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Keywords:

  • cirrhosis;
  • directly acting antivirals;
  • Hepatitis C;
  • Il28B;
  • RVR ;
  • short duration treatment;
  • SVR

Abstract

  1. Top of page
  2. Abstract
  3. Optimizing treatment of HCV genotype 2 chronic hepatitis
  4. Conclusions
  5. Disclosure
  6. References

Hepatitis C Virus (HCV) Genotype 2 accounts for 10% of the patients with chronic HCV worldwide. The current standard of care (SOC) in these patients is 24 weeks of Pegylated Interferon (PEG-IFN) plus Ribavirin (RBV), with sustained virological response rates (SVR) of 80–90%. However, there are subgroups of patients with HCV-2, such as those with advanced fibrosis/cirrhosis, in whom SVR rates are still suboptimal, and highly responsive groups in whom SVR rates reach 95%. Treatment optimization is necessary to maximize efficacy in the former group and reduce treatment-related side effects in the latter. Unfortunately, any attempt to modify the duration or dosing of the SOC according to baseline factors has been disappointing and should not be continued at present. On the other hand on-treatment HCV RNA kinetics are fundamental for individualized treatment regimens because achieving negative HCV RNA at week 4 (rapid virological response, RVR) is the key factor when the duration of PEG-IFN/RBV is tailored in HCV-2 patients. Several studies have shown that treatment can be shortened to 16 weeks in HCV-2 patients with a RVR, without increasing the risk of post-treatment relapse, thus increasing tolerance to treatment while reducing healthcare costs. On the other hand, patients who do not achieve a RVR correspond to a population of difficult-to-cure HCV-2 patients who need alternative treatment strategies which are not yet available.

Abbreviations
BID

Twice daily

BOC

Boceprevir

DAA

Directly acting antivirals

HCC

Hepatocellular carcinoma

HCV

Hepatitis C virus

IL28B

Interleukin 28B

PEG-IFN

Peg-Interferon

RBV

Ribavirin

RVR

Rapid virological response

SIL

Silibinin

SNP

Single nucleotide polymorphism

SOC

Standard of care

SVR

Sustained virological response

TID

Three times a day

TVR

Telaprevir

Hepatitis C Virus Genotype 2 (HCV-2) accounts for approximately 10% of all cases of chronic hepatitis worldwide, with a prevalence ranging from less than 5% in Turkey and certain regions of the United States, to more than 25% in Italy and South Korea [1-4]. Chronic HCV-2 infection is usually characterized by slower disease progression, in terms of the development of liver fibrosis compared with other HCV genotypes [5-7]. However, HCV-2 has also been associated with an increased risk of hepatitis C reactivation. Indeed, studies have shown that HCV-2 patients have a higher risk of a sudden increase in alanine aminotransferases (ALT) values compared with HCV-1 patients, ultimately leading to the rapid progression of chronic hepatitis C towards bridging fibrosis and cirrhosis [8, 9]. Another particular feature of HCV-2 chronic infection is the increased incidence of extrahepatic manifestations, including non-Hodgkin's lymphoma reported by some [10], and a weak association with the development of hepatocellular carcinoma (HCC) reported by others [11]. Finally, probably the most specific feature of HCV-2 infection is its high sensitivity to interferon-based regimens, for the current standard of care (SOC), a 24-week course of PEGIFN/RBV, results in SVR rates of 80–95% in these patients [12-19] (Table 1). Because of these high cure rates, HCV-2 has been defined as an easy to cure genotype and attempts have been made to further optimize treatment in this group by shortening the duration or lowering the doses of PEG-IFN and/or RBV.

Table 1. SVR rates in HCV-2 patients receiving PegIFN plus Rbv
ReferencePatientsTreatmentSVR (%)
  1. RBV, Ribavirin; Wb, weight based; Fixed, 800 mg/day.

