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Hepatitis C
Christopher Lin-Brande, MD
Amy M. Davis, MD
Krunal Patel, MD
image BASICS
DESCRIPTION
Systemic viral infection (acute and chronic) primarily involving liver
EPIDEMIOLOGY
  • Highest incidence ages 20 to 39; highest prevalence ages 40 to 59
  • Males and non-Hispanic blacks more likely to be infected (1).
Geriatric Considerations
Age >60 years less likely to respond to therapy; treat earlier if able.
Pregnancy Considerations
  • Routine HCV testing is not indicated.
  • Vertical transmission occurs in 6 of every 100 births in HCV-positive mothers; risk increases 2 to 3 times if HIV coinfection.
  • Breastfeeding is safe if no fissures.
Pediatric Considerations
  • Prevalence: 0.3%
  • Test children born to HCV-positive mothers with HCV Ab after 18 months or HCV RNA at 1 to 2 months for early diagnosis.
  • Fewer symptoms; fewer abnormal liver tests; more likely to clear spontaneously; slower rate of progression
Incidence
In 2013, CDC estimated there were 29,718 total new cases of hepatitis C. 2,138 of these were new acute cases.
Prevalence
  • ˜3.6 million in the United States (1.3%) are HCV Ab-positive.
  • Prevalence is highest in persons born between 1945 and 1965 (2.6%) (1).
  • 2.7 million have chronic HCV (HCV RNA-positive).
  • HCV-related deaths are more common than HIV-related deaths.
  • Most common cause of chronic liver disease and transplantation in the United States
  • Six genotypes (GT) were known. GT 1 is predominant form in the United States (75%). GT does not change during infection and predicts response to treatment.
ETIOLOGY AND PATHOPHYSIOLOGY
Single-stranded RNA virus of Flaviviridae family
RISK FACTORS
  • Exposure risks
    • Chronic hemodialysis
    • Blood/blood product transfusion or organ transplantation before July 1992
    • Hemophilia treatment before 1987
    • Household or health care-related exposure to HCV-infected body fluids (1.8% risk)
    • Children born to HCV-positive mothers
    • Adults born between 1945 and 1965
  • Risk behaviors and/or medical conditions
    • Prior history of injection drug use
    • Intranasal illicit drug use
    • History of incarceration
    • Tattooing in unregulated settings
    • Current sexual partners of HCV-positive persons
    • HIV and hepatitis B infection
GENERAL PREVENTION
  • Primary prevention
    • Do not share razors/toothbrushes/nail clippers.
    • Use and dispose needles properly through harmreduction programs.
    • Practice safer sex.
    • Cover cuts and sores.
  • Secondary prevention
    • No vaccine or postexposure prophylaxis available
    • Substance abuse treatment
    • Reinforce use of barrier contraception for HIV-seropositive coinfected with HCV.
    • Assess for degree of liver fibrosis/cirrhosis.
COMMONLY ASSOCIATED CONDITIONS
Diabetes, metabolic syndrome, iron overload, depression, substance abuse/recovery, autoimmune and hematologic disease, HIV, and hepatitis B coinfection
image DIAGNOSIS
PHYSICAL EXAM
  • Typically normal unless advanced fibrosis/cirrhosis
  • May have right upper quadrant (RUQ) tenderness/hepatomegaly
  • General signs of chronic liver disease: spider angioma, caput medusa, palmar erythema, jaundice, gynecomastia, Terry nails, ascites
  • Extrahepatic manifestations: arthralgias/myalgias, neuropathy, glomerulonephritis, livedo reticularis, lichen planus, pruritus, sicca syndrome, cold agglutinin disease
DIFFERENTIAL DIAGNOSIS
Hepatitis A or B; Epstein-Barr virus (EBV), cytomegalovirus (CMV); alcoholic hepatitis; nonalcoholic steatohepatitis (NASH); hemochromatosis; Wilson disease, &agr;1-antitrypsin deficiency; ischemic, drug-induced, or autoimmune hepatitis
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Screening is recommended for adults born between 1945 and 1965, anyone with exposure risks, current and former IV drug users, HIV-positive individuals, especially men who have sex with men (MSM) and patients with persistently elevated ALT.
  • CDC algorithm
    • HCV Ab
      • If nonreactive, no further action unless recent exposure is suspected (HCV RNA).
      • If reactive, test HCV RNA and genotype.
    • HCV RNA
      • If not detected, no current HCV infection. No further action in most cases but can repeat either test if recent exposure suspected
      • If detected, that there is current HCV infection, counsel and treat.
  • HCV Ab can be detected 4 to 10 weeks after infection.
  • HCV RNA can be detected 2 to 3 weeks after infection.
  • RNA detectability precedes ALT elevation.
  • AST/ALT: often normal but may be persistently elevated in chronic HCV; ALT usually is 1 to 2 times upper limit of normal; AST may be normal/elevated, but typically less so than ALT.
    • Acute hepatitis C can cause elevation of transaminases and bilirubin (direct and indirect).
  • AST/ALT ratio ≥1 associated with cirrhosis
    • If AST/ALT ratio >2, rule out alcohol abuse.
  • Persistent HCV RNA >6 months = chronic HCV
Follow-Up Tests & Special Considerations
  • Platelets, creatinine, TSH, vitamin D (may predict treatment response)
  • Liver function panel, coagulation factors
  • HCV GT
  • IL28B testing: C/C homozygote more likely to clear
  • HBV (hepatitis panel) and HIV coinfection
  • Vaccinate if seronegative for hepatitis A/B.
  • Pneumococcal polysaccharide vaccine (PPSV23)
Diagnostic Procedures/Other
Evaluate for advanced hepatic fibrosis.
  • Indirect markers: AST-to-platelet ratio index (APRI), FIB-4, FibroIndex, Forns index, HepaScore/FibroScore, FibroSure
    • Factors such as age, gender, AST, ALT, platelets, bilirubin, estimate fibrosis.
  • Direct markers: FIBROSpect II
  • Liver imaging: US, CT scan, MRI, transient ultrasound elastography, MR elastography
  • Liver biopsy (gold standard)
    • Indications: discordant indirect marker results, concurrent non-HCV liver disease, elastography not available
    • Not necessary to diagnose hepatocellular carcinoma if diagnosis is clear based on imaging
Test Interpretation
  • Biopsy measures grade (degree of inflammation) and stage (amount of existing fibrosis)
  • Scoring systems: Batts and Ludwig, METAVIR, International Association for the Study of the Liver (IASL)
image TREATMENT
GENERAL MEASURES
  • Report acute cases of HCV to health department.
  • Consider treating all patients with virologic evidence of HCV.
  • Pretreatment counseling should include thorough behavioral health and substance abuse history.
  • Optimize medical therapy for comorbid conditions prior to treatment.
  • Discuss treatment plan and likelihood of success based on individual factors such as BMI, genotype, race, stage of fibrosis, and viral load.
  • Treatment evolution of HCV (2)
    • Pegylated-interferon (PEG) plus ribavirin (RBV) regimens in the 1990s: ˜50% cure (may still be used for directly-acting antiviral agent [DAA] nonresponders)
    • Combination PEG/RBV plus DAA in early 2000s: ˜75% cure
    • All-oral DAAs in the last 4 years: >95% cure
  • New therapies increasingly all-oral, including DAAs and host-targeting antiviral agents (HTAs)
  • Goal is sustained virologic response (SVR): undetectable HCV RNA after 12 to 24 weeks of treatment.
  • HCV cascade: Of those with chronic HCV, only 50% are diagnosed, 25% are HCV RNA confirmed, 15% are prescribed treatment, and 10% achieve SVR (3).
P.471

