The standard of care (SOC) for hepatitis C virus (HCV) genotype 2 is pegylated interferon (PEG-IFN) plus ribavirin (RBV). Even though most patients can be cured with this therapy after 24 weeks, tailoring treatment can improve its safety and efficacy in special populations. Thus, shortening treatment together with a weight-based RBV dosing approach has been considered satisfactory in patients with positive predictors of response. With the development of the direct antiviral agents (DAAs), shorter, better tolerated and more efficient treatments for HCV genotype 2 will become available, including interferon-free regimens. Until these new treatments are released, the decision to treat patients with HCV genotype 2 with currently approved drugs or to wait for future options must be made, taking into account the stage of fibrosis.
The distribution of hepatitis C virus (HCV) genotype 2 is worldwide, and it is the third most prevalent genotype in most countries. It is particularly prevalent in Italy and South Korea, where it accounts for one-third of the cases of chronic HCV infection, as well as in some Latin American countries, such as Argentina and Venezuela, where the prevalence of HCV genotype 2 (HCV-2) ranges from 25 to 34% [1-5].
HCV-2 is the easiest genotype to treat with currently approved agents and the standard of care (SOC) treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV) for 24 weeks cures up to 95% of patients with chronic infection [6, 7].
Some special populations, such as chronic HCV-2 patients with advanced fibrosis, decompensated cirrhosis and patients in haemodialysis or with other significant comorbidities, may not respond satisfactorily or present contraindications to receive the SOC [6-11]. These patients could benefit from longer treatment or new approaches with more effective agents with a better safety profile.
On the other hand, chronic HCV-2 patients with favourable baseline and on-treatment predictors of response to PEG-IFN/RBV can be treated for shorter periods, thus reducing toxicity and costs . Moreover, all-oral regimens with direct antiviral agents (DAAs) are needed, even in this population, to improve the safety profile and shorten treatment duration.
Optimizing treatment with currently approved drugs
In the absence of approved alternative treatments to PEG-IFN/RBV, the optimization of treatment in chronic HCV-2 patients includes modifying treatment duration and/or RBV dose according to baseline and on-treatment predictors of response.
New all-oral regimens with improved tolerability and efficacy will be released in the near future. With this in mind the optimal management of some HCV-2 patients, especially those with mild to moderate fibrosis, may be to defer treatment until these new strategies become available.
Predictors of response to PEG-IFN/RBV in HCV-2
There are limitations to the data available in the literature on the treatment of HCV-2. First, most studies performed in HCV-2 patients have been performed together with HCV genotype 3 (HCV-3). At present, there is enough evidence showing that the response rate of HCV-2 is at least 10% higher than HCV-3. Second, because response rates for HCV-2 are so high with the SOC, studies must include a large number of patients to demonstrate significant advantages of one strategy over others.
Even though most studies have included a reduced number of HCV-2 patients with cirrhosis, this seems to be the strongest baseline predictor of response. The largest and most recent real-life study which included a significant proportion of HCV-2 patients treated with PEG-IFN/RBV for 24 ± 4 weeks, reported a sustained viral response (SVR) of 61% in patients with bridging fibrosis/cirrhosis, and 72% in patients with lower grades of fibrosis . Other studies support these results, but most of them evaluated HCV-2 and HCV-3 together and with significant differences in treatment duration.
Baseline viral load seems to have a slight effect on SVR in HCV-2 patients. This was evaluated in a meta-analysis where the SVR was 79% in patients with low viral loads vs. 75% in patients with a high viral load .
Relationship between IFNL3 (previously IL28B) polymorphism and response to treatment has been reviewed recently (14).
Available data on IFNL3 polymorphism fail to show a significant influence on SVR in patients with HCV-2. In patients who do not achieve a rapid viral response (RVR), the CC polymorphism of the rs1299860 gene could be associated with higher chances of RVR (66% vs. 45% respectively) .
On-treatment virological kinetics, particularly achieving an RVR, is the strongest predictor of SVR in HCV-2 patients. HVC-2 is the easiest genotype to eradicate with PEG-IFN/RBV because of the high rate of RVR in this genotype. Different studies have reported RVR rates of 70–90% for HCV-2, 47–77% for HCV-3 and 15–25% for HCV-1 treated with PEG-IFN/RBV [8, 11, 12, 16].
Tailoring treatment duration
Current guidelines for the management of HCV-2 recommend a similar approach. See Fig. 1 for an algorithm for the treatment of chronic HCV-2 infection.
The European Association for the Study of the Liver (EASL) guidelines provide recommendations for both HCV-2 and HCV-3 genotypes suggesting 24-weeks of treatment with PEG-IFN/RBV (800 mg/d) for most patients . However, weight-based RBV of 15 mg/kg/d is suggested in patients with unfavourable baseline characteristics. Moreover, on-treatment virological kinetics should be monitored at 4 and 12 weeks to identify slow responders in whom treatment should be prolonged to 48 or even 72 weeks. On the other hand, HCV-2 patients with a RVR and positive predictors of response could be treated for 16 weeks and achieve acceptable SVR rates.
