Optimizing Treatment with Pegylated Interferon-Ribavirin of Genotype 3 Chronic Hepatitis C: More Questions than Answers

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Article Information:


Group: 2008
Subgroup: Volume 8, Issue 4, Autumn
Date: November 2008
Type: Review Article
Start Page: 304
End Page: 309

Authors:

  • Alessio Aghemo
  • First Division of Gastroenterology, Fondazione IRCCS Maggiore Hospital, University of Milan, Milan 20122, Italy
  • Roberta D'Ambrosio
  • A.M. Migliavacca Center for Liver Disease, First Division of Gastroenterology, Fondazione IRCCS Maggiore Hospital, University of Milan, Milan, Italy
  • Maria Grazia Rumi
  • A.M. Migliavacca Center for Liver Disease, First Division of Gastroenterology, Fondazione IRCCS Maggiore Hospital, University of Milan, Milan, Italy
  • Massimo Colombo
  • A.M. Migliavacca Center for Liver Disease, First Division of Gastroenterology, Fondazione IRCCS Maggiore Hospital, University of Milan, Milan, Italy

      Correspondence:

      Affiliation: First Division of Gastroenterology, Fondazione IRCCS Maggiore Hospital, University of Milan
      City, Province: Milan 20122,
      Country: Italy
      Tel: +39 025 5035432
      Fax: +39 025 0320410
      E-mail: [email protected]

Abstract:


Hepatitis C virus (HCV) is the foremost cause of parenterally transmitted non-A, non-B hepatitis. Effective treatment with Interferon (IFN) based regimens has been shown to reduce morbidity and mortality, improve health-related quality of life, and avoid the huge costs associated with end stage liver disease. HCV-3 has been associated in Europe and the USA to illicit drug abuse in the 70's, while recent epidemiological reports have shown that HCV-3 prevalence is on the rise in both Western Europe and in Middle East. The standard of care for patients with HCV-3 is a 24 week therapy regimen with a combination of Pegylated Interferon (Peg-IFN) and Ribavirin (RBV). Despite the cumulative high rates of sustained virological response (SVR) obtained with this schedule of treatment, it is now clear that a subgroup of patients exists in which lower rates of SVR are achieved. Bridging fibrosis/cirrhosis, high baseline viremia and lack of rapid virological response (RVR) have been identified as predictors of treatment failure in many studies. Recently, "allocation" and randomization trials based on HCV-RNA negativity at week 4 (RVR) have evaluated the chance of abbreviating the treatment schedule to 12-16 weeks, since RVR emerged as a strong predictor of SVR. In this review article we will discuss the current therapeutic strategies in HCV-3 to understand in which subset of patients further treatment customization is possible.

Keywords: Chronic Hepatitis C;Pegylated Interferon;Ribavirin;Treatment

Manuscript Body:


Introduction 

Hepatitis C virus (HCV) is the primary cause of parenterally transmitted non-A, non-B hepatitis (1, 2). Chronic infection is associated with a lifetime risk of liver fibrosis, cirrhosis and hepatocellular carcinoma (3, 4). Effective treatment with Interferon (IFN)-based regimen has been shown to reduce morbidity and mortality, improve health-related quality of life, and avoid the huge costs associated with end-stage liver disease (5). Antiviral therapy for the treatment of HCV infection has evolved in recent years from IFN monotherapy to combination therapy with IFN and Ribavirin (RBV), to the present standard of care, namely Pegylated IFN (Peg-IFN) and RBV (6, 7). Among the several factors that have become evident as predictors of response to antiviral therapy, HCV genotype is the most important viral factor (8-10). Worldwide, HCV circulates as 6 major genotypes which are characterized by a different sensitivity to IFN and typical geographic distribution (11).