MEDICATION
First Line
Acute HCV: Treatment may be delayed 12 to 16 weeks after suspected inoculation to allow chance for spontaneous clearance. Regimen is same as for chronic HCV.

Genotype

Drug Regimen

1aa

Ledipasvir/sofosbuvir (Harvoni) for 12 weeks

Ombitasvir/paritaprevir/ritonavir plus dasabuvir (Viekira Pak) and weight-based RBV (Rebetol) for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis)

Sofosbuvir (Sovaldi) plus simeprevir (Olysio) with or without weight-based RBV for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis)

1ba

Ledipasvir/sofosbuvir for 12 weeks

Ombitasvir/paritaprevir/ritonavir plus dasabuvir for 12 weeks (no cirrhosis) or with the addition of weight-based RBV for 24 weeks (cirrhosis)

Sofosbuvir plus simeprevir for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis)

2

Sofosbuvir plus weight-based RBV for 12 weeks (no cirrhosis) or for 16 weeks (cirrhosis)

3

Sofosbuvir plus weight-based RBV for 24 weeks

4a

Ledipasvir/sofosbuvir for 12 weeks

Ombitasvir/paritaprevir/ritonavir plus dasabuvir and weight-based RBV for 12 weeks

Sofosbuvir plus weight-based RBV for 24 weeks

5

Sofosbuvir plus pegylated interferon plus weight-based RBV for 12 weeks

6

Ledipasvir/sofosbuvir for 12 weeks

AASLD, American Association for the Study of Liver Diseases; RBV, ribavirin.

a Three options with similar effectiveness.

