Optimizing treatment for HCV genotype 4: PEG-IFN alfa 2a vs. PEG-IFN alfa 2b; the debate continues

Authors

  • Gamal Esmat,

    Corresponding author
    1. Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
    2. Tropical Medicine Department, National Hepatology & Tropical Medicine Research Institute, Cairo, Egypt
    • Correspondence

      Gamal Esmat, MD, Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt

      Tel: +202 235728360; +202 235676138

      Fax: +202 235728131; +202 23682774

      e-mail: gesmat@gamalesmat.com

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  • Mohamed El Kassas,

    1. Tropical Medicine Department, National Hepatology & Tropical Medicine Research Institute, Cairo, Egypt
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  • Mohamed Hassany,

    1. Tropical Medicine Department, National Hepatology & Tropical Medicine Research Institute, Cairo, Egypt
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  • Mohamed Gamil,

    1. Tropical Medicine Department, National Hepatology & Tropical Medicine Research Institute, Cairo, Egypt
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  • Maissa El Raziky

    1. Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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Abstract

Hepatitis C virus (HCV) remains one of the leading causes of morbidity and mortality worldwide. Combined therapy with pegylated interferon (PEG-IFN) and ribavirin is the current standard of care treatment for HCV genotype 4. Two types of PEG-IFN are commercially available. The limited number of trials that were conducted for HCV genotype 4 and the few head to head comparisons make it impossible to know which is the best option? In this article we review all available PEG-IFN trials performed worldwide for HCV genotype 4 since 2004. Unless another molecule is developed as a standalone for the treatment of HCV, PEG-IFN will continue to be a source of debate.

Abbreviations
EVR

early virologic response

HCV

hepatitis C virus

HIV

human immunodeficiency virus

PEG-IFN

pegylated interferon

RBV

ribavirin

RVR

rapid virologic response

SOC

standard of care

SVR

sustained virological response

Chronic hepatitis C virus (HCV) infection is one of the most challenging global health problems [1, 2]. It is the main cause of cirrhosis, hepatocellular carcinoma and the most common indication for liver transplantation worldwide [2-4]; it also enhances the morbidity of other diseases such as metabolic diseases [5]. Optimizing treatment strategies and options is a priority to obtain better results to decrease disease related complications. In the past decade, pegylated interferon (PEG-IFN) in combination with ribavirin has been the standard of care for HCV in all international guidelines. These guidelines do not discriminate between the two available forms of PEG-IFN: alfa-2a (40KD) (Pegasys®; Hoffmann-LaRoche, Basel, Switzerland) and PEG-IFN alfa-2b (12KD) (Peg-Intron®; MSD, Whitehouse Station, NJ, USA) [2, 6, 7]. Although PEG-IFN alfa-2a and alfa-2b have many differences in pharmacokinetic and pharmacodynamic properties [8, 9], previous non-comparative studies have suggested that efficacy and safety profiles are similar [10, 11]. The results of head to head comparative studies are discrepant. The similar efficacy and safety results were repeated in some recent large randomized controlled studies despite being exclusively conducted on genotype 1 HCV in western world countries [12] and this was also repeated in a study enrolling patients with HIV co-infection [13]. Different results were obtained from two different randomized head to head Italian studies [14, 15] which showed that results with PEG-IFN alfa-2a were better than (PEG-IFN alfa-2b) for sustained virological response (SVR). In Asia, a large multicenter Korean study rekindled the debate because it did not show any difference in response and safety between the two types and this suggested a possible difference in response to IFN based on ethnicity and genotype [16] which was also found in a recent Turkish study [17].

At present there are six meta-analyses published in the literature comparing the two types of PEG-IFN. The results of these studies are heterogenous. The first meta-analysis included retrospective studies only. This is the only study that found PEG-IFN alfa-2b to be better [18]. Another study confirmed that both types of IFN were similar in the treatment of genotype 1 [19] while the four remaining studies showed that SVR was obtained more frequently with combination PEG-IFN alfa-2a in chronic HCV patients [20-23]. The most recent of these meta-analyses mentioned that PEG-IFN alfa-2a is better especially in genotypes 1 and 4 [23].

Figure 1.

PEG-IFN trials on HCV G4 included in or excluded from the review.