HCV-3 has been associated in Europe and the USA to illicit drug abuse in the 70's, and is considered to have spread from the Indian subcontinent. Recent epidemiological reports have shown that HCV-3 prevalence is on the rise in both Western Europe and in the Middle East, with immigration being the main culprit and intravenous drug users (IDUs) remaining at the core of HCV-3 ongoing epidemic phase (12-14). Infection by drug abuse is, in fact, the most frequent route for HCV transmission, with 50-90% of users having been infected after 5 years of illicit use of intravenous drugs. As a consequence, HCV-3 together with genotypes 1a and 4 has replaced the more common genotypes 1b and 2, spreading into Europe, among IDU and over the general population of HCV infected, probably by unsafe medical procedures, sexual exposure and vertical transmission (15, 16).

From a therapeutic standpoint, HCV genotypes 2 and 3 have long been considered as "easy to treat" genotypes, being associated with significantly higher rates of sustained virological response (SVR) compared to genotypes 1 and 4 (8-10). In fact, patients infected with HCV-2 and HCV-3 achieve SVR rates of 70-90% following 24 weeks of treatment, in contrast with those infected with HCV-1 and HCV-4 who need 48 weeks of therapy to achieve an SVR rate of roughly 40-50%. Although a precise biological explanation for the different SVR rates among genotype 1 |n|s. genotypes 2 and 3 remains elusive, it has been clearly demonstrated that viral kinetics in response to IFN therapy play an important role; and despite the difference in the first and the second phase of decline, the viral decline among "easy to treat" genotypes is up to eight times faster than that observed in other genotypes (17, 18).

As a consequence of their favourable response to antiviral therapy, genotypes 2 and 3 infections have frequently been grouped together when it comes to analyzing the efficacy data of clinical trials.  However, more recent studies suggest that this practice should be abandoned and that data derived from HCV-2 patients should not be extrapolated to HCV-3 patients since HCV-3 shows a different pattern of response to Peg-IFN and RBV than HCV-2 which ultimately translates into lower SVR rates after a 24 week treatment course (19).

In this article we will review the available current knowledge on the treatment of HCV-3, and analyze how treatment can be further customized in this subgroup of patients.

 

Materials and Methods

A systematic literature search using the PubMed citation database from 2001 to 2008 was performed to identify English-language articles based on the efficacy of antiviral therapy among patients infected with HCV-3 by using the following terms alone or in combination: Interferon, Peg-Interferon, Ribavirin, HCV, genotype 3, genotype 2, antiviral therapy, Sustained Virological Response (SVR), Rapid Virological Response (RVR), abbreviated therapy. Reference lists of all identified articles were checked for relevance.

We included all the studies evaluating abbreviated treatment schedules but only the prospective and retrospective studies in which data of HCV-3 patients could be extrapolated from those with HCV-2.

As a policy, we chose to not include data derived from abstract books of international meetings. 

 

Differences between HCV-2 and HCV-3

The long-lasting practice to assess safety and efficacy of IFN-based therapies by cumulatively pooling data of HCV-2 and HCV-3 patients has been recently challenged by the Zeuzem study (19) which invariably demonstrated HCV-3 to be less sensitive to Peg-IFN alpha-2b (Pega2b) and RBV than HCV-2, suggesting that this difference was the consequence of higher rates of post-treatment relapse in the former group.

Following this study, information has gathered in the literature confirming these results. In fact, even in the absence of a randomized controlled study, HCV-3 patients have invariably achieved lower SVR rates when compared to HCV-2 patients in all studies (Table 1) (19-23). Moreover, in these studies, steatosis and HCV viremia emerged as important predictors of treatment failure in HCV-3 but not in HCV-2 patients, suggesting that moderators of treatment outcome differ between these two genotypes.

 

Table 1. Differences in SVR rates between HCV genotype 2 and 3.

Author

No.

HCV-2

No.

