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Clinical Manual: Hepatitis C Treatment

February 23, 2008

This document was designed to give providers practical information about anti-hepatitis C treatment. It includes links to other related electronic documents on this site, as well as the Patient Treatment Tracking Chart, a downloadable chart for patients to record their labs and side effects during therapy.

Key Points

  • Treatment for hepatitis C virus (HCV) nearly always involves a combination of an interferon, given by injection, and ribavirin, given in pill form.
  • Treatment often has a lot of side effects, particularly fatigue, muscle aches, and mild anxiety. Many people are able to continue to work at their jobs while on therapy, but some are not.
  • The main goal of treatment is to have the virus removed from a patient's blood long-term. This is called "sustained virological response" (SVR), defined as no virus present in a blood sample 6 months after completion of therapy. In many cases, SVR is associated with a much lower risk for adverse health consequences from HCV.
  • Treatment is not the best option for every patient. The benefits of treatment are the most clear in patients with greater degrees of liver disease and more treatable genotypes (2 and 3).

Patient Handouts

Pretreatment Considerations

Providers embarking on counseling about or managing HCV treatment for a patient should be familiar with the side effects of treatment and its expected clinical course. Patients who begin treatment in 2005 tend to have one or more of several characteristics:

  1. They are motivated and interested in "trying to get rid of the virus" so they don't have to worry or think about it.
  2. They are infected with HCV genotypes 2 or 3.
  3. They have significant liver disease (eg, Stage 2-4 scarring on a liver biopsy, using a scale with Stage 4 indicating cirrhosis, or clinical or radiological evidence of cirrhosis).

Many patients have a "complete data set" before starting hepatitis C therapy. This includes:

  • HCV viral load. This results of this test, quantifying the amount of virus in their blood on a particular day, usually are given in "international units (IUs) per mL" and often additionally as "copies per mL." The IU measure was established to be very similar among different laboratories, so that a viral load measured in IUs by one laboratory should be equivalent to that measured by another laboratory. Values in copies/mL may vary among laboratories. Practitioners also should bear in mind that viral load often fluctuates 10-fold or more in a given patient without any clear reason.

    • viral loads >800,000 IU/ml or >2x106 copies/ml are considered "high."1,2 Some laboratories will give values merely as a range (eg >800,000 IU/ml). Since a "2-log reduction" after 12 weeks of interferon therapy often requires precise knowledge of pretreatment viral load, practitioners may ask their referral laboratory to further "dilute" samples to yield an estimate of the height of viral loads outside their usual dynamic range.
    • "High" viral loads are associated with lower viral clearance rates in all published studies of interferon and ribavirin therapies.
  • HCV genotype. This refers to the strain (genotype 1-6) of the virus with which the patient is infected. Roughly 75% of Americans infected with HCV have genotype 1 infection.1,3 Having genotype 1 infection, however, means that interferon and ribavirin therapy are recommended for 48 weeks, and that SVR is in the range of 50% in patients treated with a pegylated interferon and ribavirin who complete a full course of therapy. This rate may even be substantially lower in some groups of patients (eg, 19% in one study of African American patients.4

    • SVR is much greater in patients treated for genotypes 2 or 3, who have viral clearance 70-80% of the time.1,5
  • Liver disease staging. Treatment against HCV in patients who have significant liver scarring (fibrosis), including early cirrhosis, should not be delayed indefinitely, if possible. Disease staging is determined by a liver biopsy in patients who do not have clear clinical or radiological evidence of cirrhosis.
  • Medical and psychiatric history. Patients' medical and psychiatric histories also need to be taken into account in detail before initiating interferon and ribavirin therapies. Chronic obstructive pulmonary disease, coronary artery disease, anemia, and history of thyroid disease are among the common medical conditions that can be worsened significantly by therapy or its common side effect, hemolytic anemia. Patients with baseline depression, psychotic illness, or other significant psychiatric illness can often experience worsening of these conditions.
  • Social circumstances. Interferon and ribavirin are almost never emergency therapies, and they predictably have a negative effect on a patient's life and functioning. Patients should be at a point in their lives in which they can handle such a stress. The need for therapy in the short term should be seriously questioned in:

    • patients who actively drink alcohol or abuse drugs, as these behaviors tend to place their lives at risk in the short term, reduce compliance with medical therapies, and likely cause lower SVR;
    • patients who are the sole earner in their household or whose job performance cannot suffer without the risk of job loss; and
    • patients who are unreliable with follow-up appointments, as close follow-up is required during therapy.

Decisions also are made within the context of the patient's health insurance coverage. Many patients cannot afford to pay out-of-pocket for the medications, which often cost $15,000 to $20,000 for 48 weeks of therapy, not including monthly office visits and blood work. As such, nearly all patients are treated thorough benefits provided by the VA, other federal or state agencies, or private/group health insurance plans.

Deciding to Embark on Therapy

Once providers and patients have a complete data set, or have reached agreement on proceeding without one (eg, no liver biopsy when a patient or provider wants to make a treatment decision without one), conclusions about whether to treat and timing of treatment can be reached. These decisions are made principally by weighing each of the factors described above. HCV viral load and genotype tests allow providers to give estimates of response (SVR) to therapy and to make decisions regarding dosage and duration of therapy. Timing of therapy is largely a matter of informed discussion with the patient. Generally, deciding whether to start a patient on therapy at a certain visit or 6 months or a year later is less important than helping to ensure that the patient is able to complete an entire course of therapy uninterrupted.

