks
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
Genotypes 2 - 3
 Assess titers after week 24 of pegIFN-ribavirin therapy
 Consider assessing at week 12:
 Early virologic response: ≥2-log reduction in titers
 If patients don’t achieve, discontinue Rx
 If patients do achieve, then titers should be undetectable
by 24 weeks (if not, halt treatment)
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
Are there other drug regimens with
documented effectiveness?
 Interferon-free regimens
 Would be revolutionary advance in treatment
 Studies still needed (? best combination, duration)
 Concern: relapse after completion of therapy
 ? Delay treatment for mild disease until newer drug
combinations available
 Especially significant for regimens w/o pegIFN
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
Is it possible to cure hepatitis C infection?
 Cure = SVR to interferon-based therapies ≥2 years
 Relapse still possible but unlikely
 SVR associated with decreased liver-related morbidity and
mortality
 Note: Patients can be re-infected after successful treatment
(antibody isn’t protective)
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
When is liver transplantation indicated?
 Model for End-Stage Liver Disease (MELD) score ≥10
or
 First major portal hypertension complication occurs
 Ascites, hepatic encephalopathy, variceal bleeding
or
 Hepatocellular carcinoma
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
What is the risk for hepatocellular carcinoma?
 Occurrence: 3% per year after development of cirrhosis
 Surveillance: ultrasonography every 6 months
 Serum α-fetoprotein no longer recommended
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
When is specialty consultation indicated?
 Hepatologist or infectious disease specialist
 To distinguish HCV infection from other liver diseases
 To determine need for liver biopsy
 To guide next step if nonresponse to pegIFN-α - ribavirin
 To evaluate for liver transplantation
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
CLINICAL BOTTOM LINE: Treatment…
 Individualize decisions on treatment based on…
 Stage of disease
 Clinical and lab evaluation
 Patient preference; any Rx contraindications
 Standard treatment: pegIFN-α and ribavirin
 Genotype determines dose & duration
 For patients with genotype 1: boceprevir or telaprevir
approved for addition to the treatment regimen
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.