HCV-3

 

 

 

 

 

Zeuzem et al. (19)

42

93%

183

79%

Mangia et al. (20)

53

76%

17

76%

Shiffman et al. (21)

356

75%

369

66%

Powis et al. (22)

67

81%

101

70%

Ferenci  et al. (23)

18

78%

123

67%

 

Predictors of treatment outcome in HCV-3

The standard of care for patients with HCV-3 is a 24 week therapy regimen with a combination of Peg-IFN alpha-2a (Peg|a|2a) or Peg-IFN alpha-2b plus RBV (24, 25). This recommendation stems from the Hadziyannis (10) study and the Zeuzem (18) study respectively, which showed no benefit of a 48 week treatment schedule in terms of overall SVR rates. However, data on the efficacy of IFN-based therapies, as well as the identification of moderators of treatment outcome in HCV-3 patients, must be considered with caution since they are mostly derived from further optimization or small cohort studies which might have been underpowered to detect significant differences in the subgroup analysis. Despite all these problems, it is noteworthy that bridging fibrosis/cirrhosis, high baseline viremia and lack of rapid virological response (RVR), i.e. HCV-RNA positivity at week 4 of treatment, have consistently emerged as predictors of treatment failure (Table 2) (19, 21, 22, 26, 27).

 

Table 2. Predictors of treatment failure in HCV-3 with corresponding SVR rates.

Variable

 

SVR

p

Bridging fibrosis/cirrhosis

 

 

 

     Aghemo et al. (26)

Yes vs. no

35% vs.  84%

P=0.0005

     Powis et al. (22)

Yes vs. no

17% vs. 70%

P=0.004

High level of viremia

 

 

 

     Zeuzem et al. (19)

Yes vs. no

70% vs. 86%

P=0.015

     Von Wagner et al. *(27)

Yes vs. no

67% vs. 84%

P=0.01

Steatosis > 5%

 

 

 

     Zeuzem et al. (19)

Yes vs. no

NA°

P=0.015

Absence of RVR

 

 

 

     Zeuzem et al. (19)

Yes vs. no

69% vs. 85%

P=0.038

     Shiffman et al. *(21)

Yes vs. no

39% vs. 85%

P<0.0001

* Standard duration group
° Not available

 

While the role of cirrhosis as a predictor of treatment failure in HCV-1 has been extensively demonstrated, its influence on SVR rates in HCV-3 patients has been only recently shown. In fact, the small number of HCV-3 cirrhotic patients enrolled in registration trials, coupled with the joint analysis of HCV-2 and 3 patients, prevented its emergence as a significant moderator of treatment outcome. Two recent papers from Italy and Canada, analyzing HCV-3 patients separately, have clearly demonstrated the dismal SVR rates achieved by Peg-IFN alpha-2b and Peg-IFN alpha-2a combo therapy in the presence of cirrhosis (35% and 17% respectively) (22, 26). While in the Italian paper this finding could be clearly attributed to the high rates of post-treatment relapse observed in cirrhotic patients (57% n|s. 9%), this information was missing in the Canadian study (28). 

Similarly, two studies showed that high baseline viremia determines lower SVR rates in HCV-3 patients (19, 27). However, a controversy exists on which cut-off value is more appropriate to define high viral load (>600.000 IU/mL n|s. >800.000 IU/mL) and on which method is more reliable for HCV-RNA quantification, making this information difficult to extrapolate into clinical practice.

The evidence on the negative predictive power of lack of RVR is more solid, since patients who are still HCV-RNA positive at week 4 have achieved SVR rates of between 39% and 59% in published studies (19, 21). These data, in fact, have been generated by multicenter studies enrolling a large number of patients and by definition are less likely to be influenced by enrolment biases and carry the strongest grade of evidence (29). Less clear is the influence of steatosis on treatment outcome, especially since HCV-3 has been shown to directly induce liver steatosis which regresses following viral eradication (30). While initial data suggested >5% steatosis to be associated with lower SVR rates, this finding could not be confirmed by other subsequent studies (31, 32), especially if non-invasive methods like fibroscan are used to define the degree of liver fibrosis (33).