Rizzetto9324 weeks PegIFNalfa2a + RBV wb or fixed86
Rumi13624 weeks PegIFNalfa2b + RBV wb78
Shiffman35624 weeks PegIFNalfa2a + RBV fixed82
Aghemo15724 weeks PegIFNalfa2b + RBV wb80
Rumi14324 weeks PegIFNalfa2a or 2b + RBV fixed or wb89
Ascione9924 weeks PegIFNalfa2a or 2b + RBV wb84
Marcellin102524 weeks PegIFNalfa2a or 2b + RBV fixed or wb71

Optimizing treatment of HCV genotype 2 chronic hepatitis

  1. Top of page
  2. Abstract
  3. Optimizing treatment of HCV genotype 2 chronic hepatitis
  4. Conclusions
  5. Disclosure
  6. References

Baseline predictors of treatment outcome in HCV-2 patients

A precise definition of the predictive factors of treatment outcome in HCV-2 patients has been limited by the practice of analysing HCV-2 and HCV-3 patients together. This approach has been shown to be scientifically unsound because certain factors that affect treatment outcome in HCV-3 patients, such as baseline HCV viraemia and steatosis, do not influence the efficacy of PEG-IFN/RBV in HCV-2 patients [20]. This is also true for single nucleotide polymorphisms (SNPs) in the Interleukin 28B (IL28B) region, which have been found to be strong predictors of outcome in HCV-1 and 4 patients [21-23]. The impact of IL28B on SVR rates in HCV-2 and 3 patients seems to be slight [24], but when data are stratified by HCV genotype most studies have failed to show any clinically relevant impact of IL28B in HCV-2 patients, with some impact in HCV-3 patients [25]. The IL28B only seems to be predictive in HCV-2 patients who fail to reach an RVR, because SVR rates are still high in those with the treatment favourable IL28B genotype. Mangia et al. found that in HCV-2 patients without a RVR -whose SVR rates are usually between 45 and 55% – the SVR rates in patients with the IL28B rs1299860 CC genotype were much higher than those with CT/TT (66% vs 45% respectively) [26].

The strongest baseline predictor of treatment failure in HCV-2 patients is the presence of bridging fibrosis/cirrhosis. SVR rates in this subgroup of patients have been shown to be suboptimal with rates as low as 50%. In a recent analysis of a cohort of more than 1000 HCV-2 patients receiving PEG-IFN alfa2a or alfa2b/RBV therapy, bridging fibrosis/cirrhosis was a strong predictor of treatment failure: SVR rates were 72% in patients without bridging fibrosis/cirrhosis and 61% in those with advanced hepatitis [19]. This study associated the lower SVR rates in patients with advanced fibrosis/cirrhosis to higher rates of post-treatment relapse (16% vs 10.8%) which has already been shown in several other studies with both PEG-IFN molecules [15, 27, 28]. Although the finding that cirrhosis negatively influences SVR rates in HCV-2 patients is scientifically relevant, from a clinical standpoint it does not significantly influence the treatment decision. In fact patients with cirrhosis require treatment, even if it is relatively ineffective, because they are one of the highest risk HCV patient populations. In addition, at present the presence of advanced fibrosis/cirrhosis cannot be successfully treated by any alternative treatment regimen or schedule.

On-treatment predictors of treatment outcome in HCV-2 patients

On-treatment HCV RNA kinetics are more clinically relevant than baseline factors in HCV-2 patients, because they have more predictive value for treatment outcome and also allow the therapeutic schedule to be individualized. An RVR, which is achieved in 70–90% of HCV-2 patients, is strongly associated with a SVR because nearly 90% of these patients reach viral eradication [14, 29, 30] (Table 2). Most important, patients who achieve a RVR can be considered for shorter treatment schedules. This has been investigated in several studies in which HCV-2 RVR patients were randomized to receive 12–16 weeks of PEG-IFN/RBV vs the standard 24-week duration [29-32]. The results of these studies are similar and suggest that SVR rates are not significantly different in this highly responsive group between shorter and standard treatment. A recent meta-analysis reported SVR rates of 83.8% in RVR patients receiving shorter treatment and 89.3% in patients receiving standard duration treatment (RR 1.02, 95% CI: 0.97–1.06). This study also showed that weight-based dosing is crucial to obtain similar SVR rates in short treatment regimens, because there is a trend towards higher SVR rates with standard duration treatment compared with suboptimal short treatment arms [33]. However, weight-based dosing of RBV is not the only factor to be considered in shortened therapy in HCV-2 patients with a RVR. Indeed, short therapy is not recommended in patients with other baseline predictors of treatment failure such as bridging fibrosis/cirrhosis, high BMI, high baseline viraemia and the presence of insulin resistance, because they are considered to have a higher risk of post-treatment relapse with shorter treatment [18].

