American College of Physicians: Internal Medicine — Doctors for Adults ®


Hepatitis C

From the April ACP Observer, copyright 2006 by the American College of Physicians.

Available in PDF format

Considered a "stealth virus," hepatitis C can infect a patient for as long as 30 years without causing any symptoms. Once symptoms of chronic liver disease appear, however, it may be too late for treatment. All that medicine can offer at that point is a liver transplant.

That's why many experts believe it's essential to screen people who have risk factors for contracting the virus—in spite of recent screening controversies. "If you wait until you have symptoms, then you have waited too long," explained Andrew J. Muir, ACP Member, clinical director of hepatology at Duke University Medical Center in Durham, N.C., and editorial consultant for ACP's hepatitis C PIER module.

Hepatitis C viruses, shown here by transmission electron microscopy. Many of the 3 million Americans infected with the virus have not yet been diagnosed.

Many of the 3 million Americans infected with hepatitis C "have not been identified," Dr. Muir said, "and they won't be unless their doctor takes a history and identifies risk factors." (Also see "Weighing in on hepatitis C screening.")

Screening is also important because effective treatment now exists to eradicate the virus from as many as 50% of its carriers. "The treatment is challenging, but compared with 10 years ago, treatment response rates are much better," Dr. Muir pointed out. That improvement is due to new combinations of medicines, with pegylated interferon-alfa in combination with ribavirin now the state-of-the-art therapy.

At the same time, other drug combinations are being tested to treat hepatitis C, including protease inhibitors, the class of drugs that revolutionized HIV care. The fact that the field is evolving quickly, Dr. Muir said, is "one of the challenging things about managing hep C."

General internists have a key role to play in hepatitis C prevention, screening and diagnosis—while generalists in underserved areas often have to manage treatment as well. In other areas, Dr. Muir said, the fact that treatments are complicated, side effects are troubling and patients tend to have comorbidities all mean that treatment is often best left to specialists.

"The side effects can be managed with appropriate guidance," he said. "Providers need to be comfortable that it's safe to proceed."

This edition of ACP Observer Special Focus is designed to help optimize your ability to diagnose, treat and manage patients with hepatitis C (HCV).


About 90% of IV drug users who have shared needles are HCV-positive after one year, while snorting cocaine also appears to increase risks (presumably because of shared straws). Physicians should routinely ask patients about their use of illicit drugs. Advise users to quit or at least enroll in treatment programs, get vaccinated against hepatitis A and B, and participate in needle-exchange programs.

Warn patients about other risk factors as well. These include having sex with multiple partners; getting tattoos or body piercings with reused or otherwise unsterile equipment; or working or volunteering in health care, public safety, emergency medical services or home health care where blood-borne infection risks are highest. Advise patients in these groups to use barrier precautions, reduce accidental needle sticks, avoid sharing needles, and use disposable equipment and proper sterilization techniques.


In March 2004, the U.S. Preventive Services Task Force issued screening recommendation that found "insufficient evidence to recommend for or against routine screening for HCV infection in adults at high risk for infection."

However, many opinion leaders disagree and recommend using enzyme-linked immunosorbent assay (ELISA) to test patients with the following risk factors for antibody to HCV (anti-HCV):

  • past or present illicit drug use.
  • needlesticks or splash accidents.
  • receipt of clotting factor concentrates produced before 1987; receipt of blood, blood components or solid organ transplant before July 1992; or receipt of blood from an HCV-positive donor.
  • chronic hemodialysis treatment.
  • unexplained elevated serum alanine aminotransferase (ALT) levels.
  • health care work that includes exposure to known HCV-positive blood.
  • child of an HCV-positive woman. (Breastfeeding has not been linked to HCV transmission.)
  • history of multiple sex partners or of sexually transmitted diseases.

Because the precise means and risks of transmission are controversial, consider screening the following patients with less well-established risk factors, which include:

  • long-term sex partners of HCV-positive individuals.
  • people with tattoos or body piercings.
  • users of illicit nonintravenous drugs, who may also use—but not report—injection drugs.

Until inexpensive screening tests and highly effective therapies are developed, experts recommend against screening the general population or pregnant women for HCV.


Studies have found infection rates as high as 90% among patients who have injected illicit drugs. Between 7% and 10% of patients who received blood or blood product transfusions before 1992 test positive for HCV.

Infected patients often show few symptoms of liver disease and can have normal or only mildly elevated levels of serum liver enzymes. If an ELISA measurement is positive—with or without positive recombinant immunoblot assay (RIBA) testing—then test for HCV RNA to demonstrate active vs. past infection or for false-positive ELISA results. (ELISA sensitivity may be reduced in immunosuppressed patients, including patients with chronic renal failure.) ALT levels should either be persistently or intermittently elevated, but keep in mind that ALT levels are normal in as many as 30% of patients with chronic HCV.