Quick Notes

  • Patients who have seasonal job stress or requirements should be encouraged to begin treatment at the start of a "less busy" period.
  • Patients should research their options for reduction in work hours/short-term medical disability prior to therapy, so that if they feel worse than they anticipate, they know what options are available to them.


Most patients receiving treatment against HCV in 2005 are treated with weekly subcutaneous injections of a pegylated interferon and daily ribavirin pills. Landmark studies in 20015 and 20021 showed in randomized, controlled trials of more than 1,000 patients each that pegylated interferons and ribavirin had superior efficacy in at least some patients, and similar toxicity, compared with three times weekly interferon and daily ribavirin pills. As such, with at least some additional patients clearing HCV when treated with a pegylated interferon and ribavirin, this combination tends to be the treatment of choice. The two pegylated interferons, peginterferon alfa-2a (Pegasys) and peginterferon alfa-2b (Peg-Intron), with ribavirin, have not yet been compared head to head, and are likely of very similar efficacy. A trial comparing the two agents is under way.

Once the decision to initiate treatment is made, dosage of medication and planned duration of therapy are the next factors to be considered. These topics are discussed in detail in the Summary of Current Recommendations section of the Management and Treatment of Hepatitis C Virus Infection: Recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. Specific tips for managing individual side effects that occur during therapy are provided in the Interferon and Ribavirin Treatment Side Effects document.

After Therapy

Once therapy has ended, patients tend to feel better but also worry about the virus returning. Patients should be advised about the following:

  • They nearly always begin to "feel better" once they have stopped the medications for 2 weeks or more. They will be more energetic, and their mood will start to improve.
  • All patients and their partners need to use contraception for 6 months after treatment has been completed. Ribavirin may continue to lead to an increased risk of birth defects during this time, making pregnancy a risk.
  • Patients who have been treated with antidepressants during therapy may feel better enough to stop taking them once their therapy is over. They should do so in consultation with the practitioner who prescribed the medication, as some antidepressants are better tapered rather than abruptly stopped.

Patients also want to know about the risk of the virus returning after they complete therapy. This risk varies based on how their bodies have responded to therapy as measured by their "12-week viral load," or how much their viral load goes down during the first 12 weeks that they are on therapy. This early response to therapy is very important for long-term clearance of the virus. A favorable response to therapy is a reduction in HCV RNA by "2 logs" (100-fold) or more at 12 weeks. When this was achieved by means of therapy with peginterferon alfa-2a and ribavirin in a clinical trial,1 65% of patients achieved SVR. Only 3% of patients who did not have a 2-log drop achieved SVR.

  • Even if patients have a 2-log decline or undetectable HCV RNA at 12 weeks, and continue to have such a response throughout therapy, their risk of the virus returning with completion of therapy is still 25-35%, and they should be told this.

With Sustained Virological Response

A number of studies have documented that the liver improves when a patient has SVR to interferon-based therapy. Liver fibrosis, or scarring, tends to improve, and even cirrhosis can heal to lower levels of fibrosis.6,7 Most negative health consequences from HCV come from liver scarring, so it is felt that SVR should dramatically reduce a patient's likelihood of having HCV impact their health.

  • Patients with cirrhosis prior to HCV treatment, however, remain at risk for hepatocellular carcinoma and other health problems related to their liver even with SVR, and should continue to be monitored for these conditions.

Without Sustained Virological Response

Patients who do not clear HCV after therapy are called "relapsers" if they became HCV RNA negative while on therapy or "nonresponders" if they never became HCV RNA negative. These make up most patients who have been treated. Important points to be conveyed to them include:

  • Therapy likely has been of some benefit to them. Studies suggest that patients who are treated, even if they do not clear virus, have less liver disease6,7,8 and may even have lower rates of liver cancer going forward than do patients who have never been treated.9
  • Retreatment with currently available medications is not likely to give them a good chance of achieving SVR. One large study in which prior nonresponders to standard interferon with or without ribavirin were retreated with pegylated interferon and ribavirin reported an SVR rate of 18%.10 This rate likely is much higher than the rate that could be achieved by retreating pegylated interferon and ribavirin nonresponders with the same medications. Studies are under way to see whether, for example, consensus interferon, possibly in combination with ribavirin, can provide any improvement in SVR among nonresponders.11

Related Patient Brochures [PDF]


  1. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975-82.
  2. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004;351:438-450.
  3. McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998; 339:1485-1492.
  4. Muir AJ, Bornstein JD, Killenberg PG; et al. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med 2004;350:2265-71.
  5. Manns MP, McHutchison JG, Gordon SC, 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.
  6. Poynard T, McHutchison J, Manns M, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002 May;122:1303-13.
  7. Abergel A, Darcha C, Chavallier M, et al. Histological response in patients treated by interferon plus ribavirin for hepatitis C virus-related severe fibrosis. Eur J Gastroenterol Hepatol 2004;16:1219-27.
  8. Shiratori Y, Imazeki F, Moriyama M, et al. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med 2000;132:517-24.
  9. Shiratori Y, Ito Y, Yokosuka O, et al. Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival. Ann Intern Med 2005;142:105-14.
  10. Shiffman ML, Di Bisceglie AM, Lindsay KL, et al. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004;126:1015-23.
  11. Moskovitz DN, Manoharan P, Heathcote EJ. High dose consensus interferon in nonresponders to interferon alpha-2b and ribavirin with chronic hepatitis C. Can J Gastroenterol. 2003;17:479-82.

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This article was provided by U.S. Department of Veterans Affairs.
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