Hepatitis C: Latest Guidelines From the NIH

December 1, 2002

The most common blood-borne infection in the United States, hepatitis C is also one of the leading causes of chronic liver disease in this country. About 35,000 new hepatitis C virus (HCV) infections are diagnosed each year; by 2015, the number of persons with documented HCV infection is expected to have increased 4-fold from what it was in 1990.

The most common blood-borne infection in the United States, hepatitis C is also one of the leading causes of chronic liver disease in this country. About 35,000 new hepatitis C virus (HCV) infections are diagnosed each year; by 2015, the number of persons with documented HCV infection is expected to have increased 4-fold from what it was in 1990.

Fortunately, the increase in newly diagnosed infections has been paralleled by tremendous growth in our understanding of HCV. In 1997, the NIH issued a consensus statement that for the past 5 years has defined the standard of care with respect to the diagnosis, treatment, and prevention of HCV infection.1 The recent advances in knowledge of the disease led the NIH in 2002 to hold a second Consensus Development Conference and issue updated recommendations.2 Highlights from these guidelines are presented here. (The consensus statement may be viewed in its entirety at http://www. consensus.nih.gov.)

NATURAL HISTORY
Infection with HCV may be caused by any of 6 viral genotypes. Genotype 1 accounts for at least 70% of infections in the United States.

Acute infection. HCV RNA may be detected 1 to 3 weeks after exposure and is present by the time symptoms develop. HCV antibodies are present in only 50% to 70% of patients by the time symptoms develop but can be detected in 90% of patients 3 months after exposure. The acute infection is rarely fulminant.

Chronic infection. Chronic hepatitis C develops in up to 85% of infected persons. Women and those infected at a younger age are more likely to clear their infection. African American men appear to be the least likely to clear the infection.

In patients who remain infected, the proportion of those in whom cirrhosis develops within 20 years varies from between 2% and 4% in women and children to between 20% and 30% in transfused patients.

HIV or hepatitis B virus (HBV) coinfection appears to hasten the progression of liver disease. In addition, there is strong evidence that significant alcohol use (equivalent to 4 beers a day in men or 2 beers a day in women) accelerates the course of the disease. Lower levels of alcohol consumption may also be detrimental.

Neither viral load nor genotype appears to alter the progression of HCV infection-although genotype 1 is associated with a lower rate of responseto treatment.

HCV infection accounts for one third of the cases of hepatocellular carcinoma (HCC) in the United States. HCC develops almost exclusively in patients with cirrhosis. Risk factors for HCC are largely the same as those for cirrhosis.

ASSESSMENT
Multiple tests are available to diagnose and monitor HCV infection. These include enzyme immunoassays (EIAs), recombinant immunoblot assays (RIBAs), qualitative and quantitative HCV RNA assays, and liver biopsy.

Serologic tests. An EIA detects antibodies to HCV. It is easy to perform, reproducible, and suitable for screening persons at risk. Third-generation EIAs have very high sensitivity and specificity. In immunocompetent patients with clinical liver disease or risk factors for HCV infection, a negative result on an EIA excludes chronic hepatitis C. Supplemental testing with an RIBA is still useful in some set-tings. [Editor's note: For an extended discussion of EIAs and RIBAs, see Dr Sofair's article, "Apparently Healthy Man With History of Injection Drug Use: The Initial Approach," CONSULTANT, February 2002, page 157.]

Use an FDA-approved qualitative HCV RNA assay to confirm the presence of chronic infection in patients with a positive result on an EIA or in whom early infection is suspected. These tests can detect viral loads as low as 50 to 100 IU/mL. Transcription-mediated amplification assays can detect viral loads as low as 5 IU/mL but have not yet been approved by the FDA for clinical use. A single positive response to an HCV RNA assay confirms active HCV infection. A single negative result does not exclude viremia; the test must be repeated to rule out a transient decline in viral titer that is below the limits of detection. Once active infection has been confirmed, repeated RNA testing is unnecessary except to document clearance of the infection.

Quantitative HCV RNA assays (quantitative polymerase chain reaction or branched DNA) may be useful in predicting outcome of therapy, which is more likely to be favorable in patients with a low viral load.

