Current and Future HCV Therapy

Do We Still Need Other Anti-HCV Drugs?

Salvatore Petta; Antonio Craxì


Liver International. 2015;35(s1):4-10. 

In This Article

Abstract and Introduction


Eradication of hepatitis C virus (HCV) infection, at least in compensated patients, can help improve the outcomes of liver disease such as cirrhosis, hepatocellular carcinoma (HCC) and liver transplantation, as well as perhaps extra-hepatic complications such as diabetes and cardiovascular risk. In the past few years, the landscape of antiviral therapy has evolved at a breathtaking pace from pegylated interferon (PEG-IFN) plus ribavirin (RBV) (PEG-IFN/RBV) to IFN-based strategies combining direct acting antivirals (DDAs) with PEG-IFN/RBV and finally IFN-free combinations of DAAs. In particular with these most recent developments, treatment regimens have become shorter, safer and even more effective, with a wide range of indications. Nevertheless, research continues and newer antiviral drugs are still under development. At a point when a >90% sustained virological response (SVR) is being claimed with all new available regimens, pharmacological and clinical research should be addressing unresolved areas, such as cases of suboptimal SVR or to increase effectiveness rather than pursuing the development of new 'me-too' drugs. The issues which should be given priority for further development include the following:

  • Improving the results of IFN-free regimens in patients with genotype 3 (HCV-3) infection.

  • Identifying the indications for the treatment in patients with compensated and decompensated cirrhosis.

  • Identifying standardized or personalized backup strategies in patients who do not respond to IFN-free regimens. Finally, because of financial constraints, the high cost of IFN-free strategies prevents their universal use in CHC patients and coverage by national healthcare systems. Thus, efforts must be made to document cost-effectiveness in all clinical scenarios and to develop more affordable IFN-free regimens.

The estimated global prevalence of hepatitis C virus (HCV) infection is 2.2%, corresponding to roughly 130 million HCV-infected individuals worldwide.[1] HCV is one of the main causes of chronic liver disease leading to cirrhosis, hepatocellular carcinoma (HCC) and liver transplantation worldwide. In addition, recent data also suggests that HCV infection increases the risk of morbidity and mortality because of cardiovascular diseases.[2]

A sustained virological response (SVR) is a well validated clinically relevant surrogate outcome in the management of chronically infected HCV patients because viral eradication not only prevents the occurrence of cirrhosis in chronic hepatitis C (CHC),[3] but also the development of its complications in patients with compensated cirrhosis.[4–7] In addition, as observed for HBV-related cirrhosis, SVR might improve the prognosis in patients with decompensated cirrhosis who are or are not awaiting liver transplantation, by compensating liver disease, or by influencing the recurrence of HCV-related cirrhosis and liver failure in the post-transplant setting.

In the past few years, the landscape of antiviral care in patients with chronic HCV has changed quickly; thanks to the increased understanding of the biology of HCV replication and the identification of proteins blocking the key steps. In patients with genotype1 (HCV-1) dual therapy (DT) with peginterferon alfa (PEG-IFN) and ribavirin (RBV) was replaced by PEG-IFN-based triple therapies (TT) with first generation protease inhibitors (PI)-boceprevir (BOC) or telaprevir (TVR). Recently these latter regimens were replaced by simeprevir (SIM) or sofosbuvir (SOF)-based schedules.[8–10] The two latter regimens, combined with PEG-IFN/RBV, resulted in SVR rates ranging from 30% to 92%, also reducing the treatment duration and side-effects. In HCV genotypes 2 and 3 patients, PEG-IFN/RBV strategies were replaced by SOF plus RBV for HCV-2 patients with SVR rates above 90%,[8,11–13] and by SOF plus RBV or SOF plus PEG-IFN/RBV in HCV-3 patients where the addition of PEG-IFN increases SVR rates.[8,11–13] Finally, data on small cohorts of HCV-4 patients showed that compared to DT, TT regimens based on SOF or SIM achieved SVR rates similar to that reported in HCV-1 patients.[8]

At present, drugs registered in Europe include SIM, SOF and Daclatasvir (DAC), which are combined with PEG-IFN/RBV in HCV-1 and HCV-4 patients with the SVR rates mentioned above, by an off-label combination (SOF/SIM or SOF/DAC or DAC/SIM) with/without RBV in pilot studies of small groups of patients, or in combination with RBV in HCV-2 and HCV-3 patients (for SOF only).

Recent clinical trials have shown that all oral IFN-free regimens combining the different DAA–SOF/Ledipasvir(LED) and Paritaprevir(PAR)/Dasabuvir(DAS)/Ombitasvir(OMB) achieve SVR rates ranging from 90% to 100%, independent of the severity of liver damage, the pattern of previous response to DT or first-generation PI, and without significant side-effects.[12–18] These combinations, which should be registered and available in Europe in early 2015, are characterized by a short duration (8–12 weeks), oral administration with a few pills, and by a pangenotypic profile of effectiveness for SOF/LED, but restricted efficacy in HCV-1 (and perhaps HCV-4) for the AbbVie combination.

