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

Results

Patient Disposition and Demographics

In all, 623 patients were screened, 391 were randomized, and 388 received ≥1 dose of study medication, constituting the ITT population (Fig. 1). Patient demographics and disease characteristics were similar among treatment groups (Table 1). About half of patients were enrolled in Asian countries, and most (72%) had HCV Gt 3. Using the rs12979860 tag single-nucleotide polymorphism, the IL28B Gt was recorded in 117 patients: 61 (52.1%) had the CC Gt, 52 (44.4%) had CT, and 4 (3.4%) had TT. Patients from Taiwan had a higher frequency of the IL28B CC Gt (28/31; 90.3%) than those from Western countries (33/86; 38.4%), a geographic distribution that may be reflected in the higher frequency of the IL28B CC Gt in patients with HCV Gt 2 (41/61; 67.2%) vs Gt 3 (20/56; 35.7%). This is a result of the increased frequency of Gt 2 in the Asian patients. Liver histology was not assessed in this study following standard treatment guidelines for the HCV Gt 2/3 population.[3]

Figure 1.

Study disposition. AE, adverse event; albIFN, albinterferon alfa-2b; HCV, hepatitis C virus; Peg-IFNα-2a, pegylated interferon-α-2a; EVR, early virologic response at week 12.

Efficacy

The SVR rates in the ITT population were 84.6%, 75.5%, 75.7% and 78.1% with Peg-IFNα-2a 180 μg qwk and albIFN 900, 1200 and 1500 μg q4wk, respectively (P = NS; Fig. 2). Rapid virologic responses occurred in a dose-dependent fashion in the three albIFN groups, with lower rates than with Peg-IFNα-2a (49.0% [P < 0.001], 60.2% [P = 0.01] and 70.5% with albIFN 900, 1200 and 1500 μg, respectively, vs 78.2%). The EVR and ETR rates were high in all patients. Virologic breakthrough (HCV RNA levels >LOQ on treatment after having previously achieved levels <LOD) was observed in one patient each in the Peg-IFNα-2a and albIFN 1200-μg groups, but not in the other albIFN groups. Relapse rates ranged from 13.3% to 18.1%.

Figure 2.

Virologic response (a, intention-to-treat population) and relapse rates (b). Relapse defined as hepatitis C virus (HCV) < limit of detection (20 IU/mL) at end of treatment and becoming detectable at post-treatment visit. a P <0.001; b P = 0.01. albIFN, albinterferon alfa-2b; ETR, end-of-treatment response (HCV RNA < limit of detection); EVR, early virologic response at week 12 (HCV RNA < limit of quantification [43 IU/mL] or >2-log reduction); Peg-IFNα-2a, pegylated interferon-α-2a; RVR, rapid virologic response at week 4 (HCV RNA < limit of quantification); q4wk, once every 4 weeks; qwk, once every week; SVR, sustained virologic response 24 weeks after treatment (HCV RNA < limit of detection).

Viral Kinetics

Viral load decline at week 2 was significantly greater with albIFN 1200 μg (P = 0.003) and 1500 μg (P = 0.01) than with Peg-IFNα-2a (Fig. 3). At week 4, all albIFN groups had lesser declines than did the Peg-IFNα-2a group, the difference reaching statistical significance with albIFN 900 μg (P = 0.001), reflecting the differences in RVR rates. Viral load changes between baseline and week 12, however, were similar, in line with EVR rates across all groups.

Figure 3.

Mean hepatitis C virus (HCV) RNA (log10 IU/mL) by week in (a) overall intention-to-treat population and (b) subset of 38 patients with intensive viral pharmacokinetics. albIFN, albinterferon alfa-2b; FU, follow-up; LOD, limit of detection; LOQ, limit of quantitation; Peg-IFNα-2a, pegylated interferon-α-2a; q4wk, once every 4 weeks; qwk, once every week.

In the 38-patient subgroup with intensive viral kinetics, the pattern of viral load decline was comparable to that of the overall population between weeks 4 and 12. During the first 4 weeks, viral load decline was greater with Peg-IFNα-2a at weeks 2, 3 and 4 than with albIFN 900 μg. After the second albIFN 900-ug injection at week 4, viral suppression was similar to that with Peg-IFNα-2a and the other albIFN doses.

Baseline Predictors of Sustained Virologic Response

In general, SVR rates by patient subgroup reflected the differences between treatment arms observed in the overall population (Table S1). As expected, SVR rates were higher in younger patients and those with HCV Gt 2, baseline HCV RNA <800 000 IU/mL, low γ-glutamyl transpeptidase at baseline and lower body weight. In harder-to-treat patients with HCV Gt 3 and baseline HCV RNA >800 000 IU/mL, SVR rates (range 66–74%) were ~10% lower than that of the whole population.

