Randomized Trial of Albinterferon Alfa-2b Every 4 Weeks for Chronic Hepatitis C Virus Genotype 2/3

S. Pianko; S. Zeuzem; W.-L. Chuang; G. R. Foster; S. K. Sarin; R. Flisiak; C.-M. Lee; P. Andreone; T. Piratvisuth; S. Shah; A. Sood; J. George; M. Gould; P. Komolmit; S. Thongsawat; T. Tanwandee; J. Rasenack; Y. Li; M. Pang; Y. Yin; G. Feutren; I. M. Jacobson

Disclosures

J Viral Hepat. 2012;19(9):623-634. 

In This Article

Discussion

High rates of on- and post-treatment virologic responses were observed in all treatment groups, although SVR rates were greater with Peg-IFNα-2a 180 μg qwk. The RVR rates were significantly lower with albIFN q4wk, particularly when comparing 900 and 1200 μg with Peg-IFNα-2a qwk; however, these differences resulted in smaller differences in SVR rates than may have been expected from the differences in RVR. The results obtained with albIFN q4wk showed similar EVR, ETR and SVR rates to those reported in the phase 3 ACHIEVE-2/3 trial with albIFN q2wk in patients with HCV Gt 2/3.[6] In that study, however, patients treated with albIFN 900 μg q2wk achieved a similar RVR rate to that with Peg-IFNα-2a 180 μg qwk in comparison with the lower, dose-dependent rates observed with albIFN q4wk in the present study. In an earlier phase 2 study of albIFN q4wk in patients with HCV Gt 1, a similar pattern was noted, with lower RVR rates and similar, but numerically lower, SVR rates compared with Peg-IFNα-2a qwk.[11]

The differential effect of albIFN on RVR compared with Peg-IFNα-2a may be explained by the pharmacokinetic profile that follows albIFN q4wk administration.[5] The lower plasma IFN exposure occurring at week 4 with albIFN q4wk vs albIFN q2wk or Peg-IFNα-2a qwk may delay achievement of HCV RNA negativity compared with more frequent injections. A delay in achieving initial HCV RNA undetectability results in a shorter overall duration of HCV RNA negativity on treatment, a factor associated with the likelihood of achieving an SVR.[12] The differential in RVR rates may, therefore, play some role in the SVR imbalance observed in this study. This finding raises questions regarding the intensity of the initial antiviral pressure obtained with a q4wk regimen, and the potential benefit of increasing the frequency of albIFN injections over the first 4 weeks of treatment to bolster the initial virologic response to equal that attained by the standard of care, followed by an albIFN q4wk regimen for the remainder of the treatment course. This hypothesis is supported by the higher week-2 virologic response rates, but lower RVR rates with albIFN q4wk in this study, which may be the result of attenuation of antiviral effect with the q4wk regimen. The impact of increasing RVR rates by increasing dosing in the first 4 weeks of therapy remains controversial. Studies in both Gt 1 and 2/3 have shown that RVR is the most powerful on-treatment predictor of response,[13] although IFN induction studies have shown that enhanced initial on-treatment response rates may not improve SVR rates.[14] The impact of IFN-induced early virologic responses in the evolving era of direct-acting antiviral therapies associated with high RVR rates, such as boceprevir and telaprevir, remains to be elucidated.[15,16]

The IL28B Gt was not a predictor of SVR in this chronic HCV Gt 2/3 cohort, in contrast to previous findings in patients with chronic HCV Gt 1.[8] In two recent studies, the IL28B Gt was associated with RVR, but as in the present study, not with SVR.[17,18] In a separate study of Italian patients infected with HCV Gt 2/3, the IL28B Gt was a predictor of SVR in the 78 patients who failed to achieve an RVR.[10] In the present study, small patient numbers with available IL28B genotyping and failure to achieve an RVR precluded similar analysis. Larger patient cohorts stratified according to ethnicity are required to determine the influence of IL28B on HCV viral kinetics and virologic response following IFN/RBV-based therapy in Gt 2 and 3.

The overall incidence of AEs was high (>90%) and similar across treatment groups, with similar types of AEs. There was, however, a trend for more frequent severe AEs with albIFN, and the incidence of serious AEs was significantly higher with albIFN than with Peg-IFNα-2a. Unlike in previous albIFN studies, the rates of cough were the same across treatment groups.[6,7] As in the earlier trials, more respiratory infections and a case of restrictive lung disease were noted with albIFN treatment, although similar AEs are known to occur with Peg-IFNα, as well.[19,20] The persistent numeric imbalance in serious pulmonary AEs observed with albIFN vs Peg-IFNα across trials, however, creates concern regarding the pulmonary safety of the albIFN molecule. (Note: a full analysis of the changes in pulmonary function and respiratory effects of both albIFN and Peg-IFNα-2a in the present trial has been submitted for separate publication.) Alopecia and pyrexia rates were higher with albIFN vs Peg-IFNα-2a. The lower frequency of injections with albIFN q4wk was, however, associated with lower anaemia and neutropenia rates, and thus fewer IFN dose reductions than with Peg-IFNα-2a qwk. Overall, the 900-μg dose provided the best safety profile of the albIFN treatment groups. The improvement in haematologic profile appears to be related to the pharmacokinetic profile of albIFN q4wk, with the longer interval between injections allowing for recovery from IFN-induced bone marrow suppression. Although the albIFN doses used in this q4wk study were lower on a monthly average than the 900-μg q2wk dose used in the ACHIEVE-2/3 trial,[6] pyrexia and alopecia rates remained higher than with Peg-IFNα-2a 180 μg qwk without a dose–response, suggesting that peak serum albIFN concentration may have driven these AEs rather than average concentration. Alopecia rates were higher in all albIFN groups than with Peg-IFNα-2a; whether alopecia rates were driven by peak serum concentration or were because of an intrinsic property or tissue distribution of the albIFN molecule is not clear.

While the focus of antiviral therapy for chronic HCV is projected by some to ultimately move away from IFN-based therapies, IFN-free regimens have not yet been developed beyond early trials.[21] Interferon may be required to diminish resistance to direct-acting antiviral agents, and an IFN platform with a reduced frequency of injections may be an important strategy if efficacy can be maintained with an improved AE profile. The present study demonstrates the ability to reduce the frequency of albIFN injections from q2wk to q4wk in a chronic HCV Gt 2/3 population with a small, statistically insignificant reduction in efficacy. It remains to be determined whether the combination of long-acting IFNs administered q4wk with direct-acting antiviral agents or intensification of IFN exposure in the first 4 weeks of therapy can overcome the reduction in efficacy seen in the present study.

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