Liver biopsy. Although biopsy rarely detects other unsuspected liver diseases, the procedure provides valuable information on which to base treatment decisions. Patients with normal alanine aminotransferase levels and little or no fibrosis on biopsy have a favorable prognosis and may opt to defer treatment.

Because of the shorter treatment duration and more favorable outcome in patients with genotype 2 or genotype 3 infection, a pretreatment biopsy may not always be necessary in such persons.

Screening for hepatocellular carcinoma. In patients with HCV-associated cirrhosis, HCC occurs at a rate of 0% to 3% per year. HCC screening programs that use combinations of alpha-fetoprotein measurements and ultrasonography are common in the United States despite a lack of rigorous studies to document their clinical impact. Because the risk that HCC will develop in patients without cirrhosis is very slight, do not screen such patients.

Screening for HIV infection. The risk factors for both HIV and HCV infection are similar, and coinfection appears to hasten the progression of hepatitis C. Routinely screen all patients with HIV for HCV infection, and offer appropriate counseling and HIV screening to HCV-infected patients who are at risk for HIV.

TREATMENT
Combination therapy with interferon and ribavirin is more effective than either alone, and pegylated interferon is superior to standard interferon. The best measure of treatment effectiveness is a sustained virologic response (SVR). SVR is defined as the absence of detectable RNA on a qualitative assay with a detection limit of 50 IU/mL 24 weeks after completion of treatment. Factors associated with a favorable response to treatment include:

  • Non-genotype 1 infection.
  • Lower baseline viral load.
  • Limited fibrosis or inflammation on biopsy.
  • Lower body weight.

Whom to treat. Treatment of HCV infection is recommended for those in whom the infection is most likely to progress to cirrhosis-in general, those with detectable viral loads and a liver biopsy that shows portal or bridging fibrosis and at least moderate inflammation.

Until now, many patients with HCV infection have not been treated because of injection drug use and/or alcohol abuse, advanced age, or various medical or psychiatric comorbidities (such as current psychosis or a history of psychosis; severe depression; severe neutropenia, anemia, or thrombocytopenia; severe heart disease; end-stage renal disease; and autoimmune diseases). Enhanced surveillance and treatment of many such patients is now encouraged.

Recommendations regarding treatment of specific patient populations are listed in Table 1.

 Table 1 - Treatment recommendations for specific populations of patients with HCV infection
Type of patient Treatment recommendations

Patients with normal ALT levels Although these patients tend to have histologically mild disease, it may progress to cirrhosis in some. There is no consensus on whether to perform biopsy on or to treat such persons. Base decisions on viral genotype, symptoms, patient preference and motivation, the presence of comorbidities, and biopsy findings.

Patients with mild liver disease Patients with persistent elevations in ALT levels but no fibrosis and minimal inflammation on biopsy have a very favorable prognosis and may not need treatment. However, if such patients are not treated, they may require periodic liver biopsy to assess the progression of their liver disease.

Patients with advanced liver disease SVR rates are lower in patients with cirrhosis than in those without. However, in patients with subclinical cirrhosis, treatment may prevent progression to decompensated liver disease. In those with decompensated cirrhosis, the primary treatment is liver transplantation.

Patients with acute HCV infection High SVR rates have been reported in small trials of patients with acute HCV infection who were treated with interferon monotherapy. However, the optimal timing of therapy and the most appropriate therapy for patients with acute infection are still unclear.

Active injection drug users Consider treatment of active injection drug users on a case-by-case basis and link it to ongoing treatment for substance abuse and psychiatric comorbidity. Injection drug use or methadone treatment is not an absolute contraindication to therapy for HCV infection.

Patients with HIV coinfection Because HCV and HIV infections have similar routes of transmission, coinfection is common. HIV appears to accelerate the natural course of HCV infection. Although HCV infection has been successfully treated in those infected with HIV, it is important to monitor for potential drug interactions and medication side effects, such as lactic acidosis.

HCV, hepatitis C virus; ALT, alanine aminotransferase; SVR, sustained virologic response.

Treatment of naive patients. Treat patients with genotype 1 infection for 48 weeks with pegylated interferon and ribavirin; this regimen results in an SVR in 42% to 46% of these patients. In patients with genotype 1 infection, higher doses of ribavirin (1000 to 1200 mg/d) appear to be more effective than 800 mg/d.

