Recommendations for the diagnosis and treatment of patients with Hepatitis C virus (HCV) infection

Diagnosis of HCV Infection

1. The presence of anti-HCV by second generation ELISA, and...
2. Confirmation with HCV RNA by polymerase chain reaction (PCR). If the HCV RNA is positive, then the patient is considered to have hepatitis C. If it is negative, the patient may be recovered from hepatitis C and the HCV RNA by PCR should be repeated in six months to confirm recovery. A false positive anti-HCV occurs uncommonly in this situation and can be established, if desired, by ordering an HCV RIBA (recombinant immunoblot assay), which tests for antibodies to four HCV antigens. A negative RIBA is indicative of no previous HCV infection and, therefore, a false positive anti-HCV. A positive RIBA and negative HCV RNA indicate recovery from HCV.

Management Guidelines:

Initial Evaluation

1. Patients should be asked about the following risk factors for hepatitis C:

• Injecting drug use (IDU) including the dates first started and last used
• Snorting cocaine including history of sharing straws
• Blood transfusions including all dates
• Tattoos including all dates
• Sexual contact with IV drug user or person with hepatitis and lifetime history of sexual partners.

2. A history of current and previous alcohol use should be taken and a history to include current symptoms of liver disease (i.e. fatigue, pruritus, jaundice, icterus, abdominal swelling), history of previous liver disease or hepatitis, and family history of liver disease.
3. Patients with the diagnosis of HCV infection should have the following lab testing done: ALT, AST, total bilirubin, albumin, alkaline phosphatase, glucose, prothrombin time, iron/TIBC, ferritin, CBC, urine protein, AFP and HCV genotype. An HIV screen is recommended. Testing for HBsAg, anti-HBc and anti-HBs and testing for anti-HAV IgG (or total anti-HAV) should be performed if not previously done or vaccinated.
4. Physical examination should include examination of the skin for spider angiomata, examination for liver size, presence of splenomegaly, presence of ascites, presence of jaundice, icterus or encephalopathy.
5. Persons seronegative for hepatitis B markers should receive hepatitis B vaccine if they have not already. Those negative for anti-HAV should receive hepatitis A vaccine (see recommendations below).

Follow-up

1. Lab:

If AFP:

• A Liver Clinic consult is recommended with any AFP elevation > 10, especially if a new finding. Even when the US is normal, the patient is at high risk for HCC or may have cirrhosis and may need further studies, including a liver CT and liver biopsy.

The risk of HCC in HCV appears to be particularly high in persons with cirrhosis (2-3%/year), but is not increased in those without significant fibrosis.

• If patient has cirrhosis or if advanced (bridging) fibrosis exists on biopsy, a liver US is recommended every 6 months along with AFP as the risk of HCC is high in these patients.

2. Liver Biopsy:
3. 1. A percutaneous liver biopsy is not mandatory to institute treatment but should be considered in HCV positive patients with genotype 1, particularly when the results might influence whether treatment is recommended. Patients with genotypes 2 and 3 respond more favorably to treatment than those with genotype 1 and can be treated without biopsy. A biopsy can be considered in persons with genotypes 2 and 3 who are undecided about treatment and desire further information about the status of their HCV disease. A biopsy can be considered in any patient with HCV infection who desires information on the status of his or her disease stage.
   2. Persons with mild chronic hepatitis on liver biopsy who have elected not to receive treatment should be considered for a repeat liver biopsy every 5 years to ascertain the progression of liver disease. In those patients in whom rapid progression has occurred, evaluation for anti-viral therapy should be undertaken.

3. Children born to Hepatitis C chronically infected mothers: recommend 1 time testing for hepatitis C antibody after their first birthday (at least 12 months old).

4. Patients who consume moderate to large amounts of alcohol should be encouraged to abstain from alcohol and seek alcohol counseling, as heavy use of alcohol may accelerate the progression of HCV. All HCV positive patients should be informed that no amount of alcohol has been shown to be safe in HCV infection. In addition, patients with obesity and risk factors for the metabolic syndrome should be encouraged to lose weight and exercise as the presence of steatosis in liver biopsies associated with the metabolic syndrome increases the risk of liver fibrosis.

Vaccine Guidelines

1. Hepatitis A Vaccine: Recommend 2 doses, 6-18 months apart to protect the liver in those with a negative HAV-total antibody.
2. Hepatitis B Vaccine, recommended for those:
3. 1. Not previously vaccinated or who do not recall and have no record of immunization; screen for anti-HBc (core antibody) and HBsAg:
   1. If both negative, give scheduled 3 doses.
   2. If both core and surface antibody (anti-HBs) are positive, they are immune by previous infection.
   3. If surface antibody (anti-HBs) alone is positive, they are immune by vaccine.
   4. If core (anti-HBc) and surface antigen (HBsAg) are positive, they are Hepatitis B carriers.
   5. If core (anti-HBc) positive and anti-HBs negative, then give scheduled 3 doses.
   2. Who started but did not complete the Hepatitis B vaccine series; complete remaining doses without screen.

• Hepatitis B vaccine is not recommended for hepatitis B carriers or those immune to hepatitis B.