ISSUES FOR REFERRAL
  • Involve a physician experienced with HCV therapy in all cases.
  • Refer to liver transplant program if fulminant acute hepatitis, at first complication of end-stage disease, MELD score ≥12 or at diagnosis of HCC.
COMPLEMENTARY & ALTERNATIVE MEDICINE
No evidence for effective complementary therapy in HCV/cirrhosis/HCC. Milk thistle (silymarin) safe; may reduce ALT, does not eradicate virus or improve outcomes; avoid on IFN.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
  • Treat early to prevent fibrosis. If cirrhosis is already present, treatment may not prevent decompensation.
  • If treatment is deferred, screen patients with annual LFTs, monitor for disease progression, and maintain sobriety (if alcohol dependence involved).
  • Monitor serial viral load only if on antiviral therapy.
  • Abdominal ultrasound every 6 to 12 months to monitor for hepatocellular carcinoma (expert opinion). AFP is no longer in AASLD guidelines.
Patient Monitoring
  • Serial ALT/AST; fasting glucose and CBCs
  • Follow electrolytes, thyroid-stimulating hormone (TSH), renal function, PT.
  • For 12-week course, follow-up 4 weeks after starting therapy and 12 weeks after completing therapy
    • 4-week HCV RNA: If detectable, recheck at week 6. If RNA has increased >10 times, stop therapy.
    • SVR12: Undetectable HCV RNA 12 weeks after completing therapy generally translates to long-term cure (goal of therapy).
  • SVR decreases risk of portal hypertension, hepatic decompensation, and hepatocellular carcinoma (HCC). Monitor for decompensation (low albumin, ascites, encephalopathy, GI bleed).
DIET
  • Low-fat, high-fiber diet and exercise to treat obesity/fatty liver
  • Extra protein and fluids while on IFN therapy
PATIENT EDUCATION
  • Avoid alcohol, tobacco, and illicit drugs (including marijuana); refer to rehabilitation/12-step program and monitor for relapse as appropriate.
  • Warn against claims of false cures.
  • Caution with nutritional supplements and hepatotoxic medications (may contain hepatotoxins)
  • http://www.cdc.gov/knowmorehepatitis/
PROGNOSIS
  • For every 100 persons infected with HCV
    • 75 to 85 will develop chronic infection.
    • 60 to 70 will develop chronic liver disease.
    • 10 to 20 will develop cirrhosis over 20 to 30 years (more rapid if older age at infection, male gender, alcohol/substance abuse, HIV/HBV coinfection, or diabetes/insulin resistance).
      • 1-5% annual risk of HCC
      • 3-6% annual risk of hepatic decompensation
  • Chronic HCV is curable in ˜70% of cases; in noncirrhotic genotype 2 or 3, cure rate is ˜90%.
REFERENCES
1. Denniston MM, Jiles RB, Drobeniuc J, et al. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med. 2014;160(5): 293-300.
2. Lange CM, Jacobson IM, Rice CM, et al. Emerging therapies for the treatment of hepatitis C. EMBO Mol Med. 2014;6(1):4-15.
3. Yehia BR, Schranz AJ, Umscheid CA, et al. The treatment cascade for chronic hepatitis C virus infection in the United States: a systematic review and meta-analysis. PLoS One. 2014;9(7):e101554.
Additional Reading
&NA;
  • American Association for the Study of Liver Diseases. HCV guidelines: recommendations for testing, managing, and treating hepatitis c. http://www.hcvguidelines.org/
  • Centers for Disease Control and Prevention. Viral hepatitis—hepatitis c information. http://www.cdc.gov/hepatitis/hcv/
See Also
&NA;
Hepatitis A; Hepatitis B; Cirrhosis of the Liver; HIV/AIDS
Codes
&NA;
ICD10
  • B19.20 Unspecified viral hepatitis C without hepatic coma
  • B17.10 Acute hepatitis C without hepatic coma
  • B18.2 Chronic viral hepatitis C
Clinical Pearls
&NA;
  • 1 of every 10 patients with hepatitis C has no identifiable risk factors.
  • 15-25% of HCV-infected persons spontaneously resolve infection without specific treatment.
  • Look for coinfections (HBV/HIV) and comorbid substance abuse in patients infected with HCV.