Table 2. SVR rates in HCV-2 patients stratified by RVR status
ReferencePatientsSVR
RVRNon-RVR
Mangia21376% (40/53)78% (45/58)
Shiffman34785% (210/247)53% (53/100)
Rumi23083% (151/182)52% (25/48)
Yu15095% (95/100)77% (10/13)
Marcellin102576% (662/858)45% (70/157)

Treatment optimization

To optimize PEG-IFN/RBV treatment in HCV-2 patients, shortened or lower dose regimens should be considered to increase safety and tolerance in patients with a high chance of SVR to SOC, and an extended duration or increased dosing in subgroups of difficult-to-cure HCV-2 patients.

Unfortunately, tailoring the dose of PEG-IFN or RBV according to baseline predictors of treatment outcome has been unsuccessful. A randomized study analysing the efficacy of a lower dose of RBV in HCV-2 and HCV-3 patients, showed that the 400 mg/day dose of RBV was less effective than the SOC 800 mg/day for SVR in HCV-2 patients (63% vs 78%) [34]. Moreover, the use of doses of RBV higher than 800 mg/day did not result in increased SVR rates in HCV-2 patients in PEG-IFN alfa2a or alfa2b optimization studies [35, 36]. Tailoring the duration of therapy according to baseline factors of treatment outcome has also been disappointing. Shortening treatment in patients with positive predictive factors for treatment outcome was shown to be unsuccessful by the Accelerate study, which evaluated 728 HCV-2 patients randomized to receive either 16 or 24 weeks of PEG-IFNalfa2a plus 800 mg/day of RBV [14]. This study reported consistently higher SVR rates in the SOC arm, even when results were analysed in relation to baseline viraemia, stage of fibrosis and the presence of steatosis. Although no specific trials have been designed to evaluate longer treatment in patients with negative predictors of response, such as cirrhosis, some clinical practice guidelines suggest extending treatment to 48 weeks in these patients [18]. This recommendation is based on the high relapse rates in these patients, which have been shown to be improved by extending treatment in other HCV genotypes.

Data on response-guided treatment in HCV-2 patients are more convincing. Indeed several studies and a meta-analysis have shown that 16 weeks of PEG-IFN plus weight-based RBV is sufficient in patients with a RVR, if there are no other negative predictors of treatment outcome [37]. Unfortunately, there are no data on extending treatment beyond 24 weeks in patients without a RVR. Certain guidelines suggest this approach in these patients, although we feel that the safety and tolerance of extended treatment must be discussed with the patient and future therapeutic options must also be taken into consideration before beginning 48 or 72 weeks of PEG-IFN/RBV treatment.

Alternative treatment options in difficult-to-treat patients

Although the SVR rates in patients with HCV-2 are usually high with SOC PEG-IFN/RBV, HCV eradication rates are still suboptimal in certain categories of patients and more effective treatment regimens are therefore needed.

Telaprevir (TVR) and Boceprevir (BOC) were the first two direct antiviral agents (DAA) approved in patients with HCV genotype 1. The triple therapy regimen including PEG-IFN/RBV plus TVR/BOC resulted in increased SVR rates compared with PEG-IFN/RBV alone [38]. The efficacy of these protease inhibitors in HCV genotypes other than 1 has not been clearly defined, since only two preliminary studies in small groups are available [39]. The activity of TVR in HCV-2 patients was first evaluated by Foster et al. in a study with 23 HCV-2 and 26 HCV-3 treatment naïve patients [40]. Patients were randomized to receive either 2 weeks of TVR monotherapy (Group A), 2 weeks of TVR plus PEG-IFN/RBV (Group B) or 2 weeks of placebo plus PEG-IFN/RBV (Group C). All treatment arms were then treated with 24 weeks of PEG-IFN/RBV. SVR rates were 56% in group A, 100% in group B and 89% in Group C. In HCV-2 patients TVR monotherapy resulted in a rapid decrease in HCV RNA, with a median decline of 3.27 log10 IU/mL and 3.66 log10 IU/ml at day 3 and 15 respectively (Fig. 1). However, none of the patients achieved undetectable HCV RNA at week 2, while some patients had a viral breakthrough between days 12 and 15 of monotherapy.

image

Figure 1. Mean HCV RNA values during Telaprevir (TVR) and Boceprevir (BOC) monotherapy in HCV-2 patients.

