News Author: Laurie Barclay, MD
CME Author: Désirée Lie, MD, MSEd

Disclosures

Credits Available

Physicians - up to 0.25 AMA PRA Category 1 continuing physician education credits

June 22, 2005 — For hepatitis C virus (HCV) genotypes 2 and 3, 12 weeks of therapy is as good as 24 weeks for those whose bodies clear the virus by four weeks, according to the results of a randomized trial published in the June 23 issue of the New England Journal of Medicine.

"In most patients with chronic hepatitis C virus (HCV) genotype 2 or 3 infection, therapy with pegylated interferon and ribavirin administered for a period of 24 or 48 weeks ensures a sustained virologic response," write Alessandra Mangia, MD, from IRCCS Casa Sollievo della Sofferenza Hospital in San Giovanni Rotondo, Italy, and colleagues. "Data on viral kinetics have led to the hypothesis that in patients with HCV genotype 2 or 3 in whom HCV RNA is not detectable after four weeks of therapy, 12 weeks of treatment may be as effective as the recommended course of 24 weeks."

In this study, 283 patients began treatment with a standard 24-week regimen of 1.0 μg/kg of peginterferon α-2b weekly, plus 1,000 mg or 1,200 mg of ribavirin daily, based on body weight. Of these, 70 patients were randomized to the 24-week regimen (standard-duration group) and 213 patients to a variable regimen (variable-duration group) of 12 or 24 weeks, on the basis of whether test results for HCV RNA were negative or positive at week 4. The primary outcome was no detectable HCV by polymerase chain reaction (PCR) assay 24 weeks after completion of treatment.

The two groups had no significant difference in HCV that was not detectable by PCR assay at week 4 (64% in the standard-duration group vs 62% in the variable-duration group). Sustained virologic response occurred in 53 patients (76%) in the standard-duration group and in 164 (77%) in the variable-duration group (difference, -1%; 95% confidence interval [CI], -13 to 10%).

In the variable-duration group, fewer patients receiving the 12-week regimen had adverse events and withdrew than in the group receiving the 24-week regimen (P = .045). Relapse rate, defined as HCV not detectable at the end of treatment but detectable at the end of follow-up, was 3.6% in the standard-duration group and 8.9% in the variable-duration group (P = .16). Overall, sustained virologic response rate was 80% in patients with HCV genotype 2 and 66% in patients with genotype 3 (P < .001).

"A shorter course of therapy over 12 weeks with peginterferon alfa-2b and ribavirin is as effective as a 24-week course for patients with HCV genotype 2 or 3 who have a response to treatment at four weeks," the authors write. "Patients treated for 12 weeks were spared the expense and inconvenience of extended treatment and still had a high response rate."

Study limitations include lack of quantitative estimation of HCV viremia.

"Tailoring treatment so that those with an early response are given a shorter course may make therapy more appealing to patients, without adversely affecting outcomes," the authors conclude.

One of the authors reports financial arrangements with Schering-Plough, maker of Rebetron.

N Engl J Med. 2005;352:2609-2617

Learning Objectives for This Educational Activity

• Describe outcomes of variable-duration 12-week vs standard 24-week treatment using standard therapy with peginterferon and ribavirin.
• Identify response rates of HCV genotype 2 vs HCV genotype 3 to treatment.

Clinical Context

Standard treatment for most patients with chronic HVC genotype 2 or 3 infection consists of pegylated interferon and ribavirin administered over 24 to 48 weeks, according to the authors. However, adverse effects and withdrawal rates increase after 8 to 12 weeks. Rate of death of infected cells is estimated at 1.7 to 70 days, and the decline in virus production is eight times faster in those with genotype 2 or 3 HCV vs genotype 1 HCV. The authors hypothesized that patients with genotype 2 or 3 disease may need shorter courses of therapy.

Using undetectable viral RNA levels 24 weeks after treatment as an outcome measure, they conducted a randomized, controlled trial to determine whether patients with a virologic response at week 4 of therapy would have equivalent outcomes if treated for 12 vs 24 weeks using standard therapy regimens. This is an open-label noninferiority trial conducted at 12 Italian centers.

