Options for Patients Who Do Not Respond to Treatment

Few options exist for patients who either do not respond to therapy or who respond and later relapse.

Patients who relapse after a course of interferon or peginterferon monotherapy may respond to a course of peginterferon and ribavirin combination therapy, particularly if they became and remained HCV RNA negative during the period of monotherapy.

The response rates and optimal dose (800 vs. 1,000 mg to 1,200 mg of ribavirin) and duration (24 or 48 weeks) of peginterferon and ribavirin for relapse or previous nonresponder patients have not been defined.

The algorithm for treatment given above is for treatment of naive patients.

An experimental approach to treatment of nonresponders is the use of long-term or maintenance peginterferon, which is feasible only if the peginterferon is well tolerated and has a clear-cut effect on serum aminotransferase levels or liver histology, despite lack of clearance of HCV RNA. This approach is now under evaluation in long-term clinical trials in the United States.

New medications and approaches to treatment are needed.

Most promising for the future are the use of newer antivirals, such as RNA polymerase, helicase, or protease inhibitors.

Algorithm for Treatment
Make the diagnosis based on aminotransferase elevations, anti-HCV, and HCV RNA in serum.



Assess for suitability of therapy and contraindications.

Discuss side effects and the likelihood of a beneficial treatment outcome.



Test for HCV genotype.
Consider doing a liver biopsy to assess the severity of the underlying hepatitis and need for current therapy.



Genotype 1: Test for HCV RNA level immediately before starting therapy (baseline level).



Genotype 1: Start therapy with peginterferon alfa-2a in a dose of 180 mcg weekly or peginterferon alfa-2b in a dose of 1.5 mcg per kg weekly in combination with oral ribavirin in two divided doses of 1,000 mg daily if body weight is < 75 kg (165 lbs) or 1,200 mg daily if > 75 kg.



Genotype 2 or 3: Start therapy with peginterferon alfa-2a in a dose of 180 mcg weekly or with alfa-2b in a dose of 1.5 mcg per kg weekly and oral ribavirin 800 mg daily in two divided doses.



All patients: At weeks 1, 2, and 4 and then at intervals of every 4 to 8 weeks thereafter, assess side effects, symptoms, blood counts, and aminotransferase levels.



Genotype 1: At week 12, retest for HCV RNA level. If HCV RNA is negative or has decreased by at least two log10 units (such as from 2 million IU to 20,000 IU or from 500,000 IU to 5,000 IU or less), continue therapy for a full 48 weeks, monitoring symptoms, blood counts, and ALT at 4- to 8-week intervals. If HCV RNA has not fallen by two log10 units, stop therapy.



Genotype 2 or 3: At 24 weeks, assess aminotransferase levels and HCV RNA and stop therapy.



All patients: After therapy, assess aminotransferase levels at 2- to 6-month intervals. In responders, repeat HCV RNA testing 6 months after stopping.

Considerations: Before, During, and After Therapy

Before Starting Therapy

Do a liver biopsy to confirm the diagnosis of HCV, assess the grade and stage of disease, and rule out other diagnoses. In situations where a liver biopsy is contraindicated, such as clotting disorders, combination therapy can be given without a pretreatment liver biopsy.

Test for serum HCV RNA to document that viremia is present.

Test for HCV genotype (or serotype) to help determine the duration of therapy and dose of ribavirin.

Measure blood counts and aminotransferase levels to establish a baseline for these values.

Counsel the patient about the relative risks and benefits of treatment. Side effects should be thoroughly discussed.



During Therapy

Measure blood counts and aminotransferase levels at weeks 1, 2, and 4 and at 4- to 8-week intervals thereafter.

Adjust the dose of ribavirin downward (by 200 mg at a time) if significant anemia occurs (hemoglobin less than 10 g/dL or hematocrit < 30 percent) and stop ribavirin if severe anemia occurs (hemoglobin < 8.5 g/dl or hematocrit < 26 percent).

Adjust the dose of peginterferon downward if there are intolerable side effects such as severe fatigue, depression, or irritability or marked decreases in white blood cell counts (absolute neutrophil count below 500 cells/mm3) or platelet counts (decrease below 30,000 cells/mm3).

When using peginterferon alfa-2a, the dose can be reduced from 180 to 135 and then to 90 mcg per week. When using peginterferon alfa-2b, the dose can be reduced from 1.5 to 1.0 and then to 0.5 mcg per kg per week.

In patients with genotype 1, measure HCV RNA levels immediately before therapy and again (by the same method) at week 12.

Therapy can be stopped early if HCV RNA levels have not decreased by at least two log10 units, as studies have shown that genotype 1 patients without this amount of decrease in HCV RNA are unlikely to have a sustained response (likelihood is < 1 percent).

In situations where HCV RNA levels are not obtainable, repeat testing for HCV RNA by PCR (or TMA) should be done at 24 weeks and therapy stopped if HCV RNA is still present, as a sustained response is unlikely.

Reinforce the need to practice strict birth control during therapy and for 6 months thereafter.

Measure thyroid-stimulating hormone levels every 3 to 6 months during therapy.

Patients with genotypes 2 or 3 can stop therapy at 24 weeks. Patients with genotype 1 who are HCV RNA negative at 24 weeks should continue therapy to a full 48 weeks.

At the end of therapy, test HCV RNA by PCR to assess whether there is an end-of-treatment response.



After Therapy
Measure aminotransferase levels every 2 months for 6 months.

Six months after stopping therapy, test for HCV RNA by PCR (or TMA).

If HCV RNA is still negative, the chance for a long-term cure is excellent; relapses have rarely been reported after this point.