Since 2004, HCV genotype 4 has been evaluated in PEG-IFN trials. Finding these trials is not difficult because they are relatively few. A Medline search between 2004 and 2013 revealed 42 HCV genotype 4 clinical trials. We have harmonized the data by excluding the following trials:

  1. Trials that didn't discriminate between PEG-IFN types in data collection (nine trials).
  2. Trials including patients with combination HCV-HIV infection (three trials).
  3. Trials performed in HCV genotype 4 patients along with other genotypes (three trials).
  4. Trials that used additional drugs (three trials)
  5. Only one trial that used PEG-IFN as monotherapy in treating acute HCV.

The 23 valid trials are summarized in Tables 1 and 2.

Table 1. Trials conducted for HCV genotype 4 using PEG-Interferon α2a
AuthorStudy CountryPatients numberDescriptionCirrhotics %SVR %
  1. EVR, early virological response; HCV, hepatitis C virus; PEG-IFN, pegylated interferon; RVR, rapid virologic response; SVR, sustained virological response.

Derbala et al. [28]Qatar73Advanced fibrosis (F3–F4) in 34.265.8
Males et al. [29]Egypt1001461
Ferenci et al. [30]Austria30All the enrolled patients achieved RVR and the total treatment duration was 24 weeks86.7
Gad et al. [24]Egypt9014.464.4
El Makhzangy et al. [31]Egypt9514.761.1
Varghese et al. [32]Kuwait3063.3
De Galocsy et al. [33]Belgium78Sum of data from two randomized phase III trials BerNar-1 and BerNar-2, comparing (SVR) rates between G1, G4 patients51.3
Dimitroulopoulos et al. [34]Greece60

Two groups:

Group A: 30 European

Group B: 30 Egyptians

36.7 in group A

26.7 in group B

Kamal et al. [25]Egypt109070.6
Papastergiou et al. [27]Greece80Multiethnic (Greek-Egyptians)47.5
El-Shazly et al. [35]Egypt40

Two groups:

A: 20 patients with well controlled DM

B: 20 patients without DM

0

(16 patients had no fibrosis assessment)

75 in group A

65 in group B

El Khayat et al. [36]Egypt10287 patients achieved EVR randomized to group A (treated for 24 weeks, No = 43) and group B (treated for 48 weeks, No = 44)

26 in group A

18 in group B

70 in group A

73 in group B

Urquijo et al. [37]Spain19852.7
El Raziky et al. [26]Egypt19856.359.6

Three published Egyptian trials compared both PEG-IFN types in a head to head clinical trials including only patients with genotype 4. All these three trials showed that PEG-IFN alfa-2a was significantly better than PEG-IFN alfa-2b for SVR rates. The first study in 196 patients showed that the SVR in the PEG-IFN alfa-2a group vs. PEG-IFN alfa-2b group was 64.4% vs. 53.2%, respectively; P = 0.04 [24],the second study in 217 patients showed that the SVR was 70.6 vs. 54.6%, respectively; P = 0.017 [25]. The third trial was a large retrospective cohort of 3718 Egyptian chronic HCV patients in a real life comparison and showed that the SVR rates were 59.6% vs. 53.9% respectively [26]. These data support a Greek trial also comparing both types of PEG-IFN in the treatment of 177 HCV genotype 4 patients and it also showed that PEG-IFN alfa-2a was better than PEG-IFN alfa-2b with SVR rates of (47.5% vs. 38.1%) for PEG-IFN alfa-2a & PEG-IFN alfa-2b respectively [27].

Conclusion

Pegylated interferon has improved the SVR results in a large proportion of patients with HCV. In an era when new oral antiviral drugs are becoming available thanks to the pharmaceutical industry and researchers, the two forms of PEG-IFN have been a key element in creating a competition resulting in a reduction in prices, in many sponsored clinical trials and a gradual increase in access to treatment for many patients. Nevertheless, many of the head to head comparison trials have been designed and sponsored by the pharmaceutical industry with targets that are not only scientific. Thus, a careful analysis must be made when trying to decide which PEG-IFN provides better results, and in our opinion, the debate is still ongoing.

Disclosure

The authors do not have any disclose to report.

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