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The efficacy of BOC in HCV-2 was examined by Silva et al. in a small pilot study with seven HCV-2 patients [41]. They evaluated different doses of 2 weeks of BOC monotherapy in treatment-naïve patients: 200 mg BID, 400 mg BID, 400 mg TID or placebo. The maximum decrease in HCV RNA was similar to placebo in patients receiving 200 mg BID (0.48 IU/ml log10) and 400 mg BID (0.28 IU/mL log10), while it was significantly higher in those receiving 400 mg TID (1.39 IU/mL log10) (Fig. 1). None of the patients achieved undetectable HCV RNA after 15 days of BOC monotherapy. Thus, TVR and BOC do seem to be active against anti-HCV genotype 2 and might be considered as part of a triple therapy regimen in selected patients. However, this use is off-label and no further studies will be performed by drug manufacturers.

Another drug that might be considered in difficult-to-cure HCV-2 patients is Silibinin (SIL). SIL is the major active component of Silymarin, an extract of the seeds of the milk thistle plant Silybum marianum, which has been used as a liver tonic because of its antioxidant effect. SIL is currently used intravenously for the treatment of liver toxicity from Amanita Phalloides mushrooms. SIL has multiple mechanisms of action against HCV, which have only been characterized in vitro. SIL can inhibit HCV NS5B RNA polymerase, impair HCV entry and cell to cell spread, as well as inhibit T-cell inflammatory cytokines and hepatocyte NF-kB signalling [42]. Some studies have identified powerful antiviral effects against HCV genotypes 1 or 4 [43]. The use of intravenous SIL to prevent HCV reinfection in OLT patients was also considered promising. Neumann et al. and Beinhardt et al. reported successful prevention of HCV liver graft reinfection with intravenous SIL monotherapy in two carriers of genotype 3a and 1a/4 [44, 45]. However, unfortunately, a recent case report suggests that SIL efficacy might be HCV genotype-dependent, because SIL monotherapy was not effective in preventing liver graft re-infection in a HCV-2 patient [46]. This supports in vitro results showing that SIL inhibited 1b replicons of JFH1 infection but not 2a subgenomic replicons [47].

Conclusions

  1. Top of page
  2. Abstract
  3. Optimizing treatment of HCV genotype 2 chronic hepatitis
  4. Conclusions
  5. Disclosure
  6. References

The HCV-2 infection is characterized by high SVR rates with PEG-IFN/RBV treatment. Moreover, treatment can be optimized in many of these patients who achieve a RVR by shortening the overall duration of treatment without lowering efficacy.

However, in certain HCV-2 patients with suboptimal SVR rates, modifying the SOC regimen by extending the duration of treatment or increasing drug doses has not been shown to improve treatment efficacy. Alternative therapeutic options are lacking in these difficult-to-cure HCV-2 patients, but several compounds are currently under development that should increase SVR rates in the next few years in this small group [37].

Disclosure

  1. Top of page
  2. Abstract
  3. Optimizing treatment of HCV genotype 2 chronic hepatitis
  4. Conclusions
  5. Disclosure
  6. References

Alessio Aghemo, MD. Grant and research support: Roche, Gilead Sciences. Speaking and Teaching: Roche, Janssen, Merck. Travel support: BMS, Glaxo Smith-Kline, Bayer, Janssen, Roche, Merck.

Eleonora Grassi, MD has no financial disclosure to declare.

References

  1. Top of page
  2. Abstract
  3. Optimizing treatment of HCV genotype 2 chronic hepatitis
  4. Conclusions
  5. Disclosure
  6. References