The next steps in the clinical development of anti-HCV therapy are expected in late 2015–early 2016 with the availability of pangenotypic ultrarapid (4–8 weeks) single pill regimens such as Grazoprevir/MK8742, SOF/GS5816, and BMS791325/DAC/Asunaprevir.

These advances have obviously resulted in innovations in IFN-based regimens.[19] They have resulted in SVR rates >90% with well tolerated IFN-free regimens that represent a new challenge for the treatment of HCV-related liver disease, and create new frontiers for tolerability, safety and the consequences of treatment in untreated groups such as those with decompensated cirrhosis waiting or not for liver transplantation. Thus, the key question is whether future developments should focus on new antiviral regimens, or clinical development in as yet unresolved areas? We feel that available and soon to be available drugs are generally extremely effective even if certain issues (Fig. 1) require further study: (i) suboptimal performance in patients with HCV-3; (ii) treatment of patients with compensated and decompensated cirrhosis; (iii) backup strategies in patients who do not respond to IFN-free regimens; (iv) the costs of drugs.

Figure 1.

Hot topics for the treatment of patients with chronic hepatitis C using IFN-free regimens.

The next section of this review will focus on these issues, reporting available data and suggesting future directions for clinical development.

Patients With Genotype 3 Infection are the Most Difficult to Treat With DAAs

When PEG-IFN/RBV was the treatment for HCV, the same regimen was administered to all subjects and patients were defined as easy or difficult to treat according to viral genotype. HCV- 1 and 4 were considered to be difficult-to-treat and 2 and 3 were considered to be easy to treat.[20] The SVR rates in the latter group were above 80% with shorter treatment.

The availability of IFN-free regimens has confirmed that HCV-2 patients are easy to treat while the paradigm for HCV-3 patients has been reversed compared to 'older, difficult-to-treat' HCV-1 patients. In fact, today with available DAAs, patients with HCV-3 are the most difficult to treat patients (Fig. 2). Results with an IFN-free regimen in HCV-3 patients were initially very encouraging in a small phase II study showing that 12-weeks of SOF/RBV resulted in an SVR in all HCV-2 and 3 patients.[21] In other promising preliminary results, large phase III studies in HCV-2 and 3 treatment-naïve (Fission),[8] experienced (Fusion),[11] and IFN intolerant or unwilling patients (Positron),[8] were begun to assess the effectiveness of 12–16 weeks of SOF/RBV. Overall, these studies have shown that surprisingly, while 12 weeks of SOF/RBV resulted in an SVR in HCV-2 patients independent of previous exposure to PEG-IFN/RBV and the severity of fibrosis, the latter two factors were significant for HCV-3 patients. Specifically, 12 weeks of therapy in treatment-naïve patients resulted in an SVR in 61% and 34% of non-cirrhotic and cirrhotic patients respectively.[8] Moreover the SVR rates in non-cirrhotic patients were 37% and 63% in experienced patients, in the 12- and 16- week course, respectively, and 19% and 61% in the 12- and 16-week course in non-cirrhotic patients respectively.[8,11] In particular, treatment failures were all related to relapse but not virological breakthrough confirming the high genetic barrier to resistance of SOF. These results suggest that strategies to improve SVR rates with an SOF containing regimen in HCV-3 patients should take into account an extension of prior therapy, or the addition of another anti-HCV drug (DAA or immunomodulator). Extending treatment to 24 weeks of SOF/RBV was evaluated in the Valence trial resulting in an overall SVR rate of 83%.[12,13] In particular, this was the result of higher SVR rates in treatment-naïve (93% and 92% in patients without and with cirrhosis respectively), and experienced patients without cirrhosis (87%) while rates were lower in experienced (61%) patients with cirrhosis. These results identified the difficult- to-treat category of patients and suggested that the SVR could be improved by adding another anti-HCV drug. This hypothesis was tested in two small studies. The Lonestar-2 study tested TT with PegIFN/SOF/RBV for 12 weeks in treatment-experienced HCV-2 and 3 patients.[22] The SVR in HCV-3 patients was 83% with no difference in relation to baseline cirrhosis (SVR 83% vs 83% respectively). The second study tested a combination of DAC/SOF resulting in an SVR of 89% of 18 treatment-naïve patients with HCV-3.[23]

Figure 2.

Treatment strategies in treatment naïve (A) and experienced (B) patients with HCV-3 infection with direct antiviral agents. Results from Fission (8) Fusion (11), Valence (12), Lonestar-2 (22) RCTs and Sulkowski et al. (23).

These data suggest that SOF/PEG-IFN/RBV is the most effective treatment in HCV-3 treatment-experienced patients with cirrhosis, and that this regimen is also as effective in all other HCV-3 patients as a 24 week course of SOF/RBV. Despite these strategies certain unresolved issues remain: (i) the inability to treat patients with advanced cirrhosis using an IFN- based regimen, and (ii) the high cost of a 24- week course of SOF. Thus, further research in DAAs is necessary in patients with HCV-3 to validate available data in larger cohorts and test promising new DAA combinations such as Grazoprevir/MK8742, SOF/GS5816, BMS791325/DAC/Asunaprevir, and others.