The role of race has been recently investigated in an English study conducted among Caucasian and Asian HCV-3 infected patients. In this study, lower rates of SVR were observed in the latter group, suggesting that race may in fact play a role in determining treatment outcome. However, this study is far from being conclusive, mainly due to the small sample size and the possible confounding role of the higher prevalence of cirrhotics among the Asian subgroup of patients (34).

Taken altogether, these data clearly demonstrate the presence of a subgroup of HCV-3 patients that should not be considered as "easy to treat"; however, due to limitations either in the study design or in the sample size of the studies, these data unfortunately cannot be considered as conclusive evidence, and the interplay between these variables is still unknown.

 

Abbreviated therapy for HCV-3 patients

The finding that maximal SVR rates could be achieved in HCV-3 patients with 24 weeks of treatment has prompted researchers to investigate even shorter durations of treatment for these patients. In fact, shorter treatment durations with retained efficacy would ameliorate the safety profile while reducing the costs of Peg-IFN plus RBV therapy. Following a pilot study by Dalgard et al. (35) published in 2004, 5 further studies with different designs investigated this issue (Table 3) (20, 21, 27, 36, 37).

 

Table 3. Studies investigating abbreviated therapies in patients infected with HCV-3.

Study design

No. of patients

Therapy/Duration

Allocation by RVR

 

 

 

   Dalgard et al. (35)

98

Pega2b + Rbv w.b.

14w

   Mangia et al. (20)

53

Pega2b 1.0 + Rbv w.b

12w

 

 

 

 

Randomization by RVR

 

 

 

   Von Wagner et al. *(27)

112

Pega2a + Rbv w.b

16w

   Dalgard et al. (36)

298

Pega2b + Rbv w.b

14w

 

 

 

 

Randomization at baseline

 

 

 

   Shiffman et al. (21)

727

Pega2a + Rbv 800mg

16w

   Lagging et al. **(37)

276

Pega2a + Rbv 800mg

12w

*Cut-off at 600 IU/ml; **Combined with HCV-2 pts
w.b. = weight based

 

What has emerged is that shorter treatment duration (12-16 weeks) should not be the standard of care for HCV-3 patients; since overall, they yield lower SVR rates than the conventional 24-week schedule, often as a consequence of higher relapse rates (21, 37).

The largest study conducted to investigate this issue is the ACCELERATE study, in which HCV-2 and HCV-3 patients were randomized at baseline to standard n|s. abbreviated schedule. The "16 weeks" were overall less efficient than the "24 weeks" in terms of SVR rate, but this global result was mainly related to the disappointing SVR rates in genotype 2 patients treated with the abbreviated course. Even if the observed SVR rates in HCV-3 patients were similar between the 16 weeks schedule and the standard schedule (62% n|s. 66%), the study reported significantly higher relapse rates in the former group in comparison with the latter group (31% n|s. 22%, p<0.01) (21). Moreover, the relatively low dose of RBV used in the ACCELERATE study (800 mg/die) might have influenced the overall SVR rates, being ultimately responsible for the relatively low SVR rates achieved in the standard group. The choice of a fixed dose of 800 mg/die RBV coupled with Peg-IFN alfa-2a was a consequence of the Hadziyannis study (10) which failed to demonstrate any benefit in using higher RBV doses in HCV-3 and 2 patients. However, RBV has been used at a weight-based dosing in most abbreviated therapy studies (20, 27, 36) and therefore the optimal dose of RBV required in abbreviated courses is still unknown. 

Another important finding derived from all studies published so far is that patients lacking RVR cannot benefit from abbreviated therapies, as SVR rates do not top 41% in this subgroup of patients.

When analyzing only patients with an RVR, the abbreviated course yielded similar SVR rates compared to the standard duration group, suggesting that HCV-RNA negativity at week 4 is essential to shorten the therapy (Table 4). 

