In this study we demonstrate that the efficacy of 24 weeks of treatment with 90 μg/week of peginterferon alfa-2a and 800 mg/d of ribavirin was not equivalent to standard therapy, mostly due to higher rates of relapse (25% vs 11%).
Several studies have examined the response of HCV genotype 2 or 3 infected patients to lower doses of peginterferon. These studies differed in the peginterferon used, the dose of ribavirin, and duration of treatment, as well as in the methodology of analysis and interpretation. Sood et al (24
) assessed the response of 103 patients infected with genotype 3 to a lower-dose regimen of peginterferon alfa-2b combined with weight-based ribavirin at 10-12 mg/kg/day.
The SVR rate for patients treated with peginterferon alfa-2b 1 μg/kg/week was 78.9%, compared to 92.6% with standard dose (1.5 μg/kg/week). The authors interpreted the results as showing equivalence; however, they defined a non-inferiority margin of up to 20% in response rates as the significance limit, a choice that could be debated. Similarly, Meyer-Wyss et al. (25
) found a difference of 21% (65% vs. 86%) between patients treated with 800 mg/day of ribavirin and 1 or 1.5 μg/kg/week of peginterferon alfa-2b, a difference that was not statistically significant. A non-significant difference of 9% was observed in another study (26
The consistent numeric difference between treatment groups (9% to 21%) in these studies suggests all had insufficient power to detect statistical significance. Furthermore, non-inferiority hypothesis testing is more appropriate than “classic” superiority analysis to address this question. In order to have a power of 80% to prove non-inferiority with the pre-determined margin of 10%, we would have had to include 270 patients in each group. Thus, our trial is obviously underpowered. However, the difference of 19% in SVR rates, which is in the same range as previously reported, suggests that the inability to prove non-inferiority hypothesis was not due to lack of power, but actually to true inferiority of the lower dose regimen.
In other studies, different doses of ribavirin and durations of therapy made the comparison to standard therapy difficult. An initial, dose-ranging study of peginterferon alfa-2a monotherapy (27
) did not find a difference in efficacy in non-genotype 1 infection between 90 and 180 μg/week, although the number of patients was small. Abergel et al (28
) found no difference in response rates of genotype 2 or 3 infected patients treated for 48 weeks with 800 mg/day of ribavirin and 0.75 or 1.5 μg/kg/week of peginterferon alfa-2b. A recently published uncontrolled study (29
), assessed 135 μg/week of peginterferon alfa-2a combined with 11 mg/kg/day of ribavirin and observed SVR (85%) and rapid virological response (70%) rates remarkably similar to the results in our SD group. These results suggest that the inferior response to a lower dose of peginterferon may be overcome by prolonging treatment duration or by increasing the dose of ribavirin, but direct comparisons were not made.
Analyzing the early dynamics of viral response to treatment may shed light on the mechanism of the dose response and of the genotypic difference in sensitivity to treatment. We demonstrate a marked effect of peginterferon dose on first phase decline with no effect on the second phase slope. These findings are consistent with those of Neumann et al (11
) as well as with the predictions of their model, in which the efficiency (ε) of interferon in blocking new virion production (the predominant determinant of the first phase) is dose-dependent. The second phase slope, although affected to a lesser degree by ε, is thought to mainly represent the rate of infected cell loss, by a mechanism yet unknown, and was not found to be dose-dependent. Similar to our results, a study comparing two doses of peginterferon alfa-2b combined with ribavirin in patients with genotype 1 infection (30
), found the first phase to be affected by peginterferon dose. The second phase slope was not explicitly reported but estimation from the data shown suggests it was similar between doses.
To further examine the effect of peginterferon dose, we measured serum levels of IP-10, an interferon-stimuated gene. Baseline serum levels of IP-10 have been reported to correlate inversely with SVR rates and rapid virological response (16
). In this study, this correlation was not found, probably because of the very high response rate achieved in genotypes 2 or 3 infection, and the fact that most treatment failures were due to relapse or intolerance to therapy. However, we did find a dose-dependent induction of IP-10, consistent with higher interferon effectiveness with higher doses of peginterferon. In both treatment groups, lower baseline IP-10 levels predicted a greater IP-10 induction on day 2 of treatment and, at least in the SD group, also predicted a greater virological response to peginterferon, manifested by a greater first phase decline and steeper second phase slope. These findings are concordant with reports showing that patients who have higher baseline expression of interferon-stimulated genes have a lower rate of response (15
). Thus, patients with chronic activation of the endogenous interferon system appear to have a limited ability to mount a further response to exogenously administered interferon. The lack of an intrahepatic ISG response appears to result in lower response rates for genotype 1 infected patients. However, for patients with HCV genotype 2 or 3 infection, even a less-than-optimal ISG response appears to be sufficient to achieve viral eradication.
Although many ISGs are induced by endogenous and exogenous interferon, it is unclear which specific ISGs mediate the antiviral activity and IP-10 is not necessarily one of those. Most of the published data on ISGs is derived from measurements of mRNA levels in the liver (15
) or peripheral blood mononuclear cells. There is little data on serum levels of secreted ISGs in chronic hepatitis C, apart from IP-10, for which baseline and on-treatment levels were shown to correlate with treatment response (16
). Thus, we selected IP-10 as a representative serum marker of baseline and on-treatment interferon responsiveness.
All patients who failed initial treatment responded to a retreatment course of 48 weeks with standard doses of peginterferon and ribavirin (per-protocol analysis). A qualitative comparison of the dynamics of viral response for individual patients to the two doses further supported the differences in viral responses observed between LD and SD groups. Furthermore, patients re-treated with the same dose of peginterferon had identical viral responses, during both the first and second phases, demonstrating the reproducibility of this antiviral response. These findings imply that interferon does not exert a selective pressure on the virus and that resistance to treatment (whether viral- or host-mediated) exists prior to therapy.
In conclusion, we demonstrate a dose-dependent response of patients with HCV genotype 2 or 3 infection, evident in the clinical response rate, viral dynamics and cytokine (IP-10) induction. As the lower dose was only marginally better in terms of tolerability, this regimen is not justified for most patients. However, LD therapy still yields reasonably high response rates, meaning that therapy need not be abandoned if patients cannot tolerate full dose therapy. Furthermore, failures can be successfully treated by a second, prolonged course using the standard dose of peginterferon. The genotypic difference in viral sensitivity to interferon allows patients infected with HCV genotype 2 or 3 to overcome barriers such as low peginterferon dose or pre-existing activation of the interferon system, barriers that play a greater role in the treatment of the more resistant genotype 1.