Patients with genotype 2 or 3 infections may be treated with 24 weeks of either standard interferon and ribavirin or pegylated interferon and ribavirin; these regimens result in an SVR in 76% to 82% of such patients.

Psychiatric sequelae occur in at least 20% of patients treated with interferon and can include emotional lability, depression, and even suicidal ideation. These effects may represent exacerbation of antecedent psychiatric disease or a new problem; in either case, they may persist despite discontinuation of therapy. Thus, it is extremely important to evaluate patients' mental health before and during antiviral therapy.

In addition, vaccinate all persons infected with HCV against hepatitis A. Vaccinate against HBV infection all those who are seronegative and who have risk factors for HBV infection.

Early viral response (EVR), defined as a 2 log decrease in viral load after 12 to 24 weeks of treatment, predicts SVR. Therapy may be discontinued in patients who do not achieve EVR.

Re-treatment. Certain patients who fail to achieve an SVR may benefit from re-treatment."Relapsers" are patients who achieve an initial end-of-treatment response (ETR) but no SVR. "Nonresponders" are those who do not achieve either an ETR or an SVR. Table 2 lists factors to consider when deciding whether to re-treat a relapser or nonresponder.

 Table -2 Factors to consider when deciding whether to re-treat patients with refractory HCV infection
Previous response to therapy 

HCV, hepatitis C virus.

Between 15% and 20% of nonresponders who were initially treated with standard interferon and ribavirin will achieve an SVR with pegylated interferon and ribavirin. In addition, several trials of maintenance therapy for nonresponders are currently being conducted using pegylated interferon alone; the goal of such therapy is to prevent further progression of HCV-associated chronic liver disease.

Treatment protocols for relapsers are in the experimental stage.

PREVENTION
Injection drug use accounts for more than two thirds of new HCV infections in the United States.Most infections not transmitted by injection drug use are transmitted sexually or through occupational exposure to blood. Overall, the highest prevalence of HCV infection (70% to 90%) is found in injection drug users and in those with hemophilia who were treated with factor concentrates before 1992.

Injection drug use. Methadone programs, as well as needle exchange programs, have been shown to limit HIV transmission and may help prevent HCV transmission as well. In addition, educate injection drug users about the importance of washing their hands before and after injection, not sharing equipment with others, and limiting their exposure to the blood of others.

Sexual transmission. Screen for HCV the sex partners of male and female patients with HCV infection. However, for heterosexual, monogamous couples, the risk that HCV infection will develop in the discordant partner is only 0% to 0.6% annually. Given this low level of risk, barrier contraception is not necessary for such couples but may further decrease the chances of transmission.

Needle-stick injury. The risk of HCV infection after needle-stick injury is approximately 2%. Antiviral prophylaxis is currently not recommended. However, both the source and the exposed person should be tested for HCV at the time of injury by means of EIA and RNA assay. If the source is found to be HCV-positive, retest the exposed person for HCV antibody and RNA 2 to 8 weeks following exposure (RNA is first detected 2 weeks after exposure). Consider therapy for any persons who are found to be infected.

Perinatal transmission. The risk of perinatal transmission ranges from 2% in women who are anti-HCV-positive to as high as 7% in women who have detectable RNA at the time of delivery. In women who are coinfected with HIV and HCV, the risk is as high as 20%. Currently, there are no recommendations for the administration of prophylactic medications or for specific modes of delivery. However, it is prudent to avoid fetal scalp monitoring or prolonged labor after rupture of membranes.

The best way to detect HCV infection in a newborn is to test for HCV RNA on 2 occasions between the ages of 2 and 6 months. Anti-HCV testing may also be used, although a positive test result in infants younger than 15 months may reflect passive transfer of maternal antibody.

Breast-feeding does not appear to transmit HCV.

References:

REFERENCES:1. National Institutes of Health Consensus DevelopmentConference Statement. Management of HepatitisC. Bethesda, Md: National Institutes of Health;March 24-26, 1997.
2. National Institutes of Health Consensus DevelopmentConference Statement. Management of HepatitisC: 2002. Bethesda, Md: National Institutes ofHealth; June 10-12, 2002.