Higher doses of pegylated interferon or ribavirin improve hepatitis C treatment response rates

Given that standard hepatitis C therapy with pegylated interferon plus ribavirin produces a sustained virological response (SVR) in less than 50% in patients with genotype 1 hepatitis C, researchers are continually seeking ways to improve response rates. Several studies presented at the American Association for the Study of Liver Diseases (AASLD) annual meeting, held November 11-15 in San Francisco, evaluated higher doses of one or both drugs. Although these trials were conducted in HIV-negative individuals, they have implications for the treatment of co-infected patients as well.

Increasing interferon dosing

John Gross presented data from the RENEW trial, which enrolled 936 patients at 100 sites in the United States who did not respond to previous hepatitis C treatment (relapsers, who initially responded but later experienced viral load rebound, were excluded). Participants were randomly assigned to receive pegylated interferon-alpha-2b (Viraferon-Peg or Peg-Intron) at doses of 0.5, 1.5, or 3mcg/kg/week, all with 800-1,400mg daily weight-based ribavirin.

Those who started in the lowest dose arm were reassigned to one of the others after the US Food and Drug Administration approved the 1.5mcg/kg/week dose, leaving 704 subjects who originally started in the latter two arms. Baseline characteristics were similar: about 70% men, 16% African-American, 91% with genotype 1, and 40% with advanced (stage F3-F4) fibrosis. After 48 weeks, end-of-treatment (EOT) response rates were similar in both arms (24%). However, in an intent-to-treat (ITT) analysis, more patients in the double-dose arm achieved SVR (17% vs 12%; p=0.03). The high-dose advantage was especially pronounced among Africa-Americans and those with advanced fibrosis. While patients in the double-dose arm required more dose reductions, the discontinuation rate was the same in both arms (about 35% overall; 12% due to adverse events). The researchers concluded that for re-treatment of patients who never cleared hepatitis C RNA with prior therapy, double-dose pegylated interferon was more effective than the standard dose, with similar tolerance.

Interim data from a second high-dose pegylated interferon study were presented at a late-breaker session by Patrick Marcellin. In the REPEAT trial, 950 previous non-responders to Viraferon-Peg plus ribavirin were randomly assigned to receive pegylated interferon-alpha-2a (Pegasys), either 180mcg/week for the entire course of therapy or a double induction dose of 360mcg/week decreased to 180mcg after 12 weeks (unlike Viraferon-Peg, Pegasys is typically not dosed by weight); all subjects also received 1,000-1,200 mg daily ribavirin. Baseline characteristics were similar: average age 48 years, about 66% men, 88% Caucasian, mean body weight 81 kg, 91% with genotype 1, and about 26% with cirrhosis.

At the end of the 12-week induction period (data were available for 856 subjects), 20% of patients in the double-dose arm achieved undetectable hepatitis C viral load, compared with 13% in the standard-dose group (p = 0.003). The former arm was also more likely to experience at least a 2-log drop in hepatitis C RNA (62% vs. 45%; p

Rates of adverse events, dose reductions, and treatment discontinuation (3-5%) were similar in both arms. Marcellin concluded that the double induction dose of Pegasys was more effective in producing early virological response (EVR) - even among patients with cirrhosis - but it is not yet known how many will go on to achieve SVR.

Rising ribavirin

Ira Jacobson presented data from WIN-R, the largest US hepatitis C treatment trial to date. In this study, 4,913 treatment-naive patients at 225 community sites were randomly assigned to receive ribavirin either at a standard fixed dose (FD; 800mg/day) or a weight-based dose (WBD; 800mg, 1,000mg, 1,200mg, or 1,400mg daily, respectively, for patients weighing less than 65kg, 65-85kg, 86-105kg, and 106-125kg); all participants also received Viraferon Peg 1.5 mcg/kg/week. Baseline characteristics were similar: mean age 45 years, about 63% men, about 60% with genotype 1, and 30% with advanced fibrosis; weight distribution was 14%, 41%, 34%, and 11%, respectively, in the weight categories noted above. There was no significant difference in end-of-treatment (EOT) response between the FD and WBD arms (59% vs 57%).

An ITT analysis at the end of the follow-up period revealed an overall SVR rate of 41% in the FD arm, compared with 44% in the WBD arm (p=0.02). Stated another way, the relapse rates were 19% and 15%, respectively. Among patients with genotype 1, the corresponding SVR rates were 29% and 34% (p=0.004); further analysis revealed that the difference was only statistically significant among patients with high baseline hepatitis C viral load.