The American (AASLD) guidelines suggest 24-weeks of treatment with PEG-IFN/RBV (800 mg/d) . Although it does not make specific recommendations on how to monitor on-treatment virological kinetics, it recognizes the importance of achieving a RVR to obtain a SVR. Thus, these guidelines state that HCV-2 patients who achieve a RVR could shorten their therapy to 12 or 16 weeks although this strategy may be associated with higher relapse rates. Finally, HCV-2 patients without RVR may benefit from longer treatments.
Although studies evaluating different treatment durations in patients with HCV-2 or HCV-3 provide valuable information, it is difficult to draw conclusions, because of significant variations in study design. ACCELERATE, the largest study was performed in 1469 treatment-naïve HCV-2 or HCV-3 patients who were randomized to 16 or 24 weeks of PEG-IFN/RBV (800 mg/d) . SVR was achieved in 65% and 82% of the HCV-2 patients treated for 16 and 24 weeks respectively. This study clearly suggests that a 16-week fixed treatment duration is not appropriate for all HCV-2 patients, even those with positive baseline predictors of response.
Another study including HCV-2 or HCV-3 patients evaluated shortening treatment with PEG-IFN/RBV to 12 weeks using response-guided therapy: only patients achieving a RVR were randomized to 12–16 vs. 24 weeks of treatment . This study showed that shortening treatment is safe if a RVR is achieved with similar SVR rates, especially in HCV-2 patients with positive baseline predictors of response. The dose of RBV was weight-based in all the studies that evaluated shortened treatment duration, except one. The study using RBV 800 mg/d, which is a subanalysis of the ACCELERATE study, was the only one to report a higher global relapse rate in patients with shorter treatment. This study also included a high proportion of patients with bridging fibrosis or cirrhosis. These studies emphasize the importance of a weight-based RBV strategy and careful assessment of baseline predictors of response when shortening the treatment duration in HCV-2 patients.
The evidence suggests that weight-based RBV dosing is crucial to obtain similar SVR rates in short treatment regimens, since there is a trend towards higher SVR rates with standard duration treatment compared with suboptimal short treatment arms. However, weight-based RBV is not the only factor to be considered for shorter therapy in HCV-2 patients with an RVR. Indeed, short therapy is not recommended in patients with other negative baseline predictors of response such as bridging fibrosis/cirrhosis, high body mass index, high baseline viraemia and the presence of insulin resistance because these patients are considered to have a higher risk of post-treatment relapse with shorter treatment [6, 7, 17].
Even though the assessment of RVR at treatment week 4 has been evaluated in most studies, studies suggest that RVR at week 2, particularly in HVC-2 patients, has the highest positive predictive value. Its use in tailoring the treatment duration requires further evaluation and clarification .
Improving tolerance to treatment
Patients with chronic HCV-2 infection, especially those with cirrhosis, often present different grades of cytopaenia, which could contraindicate treatment with PEG- IFN/RBV in certain cases . More frequently, cytopaenia is induced during treatment and requires dose reductions with may influence efficacy.
The United States FDA has approved eltrombopag for the treatment of thrombocytopaenia in patients with chronic hepatitis C so that interferon-based therapy can be begun and maintained. Eltrombopag is an oral thrombopoietin receptor agonist that increases platelet count by increasing megakaryocyte differentiation and proliferation. In the ENABLE-1 and ENABLE-2 studies, patients with cirrhosis and <75 000/mm3 platelets were initially treated with eltrombopag and subsequently randomized to receive eltrombopag or placebo combined with PEG-IFN/RBV . EVR occurred in 84% of the eltrombopag group and 67% of the placebo group of HCV-2 and HCV-3 patients and SVR occurred in 35% and 24% respectively. A higher incidence of thromboembolic events were observed in the ENABLE-2 study which was presented at the 2012 EASL Meeting, results which are similar to other studies in patients with cirrhosis and thrombocytopaenia treated with eltrombopag, suggesting a possibly higher risk of portal vein thrombosis.
Anaemia and neutropaenia can also complicate or contraindicate treatment with PEG-IFN/RBV in HCV-2 patients .
Even though a proportion of HCV infected patients in clinical practice receive erythropoiesis-stimulating agents and/or granulocyte-colony stimulating factor for the management of anaemia or neutropaenia during treatment with PEG-INF/RBV, the impact of these strategies on treatment outcome remains unknown. This issue has not been specifically addressed in HCV-2 patients. These strategies might be especially useful in patients with cirrhosis who are at the highest risk of developing cytopaenia and in whom PEG-IFN or RBV-dose reductions could limit treatment efficacy.
