Safety and efficacy of Hansenula-derived PEGylated-interferon alpha-2a and ribavirin combination in chronic hepatitis C Egyptian children

Abstract

Aim: To investigate the safety and efficacy of a Hansenula-derived PEGylated (polyethylene glycol) interferon (IFN)-alpha-2a (Reiferon Retard) plus ribavirin customized regimen in treatment-naïve and previously treated (non-responders and relapsers) Egyptian children with chronic hepatitis C infection.

Methods: Forty-six children with chronic hepatitis C virus (HCV) infection were selected from three tertiary pediatric hepatology centers. Clinical and laboratory evaluations were undertaken. Quantitative polymerase chain reaction (PCR) for HCV-RNA was performed before starting treatment, and again at 4, 12, 24, 48, 72 wk during treatment and 6 mo after treatment cessation. All patients were assigned to receive a weekly subcutaneous injection of PEG-IFN-alpha-2a plus daily oral ribavirin for 12 wk. Thirty-four patients were treatment-naïve and 12 had a previous treatment trial. Patients were then divided according to PCR results into two groups. Group I included patients who continued treatment on a weekly basis (7-d schedule), while group II included patients who continued treatment on a 5-d schedule. Patients from either group who were PCR-negative at week 48, but had at least one PCR-positive test during therapy, were assigned to have an extended treatment course up to 72 wk. The occurrence of adverse effects was assessed during treatment and follow up. The study was registered at www.ClinicalTrials.gov (NCT02027493).

Results: Only 11 out of 46 (23.9%) patients showed a sustained virological response (SVR), two patients were responders at the end of treatment; however, they were lost to follow up at 6 mo post treatment. Breakthrough was seen in 18 (39.1%) patients, one patient (2.17%) showed relapse and 14 (30.4%) were non-responders. Male gender, short duration of infection, low viral load, mild activity, and mild fibrosis were the factors related to a better response. On the other hand, patients with high viral load and absence of fibrosis failed to respond to treatment. Before treatment, liver transaminases were elevated. After commencing treatment, they were normalized in all patients at week 4 and were maintained normal in responders till the end of treatment, while they increased again significantly in non-responders (P = 0.007 and 0.003 at week 24 and 72 respectively). The 5-d schedule did not affect the response rate (1/17 had SVR). Treatment duration (whether 48 wk or extended course to 72 wk) gave similar response rates (9/36 vs 2/8 respectively; P = 0.49). Type of previous treatment (short acting IFN vs PEG-IFN) did not affect the response to retreatment. On the other hand, SVR was significantly higher in previous relapsers than in previous non-responders (P = 0.039). Only mild reversible adverse effects were observed and children tolerated the treatment well.

Conclusion: Reiferon Retard plus ribavirin combined therapy was safe. Our customized regimen did not influence SVR rates. Further trials on larger numbers of patients are warranted.

Keywords: Children; Chronic hepatitis C; Hansenula polymorpha; PEGylated interferon; Response rate; Ribavirin; Treatment.

Figures

Figure 1

Treatment algorithm and response to therapy. At weeks 4, 24 (52.17%) patients attained a rapid virological response (RVR) and 22 (47.82%) had no RVR. At week 12, five patients (10.86%) had breakthrough, while the remaining 19 patients had an early virological response (EVR). Those patients, in addition to five patients who turned negative from ones with no RVR formed a total of 24 (52.17%) patients with EVR. At week 24, those who had breakthrough continued to be polymerase chain reaction (PCR)-positive and eight patients from those with EVR had breakthrough. The remaining 16 patients, in addition to two patients from those with no EVR, turned PCR-negative, making a total of 18 (39.13%) patients with negative PCR. At week 48, three of those 18 patients had breakthrough, while the remaining 15 patients and one patient from those positive at week 24, in addition to three patients who had breakthrough at week 24 (making a total of 19 patients), had negative PCR. Of the 19 negative-PCR patients, nine had an SVR at week 72 and two patients dropped out. The remaining eight patients had an extended 6-month therapy (three patients had breakthrough and five patients were PCR-negative at their ETR). At week 96, three out of five patients with extended course had relapse, while the other two patients attained an SVR, making the total SVR 11 out of 44 (25%). EOT: End of treatment.

Figure 2

Alanine aminotransferase and aspartate aminotransferase mean levels during treatment in responders and non-responders. A: Alanine aminotransferase (ALT) mean levels remained normal in responders all through the follow up period, while in non-responders, after starting as normal, they increased again to significantly higher levels than in responders from week 12 onwards, especially at weeks 24 and 48 (1P = 0.007, 0.003 respectively); B: Aspartate aminotransferase (AST) mean levels remained normal in responders all through the follow up period, while in non-responders, after starting as normal, they significantly increased again in week 24 (1P = 0.007) and once more in week 72. The dashed line represents the upper limit of normal.