Interleukin 28B Genetic Variation and Virologic Response

In the subset of 117 patients with IL28B genetic testing, the IL28B genetic variation did not affect baseline viral load: 72.1% of patients with the CC Gt had a baseline HCV RNA level >800 000 IU/mL vs 64.3% with a non-CC Gt (P = NS). There was no difference in overall SVR rates between patients with the CC Gt (50/61; 82.0%) and CT or TT Gt (44/56; 78.6%; P = NS), and no difference within treatment groups (Table 2). Virologic response rates did not differ between the 117 patients with IL28B genetic testing and the 271 who were not genotyped: 62.4%vs 64.2% for RVR and 80.3%vs 77.1% for SVR. The IL28B genetic variation did not demonstrate a consistent effect on RVR. Overall, RVR rates were 67.2%vs 57.1% in patients with vs without the CC Gt (P = NS). Within treatment groups, differences in RVR between patients with and without the CC Gt were not consistent and were limited by the small sample size. In multivariate analyses, the IL28B Gt was not identified as a significant factor of virologic response. Significant variables for RVR and SVR were viral load at baseline, HCV Gt and HCV disease duration, as well as albIFN 900-μg q4wk vs Peg-IFNα-2a 180-μg qwk treatment group for RVR only and patient age for SVR only (Table 3). Because of the low number of patients who did not achieve RVR and were also tested for the IL28B Gt (3 with Peg-IFNα-2a), it could not be determined whether the host IL28B Gt was a predictor of response in this patient subset, as previously reported.[10]

On-treatment Predictors of Sustained Virologic Response

Rapid virologic response, as well as HCV RNA <LOD at week 2 or 4, had a high positive predictive value for SVR in all treatment groups (Table S2). The negative predictive value of RVR for SVR was, however, lower with albIFN 900 μg (40.4%) and 1200 μg (46.3%) than with albIFN 1500 μg (54.8%) or Peg-IFNα-2a (52.9%).

Adherence to Therapy

Adherence was high in all treatment groups, with 85.9–95.1% of patients achieving ≥80% adherence to both IFN and RBV treatment (Table S3). Fewer patients had IFN dose reductions with all albIFN doses than with Peg-IFNα-2a 180 μg qwk, and fewer RBV dose reductions occurred with albIFN 900 and 1200 μg q4wk. The proportions of patients with ≥80% adherence to IFN were higher with albIFN (92.2–98.0%) than with Peg-IFNα-2a (88.5%; P = 0.05), although the proportions of patients with ≥80% adherence to RBV were similar in all treatment groups (89.5–95.1%). Overall, 3.8%, 5.8%, 5.8% and 6.7% of patients with Peg-IFNα-2a and albIFN 900, 1200 and 1500 μg, respectively, did not complete the study.

Adverse Events

Adverse events leading to dose reduction or interruption of IFN or RBV were less frequent with albIFN 900 μg q4wk than with Peg-IFNα-2a 180 μg qwk (P = 0.03; Table 4). The numerically higher rate of patients with a serious AE in the albIFN 900-μg group (10.8%) than in the Peg-IFNα-2a (3.8%) and albIFN 1200-μg (2.9%) and 1500-μg (2.9%) groups was because of the high number of post-treatment serious AEs (six of 11; Table 5). One death was reported in the study with albIFN 1200 μg because of intentional narcotic overdose.

The rates of neutropenia <750 and <500/mm3 were significantly lower with albIFN 900 μg q4wk than with Peg-IFNα-2a 180 μg qwk (5.0%vs 17.9% [P = 0.03] and 1.0%vs 9.0% [P = 0.01], respectively; Table 4); a similar trend was observed with the other albIFN doses. Anaemia (haemoglobin <10 g/dL) was also less frequent with albIFN 900 μg (11.9%) and 1200 μg (18.4%) than with Peg-IFNα-2a (25.6%; overall comparison P = 0.02). The reduced frequency of haematologic AEs led to fewer albIFN dose reductions.

The common AEs associated with albIFN treatment were those typically observed with IFNα (Table 4). The incidence rates of pyrexia and alopecia were higher with albIFN than with Peg-IFNα-2a. A dose–response relationship was noted in the albIFN groups for alopecia, but not for pyrexia. A trend for a lower incidence of AEs was seen with albIFN 900 μg q4wk vs Peg-IFNα-2a 180 μg qwk for fatigue and asthenia. Most other AEs had similar incidence rates across treatment groups. These common AEs were mostly mild in severity and rapidly reversible after treatment termination.

Pulmonary Adverse Events

Rates of cough were similar with Peg-IFNα-2a and albIFN 900 and 1200 μg, but higher with 1500 μg (Table 4). Dyspnoea was reported in 11.3% of patients and exertional dyspnoea in 7.0%, with no difference between treatment groups. Most of these common pulmonary AEs were of mild intensity, and no severe case was reported.

Four serious pulmonary AEs occurred with albIFN vs none with Peg-IFNα-2a. Three cases of pneumonia occurred with albIFN 900 μg – one of which led to treatment discontinuation – and one with 1200 μg, whereas none was reported with albIFN 1500 μg or Peg-IFNα-2a (Table 5). All cases of pneumonia resolved after appropriate therapy. One case of restrictive lung disease – reported at week 12 with albIFN 1500 μg – led to treatment discontinuation and reversed after the end of treatment.

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