Patients with genotype 2 or 3 had similar SVR rates regardless of dose or treatment length (24 or 48 weeks). Weight-based dosing had a “profound impact” among African-American patients, who had an SVR rate twice as high in the WBD arm (10% vs 21%; p = 0.004). While SVR declined as patient body weight increased in the FD arm, response was similar regardless of weight in the WBD arm. More than one-third of patients in both arms discontinued the study prematurely for any reason; Jacobson explained that this high drop-out rate is typical of trials under “real world” conditions. The frequency of serious adverse events was similar in both arms (11-12%). Jacobson concluded that 1,400 mg ribavirin is “safe and effective,” noting that the drug “did not cause more anaemia in larger patients who received larger doses.” This study provides further evidence that an adequate dose of ribavirin is key to preventing relapse after hepatitis C therapy.

In another study, however, weight-based ribavirin dosing did not lead to improved virological response. Paul Gaglio presented data from non-randomised study of former non-responders and relapsers. One cohort of 247 subjects received 1.5 mcg/kg/week Viraferon-Peg plus fixed-dose 800mg daily ribavirin. A second cohort of 207 subjects received the same dose of Viraferon-Peg plus weight-based ribavirin at the same doses as in WIN-R. Both cohorts had similar distribution of genotypes, prior treatment history, body weight, and HCV viral load, but the WBD cohort included more women and African-Americans. In an ITT analysis, SVR rates were similar in the FD and WBD cohorts (17% vs 20%, respectively); among patients with genotype 1, the corresponding rates were unexpectedly low, at 15% and 19%. Previous relapsers were more likely to achieve SVR than prior non-responders, but again, rates did not differ significantly between the FD and WBD cohorts. Unlike Jacobson’s study, weight-based dosing provided no benefit for African-American patients (SVR about 12% in both arms). While not helpful, weight-based dosing also was not detrimental, as similar percentages in both cohorts required ribavirin dose reduction or discontinuation. “In all patient groups studied,” Gaglio concluded, “weight-based ribavirin was not associated with improvement in SVR when compared to fixed dosing of ribavirin.”

EPO to the Rescue

Many patients are unable to tolerate high doses of ribavirin due to a common side effect, haemolytic anaemia. Mitchell Shiffman presented data from a study in which erythropoietin (EPO, brand names Procrit, Eprex, Epogen), a hormone that stimulates red blood cell production, enabled patients to tolerate higher doses of ribavirin. In this trial, 150 treatment-naive patients with genotype 1 HCV were randomly assigned to receive Viraferon-Peg 1.5mcg/kg/week plus either a typical weight-based dose of ribavirin (WBD; 13.3 mg/kg/day or 800-1,400mg), the same doses of ribavirin plus EPO 40,000 units/week (WBD plus EPO), or high-dose weight-based ribavirin (15.2mg/kg/day or 1000-1600mg/day) plus EPO (HDWBD plus EPO). Baseline characteristics were similar in all arms: mean age 48 years, about 60% men, about 40% African-American, mean body weight about 82kg, about 6% with cirrhosis, and baseline haemoglobin (Hgb) about 15 gm/dL.

Patients started EPO at the outset of the study if their baseline Hgb was below 15, or added it as soon as Hgb fell to this level. EVR and EOT response rates were similar in all three arms (EVR 68% in the WBD arm, 65% in the WBD plus EPO arm, and 63% in the HDWBD plus EPO arm; EOT 46%, 31%, and 53%, respectively). After 48 weeks of therapy plus follow-up, 29% in the WBD arm, 19% in the WBD plus EPO arm, and 49% in the HDWBD plus EPO arm achieved SVR (p

While EVR, EOT, and SVR rates were all lower in African-Americans compared with Caucasians, both groups saw a similar relative benefit with the higher ribavirin dose. As expected, both arms receiving EPO experienced less anaemia. Ribavirin dose reduction was required in 40% of the WBD arm, 10% of the WBD plus EPO arm, and 31% of the HDWBD plus EPO arm (p

Although there are still inconsistencies in the data, it appears evident that higher doses of pegylated interferon can help patients achieve virological suppression, and higher doses of ribavirin can help keep hepatitis C suppressed after treatment is completed. Fortunately, a considerable proportion of patients appear able to tolerate these increased doses quite well.