A liver biopsy is used to assess disease severity, but is not absolutely required either to make a hepatitis C diagnosis or to initiate treatment. Biopsy is helpful in cases where the patient has persistently normal serum aminotransferase levels or other potential contraindications to therapy. A biopsy, which also provides information about the presence of cirrhosis, should be done only by trained, experienced clinicians, usually a gastroenterologist, hepatologist or interventional radiologist.

Consider an HCV diagnosis when chronic liver disease symptoms cannot be attributed to any other cause. (About 40% of chronic liver disease in the U.S. has been attributed to chronic HCV infection.) Suspect a hepatitis C diagnosis with the following signs and symptoms:

  • unexplained fatigue or malaise
  • jaundice
  • fluid retention
  • GI bleeding
  • hepatomegaly or splenomegaly
  • unexplained signs of portal hypertension
  • extrahepatic manifestations of HCV infection

Both liver-specific and extrahepatic disorders have also been linked to HCV and may be complications of the infection. Physicians should therefore consider the diagnosis when facing these disease states:

  • cirrhosis
  • end-stage liver disease
  • hepatocellular carcinoma
  • cryoglobulinemia
  • membranoproliferative glomerulonephritis
  • porphyria cutanea tarda
  • autoimmune thyroiditis

Many other non-liver diseases are thought to be associated with chronic HCV infection, including Sjogren's syndrome, lichen planus, seronegative arthritis, aplastic anemia, B-cell non-Hodgkin's lymphoma, Mooren's corneal ulcer and diabetes mellitus.

For patients with chronic hepatitis, physicians need to consider—and test for—other hepatic disorders, including hepatitis B, and nonviral causes of liver disease, such as alcoholic or automimmune hepatitis, hemochromatosis or Wilson disease. When additional causes of hepatitis exist, internists should consult a hepatologist to make sure coexisting diseases are treated and to avoid an inaccurate assessment of response to chronic hepatitis C treatment.


Non-drug therapy

Alcohol seems both to accelerate the progression from chronic HCV to cirrhosis and affect how well patients respond to HCV treatment, so counsel patients to abstain from alcohol. No conclusive evidence supports the use of common herbal therapies, such as milk thistle.

Drug therapy

No specific predictors can identify which patients are among the between 20% and 30% of HCV-infected individuals likely to progress to cirrhosis. Experts therefore recommend early HCV treatment with combination therapy before the disease progresses.

Exceptions include those patients who seem to be at low risk for developing progressive disease, such as individuals who have lived with HCV infection for more than 30 years with minimal histologic evidence of hepatic fibrosis.

For HCV patients with compensated liver disease, the combination of pegylated interferon-alfa and ribavirin produces the best virologic response. The combination works better than interferon-alfa monotherapy or a combination of standard interferon-alfa plus ribavirin. Patients with depression or severe mental illness should be treated on a case-by-case basis. Patients with compensated cirrhosis can be treated as well, but their response rates may be low.

The recommended drug therapy dosage is pegylated interferon alfa-2b, 1.5 g/kg sc weekly, or pegylated interferon alfa-2a, 180 g sc weekly, plus ribavirin. Ribavirin dosage varies with genotype, from 800 mg-1400 mg for patients with genotype 1 to 800 mg for patients with genotype 2 or 3. Assess patients' response to treatment after three months. For patients with genotype 2 or 3, six months of therapy is usually sufficient.

If patients cannot take ribavirin, physicians should instead consider prescribing pegylated interferon-alfa monotherapy and then measuring HCV RNA after six months. Continue treatment for one year if negative or discontinue treatment if RNA is positive. An alternative to antiviral therapy for patients with histologically mild disease and no evidence of fibrosis is performing periodic liver biopsies and, if the disease has progressed, initiating treatment. This wait-and-see strategy may, however, be less cost effective than early treatment of mild disease.

Some studies suggest an association between chronic hepatitis C plus super-infection by hepatitis A (HAV) or B (HBV) and an increased risk of acute liver failure. Physicians should therefore test all HCV patients for HAV and HBV infection and vaccinate susceptible patients before starting HCV treatment.

Patients who relapsed to interferon monotherapy or interferon and ribavirin treatment should be retreated with pegylated interferon and ribavirin unless the initial treatment resulted in serious adverse events, such as severe depression, suicidal ideation or anemia. As many as 10% of patients treated with interferon monotherapy and 20% of those on combination therapy have to stop treatment due to side effects. (Also see "Side effects of drugs used to treat hepatitis C.")

Discontinue treatment if patients develop severe depression or suicidal ideation. Patients who suffer mild side effects can benefit from dose reductions, and short-term discontinuation (less than two weeks) of combination therapy does not reduce the sustained response rate.