Study Highlights

• Patients were age 18 to 70 years, had antibodies to HCV, had infection with genotype 2 or 3 HCV, had abnormal liver function, and had not received prior therapy.
• Exclusion criteria were leukocyte count lower than 3,000/mm³; platelet count lower than 80,000/m³; hemoglobin level lower than 12 and 13 g/dL for women and men, respectively; HIV infection; other chronic disease; and pregnancy.
• Patients were randomized in 1:3 ratio to receive either 1.0 μg/kg of peginterferon with 1,000 mg or 1,200 mg of oral ribavirin (if > 75 kg) for the standard duration of 24 weeks (n = 70), or variable-duration therapy (n = 213) based on week 4 HCV RNA levels.
• Those who achieved undetectable levels of HCV RNA in the variable-duration group were assigned to 12 weeks of therapy (n = 133). Those who did not received 24 weeks of therapy.
• 266 patients had liver biopsies before randomization, with steatosis graded as mild (< 30% of affected hepatocytes), moderate (30% - 60%) or severe (> 60%).
• Outpatient assessment was conducted at weeks 4, 8, 12, and 24, and 24 weeks after treatment ended.
• Primary endpoint was sustained virologic response, defined as undetectable serum HCV RNA levels by PCR 24 weeks after treatment was completed. Secondary endpoints were adverse effects.
• Mean age was 48 years, 56% were male, mean body mass index was 26 mg/kg², and 60% had an unknown route of HCV transmission. 75% had genotype 2 HCV, and the remaining had genotype 3. One third had moderate or severe steatosis.
• At week 4, 64% of patients in the standard-duration group and 62% in the variable-duration group had undetectable RNA levels.
• 24 weeks after completion of treatment, 76% in the standard-duration group and 77% in the variable-duration group had sustained virologic response. This satisfied the criterion of noninferiority for the variable-duration group.
• 91% of patients in the 24-week-duration therapy group and 85% in the variable-duration group who received 12 weeks of therapy had a sustained virologic response (difference, -6%; 95% CI, -16% to 4%).
• Rate of relapse (HCV detectable at end of follow-up) was 3.6% in the standard-duration group and 8.9% in the variable-duration group (P = .16).
• Relapse was more likely in patients whose alanine aminotransferase levels were no more than 3 times normal, compared with those with higher levels (14% vs 2%; P = .06).
• Those in the 12-week therapy group who had persistent HCV RNA levels at 24 weeks after treatment were offered a further 24 weeks of therapy. In 9 of 10 patients who had a further 24 weeks of therapy, the disease responded to treatment.
• Overall, 80% of patients with genotype 2 and 66% with genotype 3 had a sustained virologic response at 24 weeks after treatment, a difference of 14% (95% CI, 2% to 27%; P < .001).
• There was no statistical difference in the proportion of genotype 2 vs genotype 3 patients with undetectable RNA by week 4 (64% vs 59%; P = .47).
• Response rate at the end of follow-up among those with genotype 2 was 89% in the standard-duration group vs 87% in the variable-duration group.
• In patients with genotype 3 with a 4-week response, response rates at 24 weeks after treatment were 77% in the variable-duration group vs 100% in the standard-duration group.
• Adverse effects resulted in withdrawals significantly less often in the variable-duration group (P = .045).
• Adverse events of depression and thyroid dysfunction were 6% in the variable-duration group and 13% in the standard-duration group.
• Rate of anemia was 5% in the variable-duration group and 12% in the standard-duration group.

Pearls for Practice

• Both variable-duration treatment of HCV with peginterferon and ribavirin and standard 24-week therapy conferred similar virologic response rates. Among those who relapsed while receiving variable-duration therapy, a further 24 weeks of therapy provided the same response. Patients with chronic HCV treated with variable- vs standard-duration therapy have fewer adverse effects of depression, thyroid dysfunction, and anemia.
• Patients with genotype 2 HCV have a higher sustained virologic response rate to treatment than do those with genotype 3 HCV.

1. According to the current study by Mangia and colleagues, the use of variable-duration therapy vs standard 24-week therapy for chronic HCV infection is associated with all of the following outcomes except:  (Required for credit) Similar levels of undetectable HCV RNA at week 4 Similar sustained 24-week virologic response Similar relapse rates at end of follow-up Similar rate of withdrawal because of adverse events 2. In the current study by Mangia and colleagues, which of the following was the main difference seen between treatment responses for genotype 2 and for genotype 3 HCV disease?  (Required for credit) Rate of sustained virologic response was higher for genotype 2 Rate of adverse events was lower in genotype 2 Rate of relapse was higher for genotype 3 Rate of virologic response at week 4 was higher for genotype 3

About News CME

News CME is designed to keep physicians abreast of current research and related clinical developments that are likely to affect practice, as reported by the Medscape Medical News group. Send comments or questions about this program to cmenews@webmd.net.

Legal Disclaimer

The material presented here does not reflect the views of Medscape or the companies providing unrestricted educational grants. These materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers or continuing education participants should verify all information and data before treating patients or employing any therapies described in this educational activity.