Treatment of Chronic Hepatitis C with Combination Therapy

The current recommended treatment for chronic HCV infection (positive anti-HCV and positive HCV RNA by PCR for > 6 months) is a combination of pegylated interferon and ribavirin. Pegylated interferon has largely replaced standard interferon because of improved efficacy, particularly in genotype 1 infection, and convenience (once weekly versus three times per week subcutaneous injections). There are two versions of pegylated interferon, alfa-2a (Pegasys®) and alfa-2b (Peg-Intron®). These appear to have comparable efficacy when combined with ribavirin. Pegylated interferon alfa-2a is administered in a standard dose of 180 micrograms weekly whereas pegylated interferon alfa-2b is administered in a weight-based dose.

There are multiple side effects of interferons. Some of these include bone marrow suppression, particularly neutropenia and thrombocytopenia; flu-like symptoms including malaise, fatigue, achiness and low grade fever; emotional symptoms including depression, irritability and loss of concentration; nausea, vomiting, anorexia and weight loss; precipitation of thyroid disease, and rarely, permanent visual loss.

Ribavirin is taken orally twice a day. The dose is weight-based in treatment of genotype 1(1000 mg/day in persons < 75 kg. and 1200 mg/day in those > 75 kg) but a smaller standard dose of 800 mg/day has been shown to be effective in treatment of genotypes 2 and 3. Ribavirin causes hemolysis, usually resulting in a 2-4 gram hemoglobin drop during treatment, and insomnia. It is teratogenic and effective contraception must be used during treatment and for 6 months thereafter, whether the person being treated is male or female. Ribavirin is contraindicated in renal failure and coronary artery disease. Current guidelines recommend a 48-week duration of treatment for genotype 1 and a 24-week duration for genotypes 2 and 3. The absence of HCV RNA by PCR 6 months after the end of a treatment course is considered a sustained virologic response (SVR). The estimated response rates to therapy based on several multicenter trials are 40-50% in genotype 1 and 70-80% in genotypes 2 and 3. The SVR is better in those with a baseline HCV RNA level < 800,000 international units/ml and in those with less fibrosis on biopsy. Conversely, the response is worse in those with higher baseline HCV RNA levels and more advanced fibrosis, particularly cirrhosis.

Further dosage information and management of treatment can be obtained by consulting the drug package insert. Shorter courses of treatment (14-16 weeks total) may be given in patients with genotypes 2 and 3 who are HCV RNA negative 4 weeks after starting therapy but are not yet FDA approved.

Persons who actively abuse alcohol or drugs or have been unreliable keeping appointments are poor candidates for treatment of hepatitis C. Those with significant chronic medical problems or mental health disorders should be evaluated further to determine if these represent contraindications to treatment.

Monitoring patients during therapy: see protocols.

When to stop therapy prematurely:

1. Failure of HCV RNA level to drop at least 2 logs at 12 weeks.
2. HCV RNA positive at 24 weeks in patients infected with genotype 1.

HIV Coinfection:

All persons with HIV disease should have an anti-HCV test. Immunosuppressed persons (CD4 count < 200) with a negative anti-HCV and elevated ALT or clinical suspicion of hepatitis C should have an HCV RNA by PCR. Persons who are coinfected with HCV and HIV may have a more rapid progression of their HCV liver disease. Although treatment of HCV infection is possible and should be considered in coinfection if CD 4 counts are above 200, the SVR rates have generally been found to be lower than in those without HIV. Because of the potential for adverse interactions between anti-retroviral and HCV medications, persons with coinfection should be referred to a hepatologist or other specialist with expertise in treatment of HCV/HIV coinfection.

Acute Hepatitis C:

Most persons with chronic hepatitis C do not present with an acute hepatitis. Of those who do, only about 25% develop jaundice. The diagnosis of acute hepatitis C can be difficult to make because the anti-HCV may take up to 12 weeks after exposure to become positive. An HCV RNA by PCR becomes positive within 1 or 2 weeks, however, and can confirm diagnosis if the anti-HCV is negative. Enzyme elevation is modest in acute hepatitis C, with ALT and AST often < 1,000, and fulminant hepatitis is rare. Hepatitis C may resolve spontaneously in up to 50% of those who present with acute hepatitis. Several studies have indicated that those who do not become HCV RNA negative within 8-12 weeks should be treated promptly. Although there are no definitive guidelines for such treatment, there is evidence that a 24-week course of pegylated interferon alone can produce an SVR of up to 90%, regardless of genotype. Persons diagnosed with acute hepatitis C should be referred to the liver clinic for consideration of treatment if they do not become HCV RNA negative within 12 weeks.

References:

1. National Institutes of Health consensus development conference statement: Management of hepatitis C. Hepatology 2002; 36: S3-S20.
2. Strader DB, Wright T, Thomas DL, Seef LB. AASLD Practice Guideline: Diagnosis, management, and treatment of hepatitis C. Hepatology 2004; 39(4): 1147-71.
3. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001; 358:958-965.
4. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. NEJM 2002; 347:975-82.
5. Gerlach JT, Diepolder HM, Zachoval R, Gruener NH, Jung M-C, Ulsenheimer A et al. Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology 2003; 125:80-88.
6. Mondelli MU, Cerino A, Cividini A. Acute hepatitis C: diagnosis and management. J Hepatology 2005; 42: S108-S114.
7. Santantonio T, Fasano M, Sinisi E, Guastadisegni A, Casalino C, Mazzola M et al. Efficacy of a 24-week course of PEG-interferon a-2b monotherapy in patients with acute hepatitis C after failure of spontaneous clearance. J Hepatology 2005; 42:329-33.

Revision 3.2006