 

Table 4. SVR rates in HCV-3 patients achieving an RVR.

Reference

Abbreviated Therapy

Standard Therapy

P

Dalgard et al. (35)

89%

-

-

Mangia et al. (20)

77%

100%

0.2

Von Wagner et al. (27)

76%

75%

0.9

Shiffman et al. (21)

80%

85%

0.2

Dalgard et al. (36)

84%

92%

0.1

Lagging et al. (37)

71%

91%

0.001

 

However, three important issues should not be overlooked when analyzing this finding. First of all, the only study designed to demonstrate the non-inferiority of a 14-week course versus the standard 24-week treatment schedule, although reporting high SVR rates in both groups (84% n|s. 92%, respectively), failed to achieve its endpoint (37). Secondly, the abbreviated schedules were associated with higher relapse rates in all studies (Fig. 1). Thirdly and most important of all, two studies demonstrated that bridging fibrosis/cirrhosis and high baseline viremia were predictors of treatment failure even in this subset of highly responsive patients (22, 26). Altogether, in our opinion, these data suggest that while RVR is essential to consider shorter treatment courses, it is in no way sufficient since in the presence of known predictors of treatment outcome, such as cirrhosis and/or high baseline viremia, the abbreviated treatment schedules achieve significantly lower SVR rates when compared to the standard duration therapy. In our opinion, before shorter treatment durations become universally acceptable for patients with an RVR, further randomized studies with attention to the aforementioned baseline moderators of treatment outcome are mandatory.

Figure 1. Relapse rates in standard and abbreviated courses of therapy in HCV-3 patients achieving an RVR.

 

Extending treatment duration in "hard to treat" patients

While the relevance of identifying predictors of treatment failure in HCV-3 patients should not be discarded, unfortunately we still have no answer on how to improve SVR rates in these "hard to treat" patients. Since post treatment relapse more than primary non response is ultimately responsible for the high rates of treatment failure observed in cirrhotics and in those with high baseline viremia (18, 26, 38, 39), the use of triple therapy with protease inhibitors, which have shown to achieve potent and rapid viral suppression in HCV-1 patients (40-42), might not be the answer in HCV-3 infected patients. However, to answer this question, Phase II studies have been designed and are currently ongoing in Europe. In theory, as a means to reduce post treatment relapse rates, treatment extension to 48 weeks might be advisable as recommended in HCV-3/HIV co-infected patients (43). Moreover, extended treatment schedules, such as the 72 week-therapy course studied in HCV-1 slow responders, a subgroup of patients characterized by high post treatment relapse rates, have shown to significantly improve SVR mainly through a reduction in relapse rates (44-46). However, to our knowledge, no data has been published on this strategy in HCV-3; therefore, in the absence of a randomized study, this approach should not be employed in clinical practice.

 

Conclusions

This review challenges the commonly held opinion that HCV-3 infection is an "easy to treat" genotype, as demonstrated by the less than optimal SVR rates in a subgroup of patients who can be identified by the presence of bridging fibrosis/cirrhosis, high baseline viremia and lack of an RVR. The influence of liver steatosis, on the contrary, still needs further confirmation. To date, we have no data on how to improve treatment efficacy in this subgroup of patients; in fact, while treatment extension to 48 weeks might be of benefit, it cannot be formally recommended in clinical practice.

Abbreviated courses of Peg-IFN/RBV therapy (12-16 weeks) should be proposed only to patients with an RVR as they yield significantly lower SVR rates in patients who are still HCV-RNA positive at week 4. Still, the patient should be informed that a higher risk of post-treatment relapse is to be expected. Moreover, we think that before universal acceptance of abbreviated therapies as the standard of care for HCV-3 patients with an RVR, further data is needed to explore the interplay between RVR, degree of fibrosis, levels of baseline HCV-RNA or other relatively unknown predictors such as BMI to assess the real efficacy of this strategy in these patients.

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