For some patients, the risks of antiviral drugs outweigh the benefits. The following groups of patients shouldn't receive treatment, unless they are cared for by experienced hepatologists:

  • older patients who have serious comorbid disorders—such as significant coronary or cerebral artery disease—that are likely to reduce life expectancy, or who have clinically important and uncontrolled autoimmune diseases;
  • patients with renal insufficiency, decompensated cirrhosis or hepatocellular carcinoma;
  • pregnant women or those unable to practice birth control;
  • bone marrow or solid-organ transplant recipients;
  • patients suffering from uncontrolled depression or other severe neuropsychiatric disorders, or who demonstrate suicidal ideation; and
  • patients who do not comply with office visits or medication, or those who continue to consume alcohol or inject illicit drugs.

During treatment, physicians should monitor blood counts, thyroid function, serum ALT levels and HCV RNA. There is no optimal therapy for patients who do not respond to interferon-based therapy.


Although no studies have compared the management of hepatitis C by specialists vs. generalists, consider consulting with gastroenterologists, hepatologists or infectious disease specialists for all HCV patients. Consultation can be particularly useful when managing complex HCV-associated cirrhosis with decompensation, extrahepatic manifestations of HCV infection, or coinfection with HBV or HIV. (Patients coinfected with HIV require HIV treatment.) It also may help patients who have relapsed or have not responded to initial treatment.

Consider transplant center referral for HCV patients with Child-Pugh scores of 7 or higher, gastrointestinal bleeding caused by portal hypertension, or spontaneous bacterial peritonitis.

Life-threatening complications of cirrhosis—including bleeding, infection or metabolic concerns—usually require hospitalization and intensive care. They also suggest end-stage liver disease and the need to refer for transplant evaluation.


Urge chronic hepatitis C patients to avoid alcohol.

Recognize that anxiety is a common reaction to an HCV-infection diagnosis—and that participating in support groups can help reduce anxiety. Physicians can also ease anxiety by teaching patients about the natural history of the disease and assuring them that most patients with HCV never develop cirrhosis or liver cancer.

Teach patients about HCV transmission, particularly the low rate of sexual transmission among monogamous partners. For young women, stress the low risk of transmission to newborns, but counsel against breastfeeding when nipples are cracked or bleeding. Advise patients to avoid sharing razor blades, toothbrushes or nail clippers.

Patients are more likely to complete treatment regimens if they can understand, anticipate and cope with side effects. Tell patients how they can reduce treatment side effects by maintaining hydration and taking acetaminophen or a nonsteroidal anti-inflammatory drug before and after interferon injections to reduce drug-induced flu-like symptoms.

Encourage patients to report all unexpected adverse events and let them know that most adverse symptoms—such as depression—can be reversed by stopping therapy. Note that as many as 2% of patients treated with interferon develop permanent hypothyroidism that will require lifelong thyroid hormone replacement.

The PIER module for hepatitis C is online.


The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.


Weighing in on hepatitis C screening

When the U.S. Preventive Services Task Force examined the evidence regarding screening asymptomatic people for hepatitis C infection, it came out against routine screening. It also said there was "no evidence" that screening adults at high risk would lead to improved long-term health outcomes.

That recommendation, published in the March 16, 2004, issue of Annals of Internal Medicine, sparked an immediate response from liver disease experts, who banded together to refute it. In an article published in the Nov. 2, 2004, issue of Annals, a broad coalition of experts—including those from the Centers for Disease Control and Prevention, the American Liver Foundation, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America—called for screening adults for risk factors and offering testing to those at increased risk.

Bruce R. Bacon, FACP, professor of internal medicine and director of gastroenterology and hepatology at Saint Louis University School of Medicine, is past president of the American Association for the Study of Liver Diseases, and a coauthor of that Nov. 2, 2004, Annals article. He spoke with ACP Observer Special Focus about screening adults for HCV antibodies:

On why he favors screening:

If you are a liver specialist or a gastroenterologist, you see terrible consequences from delayed diagnosis of hepatitis C—people with awful end-stage liver disease who die, who need transplants or who get liver cancer. For a disease that takes 30 or 40 years, it's irrational to say it's OK not to screen for the disease because studies haven't been done that show that screening affects death. I think that's faulty logic, and it isn't the way we practice medicine.

Also, we have treatment now that can cure 60% of the people with the virus. Why would you not look for a disease in people who have risk factors when you have available treatment? Screening tests are accurate and inexpensive.

On who should be tested:

We don't say screen the general population, but you should screen people who have some risk factors. If you had a blood transfusion before 1992, you had between a 7% and a 10% chance of getting hepatitis C.

Primary care physicians should also ask patients if they ever shared needles or snorted cocaine, or used any other intranasal or intravenous drugs. They should ask if they ever had piercings or tattoos in a non-sterile environment, if they ever had elevated liver enzymes, or if they ever have come into contact with anybody who has hepatitis C.


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