New therapeutic strategies
Although combination therapy with PEG-IFN/RBV is still the SOC for chronic HCV-2 infection, major progress have been made in the past few years with DAAs (20). The phase II and III study results of some promising DAAs were presented recently and will be discussed below.
The potent pan-genotypic nucleotide analogue sofosbuvir (formerly GS-7977) has been evaluated in an all-oral regimen in naïve genotype 2 and 3 patients (FISSION study, phase III), in genotype 2 and G3 intolerant or ineligible patients, or in genotype 2 or 3 patients who do not wish to receive PEG-IFN (POSITRON study, phase III) [21, 22]. It was administered for 12 weeks in both studies, in combination with RBV (1000–1200 mg/d).
Sofosbuvir plus RBV was compared to treatment with PEG-IFN/RBV in the naïve patients for 24 weeks. The objective of non-inferiority was demonstrated: SVR-12 was achieved in 67% of the patients in both arms. However, in the genotype 2 population, sofosbuvir was better than SOC in achieving SVR-12 (97% vs. 78%).
In the POSITRON study, treatment with sofosbuvir plus RBV was compared with placebo. As expected, the SVR-12 rate was 93% in genotype 2 compared with 0% in the placebo group.
Even though few patients with cirrhosis were enrolled, the stage of fibrosis did not influence SVR-12 in the sofosbuvir arm in either study. The combination of sofosbuvir and RBV was well-tolerated.
Daclatasvir (BMS-790052) is a potent HCV NS5A inhibitor that has been evaluated in naïve genotypes 2 and 3 patients in combination with PEG-IFN/RBV (COMMAND study, phase II) , and with sofosbuvir with or without RBV (AI444-040 study, phase IIa).
In the COMMAND study, a response-guided therapy algorithm was used. Therefore, patients receiving daclatasvir who achieved the protocol-defined response stopped treatment at 12 or 16 weeks. Patients receiving daclatasvir who did not achieve the protocol-defined response and patients in the control arm (PEG-IFN/RBV) received a 24-week treatment course. SVR (24 weeks) was 83% in both the daclatasvir arms vs. 63% in the control arm in the genotype 2 population. Interestingly, most patients who received daclatasvir qualified for shorter treatment. None of the genotype 2 patients who received daclatasvir had cirrhosis.
The 24-week all-oral sofosbuvir plus daclatasvir regimen with or without RBV (AI444-040 study) was evaluated in a study including genotypes 1, 2 and 3 naïve patients without cirrhosis. The results were presented at the 2012 EASL meeting. Individual data for genotype 2 is not available, but SVR-24 was between 88% and 100% in genotypes 2 and 3 patients analysed together, with a good safety profile. A comparison of these results with those from the combination of sofosbuvir and RBV in genotype 2 patients raises the question of whether sofosbuvir and RBV will be safe and good enough to treat all subpopulations of patients or, if on the contrary, there is still some need for more potent DDAs combinations.
The combination of PEG-IFN lamda-1a/RBV and RBV was evaluated in the Phase IIb study EMERGE, in which genotypes 1, 2, 3 and 4 naïve patients without cirrhosis were randomized to PEG-IFN lamda 1a (120, 180 or 240 μg weekly)/RBV or to PEG-IFN alfa-2a/RBV. The results were also presented at the 2012 EASL meeting. The PEG-IFN lambda-1a arms were associated with fewer musculoskeletal events, influenza-like symptoms and adverse haematological events. Higher rates of hyperbilirubinaemia and more frequent psychiatric events (insomnia and irritability) occurred in patients who received PEG-IFN lambda-1a. SVR-24 rates were similar in PEG-IFNlambda-1a arms vs. PEG-IFN alfa-2a, and ranged from 58% to 70% in genotype 2 patients.
After years without major progress in the treatment of chronic hepatitis C in genotype 2 patients, the results of these studies and the expected results in many ongoing trials are exciting. It is not clear whether a single treatment will become the new SOC or whether an individualized therapeutic approach will prevail.
PEG-IFN/RVB is the current SOC for HCV-2 patients. Most patients can be cured with this strategy. However, treatment tolerance is not optimal and a subgroup of patients fail to obtain a SVR.
Treatment with DDAs should certainly improve tolerance and will most probably also improve efficacy (more difficult to demonstrate since chance to cure in HCV-G2 with SOC are higher than 90%?). However, worldwide access to these drugs might be limited by costs, especially in the developing countries.
Meanwhile, treatment of HCV-2 patients must be individualized. Patients with low-grade fibrosis might be candidates to wait for new treatments. Patients with significant fibrosis should be treated with PEG-INF/RBV, and the treatment duration and RVB dose should be tailored according to baseline and on-treatment predictors of response.
Finally, the use of haematopoietic growth factors will help certain subsets of patients with baseline cytopaenia or who develop treatment-related cytopaenia and cannot wait for the approval of DAAs.