Patients With Compensated or Decompensated Cirrhosis are Candidates for IFN-free Regimens

The option of using DAAs and combining them in safe and effective IFN-free regimens extends the landscape of antiviral treatment. This is especially true in patients who are at risk of complications or in whom IFN-containing strategies are contraindicated and for whom an SVR could significantly improve the liver-related prognosis. These patients have advanced fibrosis/compensated cirrhosis or decompensated cirrhosis. Results in the former group can be found in analyses of clinical studies with a low number of patients with advanced fibrosis/cirrhosis, and one study that was specifically designed to evaluate the effectiveness of IFN-free regimens in patients with compensated cirrhosis. The ION-1 and ION 2 trials are phase III clinical studies assessing the effectiveness of SOF/LED for 12- or 24-weeks with and without RBV in HCV-1 treatment-naïve (ION-1)[12,13] or experienced (ION-2)[14] patients. The studies included 865 and 440 patients, respectively, 16% with cirrhosis in the ION-1 and 20% with cirrhosis in the ION-2 study. Even if the low number of patients with cirrhosis included in the studies is taken into account, results showed that there was no significant difference in SVR12 rates among treatment-naïve patients with cirrhosis in any of the different arms (94–100%) and compared to patients without cirrhosis (97–99%). Cure rates in the 12-week arms were slightly lower in treatment-experienced patients with cirrhosis (86% without and 82% with RBV), while all patients with cirrhosis treated for 24 weeks achieved an SVR whatever the regimen. Similar promising results were reported in the COSMOS study assessing the effectiveness of SOF/SIM for 12–24 weeks with and without RBV.[24] In the small subgroup of treatment-naïve/experienced F3-F4 patients (n = 41) the SVR rate ranged from 85% in the 12-week arm to 100% in the 24-week arm, with no obvious impact of the addition of RBV. Overall, these studies showed that oral, IFN-free regimens were effective in patients with cirrhosis, and even suggested an improvement in some cases with longer duration regimens, even if they did not have enough power to identify subgroups of patients with lower SVR rates. The TURQUOISE-II study[16] was designed to assess the effectiveness of PAR/DAS/OMB plus RBV for 12 or 24 weeks in a large cohort of 380 treatment naïve or experienced patients with HCV-1 infection and cirrhosis with/without portal hypertension. This study was discussed recently.[25] SVR rates were 92% (97.5% CI 88–96%) at 12 weeks compared to 96% (CI 93–99%) at 24 weeks. Interestingly HCV-1a non-responder patients were identified as difficult to treat and achieved an SVR of 80% in the 12-week arm compared to 93% in the 24-week arm. This study further confirms that the results of IFN-free regimens are generally good in compensated patients with cirrhosis even if further clinical development is necessary in certain groups to improve SVR rates.

The real challenge of IFN-free regimes is treating patients with decompensated cirrhosis. This issue creates interesting avenues of research on antiviral effectiveness and clinical outcomes. At present there is no conclusive evidence on the effectiveness of antivirals in this difficult clinical setting. The only available recent data reported an SVR rate of 65% in 20 patients with HCV-1 decompensated Child B cirrhosis who received LED/SOF. The remaining 7 patients experienced a virological relapse.[26] These preliminary results must be confirmed and validated, even if they support the notion that the greater the severity of liver disease the lower the SVR rate in IFN-free regimens, probably because cirrhotic livers are less able to clear or cure infected cells. However, the other key issue in patients with decompensated cirrhosis is whether virological eradication can result in clinical improvement and compensated liver disease with possible removal from liver transplantation waiting lists, as observed in other clinical settings such as alcoholic hepatitis and HBV-related cirrhosis. Data are not available in this clinical setting where IFN is contraindicated, and where RBV can be a risk, and huge clinical advances are expected.

Existing evidence suggests that available and soon-to-be available IFN-free regimens are effective in patients with compensated cirrhosis, even if further clinical studies are necessary to identify difficult to treat patients (HCV-1a cirrhosis? cirrhotic non-responders?) requiring longer treatment and/or the addition of another DAA with/without RBV. On the other hand, data are needed in patients with decompensated cirrhosis, where the history of DAA-based regimens has barely begun.

Other areas of research in patients with cirrhosis are the use of RBV, and in particular, identifying clinical settings where RBV improves SVR, and finally, safety issues. Data on the safety of IFN-free regimens in patients with cirrhosis are only available for certain combinations and in patients with well-compensated disease. However, the impact of these drugs in patients with compensated cirrhosis – with older disease and co-morbidities – as well as in patients with decompensated liver disease must be evaluated.

Backup Strategies for Failure of DAAs: New Generation DAAs or IFN/RBV ?

The high number of HCV-1 patients treated with TVR or BOC-based TT in phase II and III clinical trials and then in clinical practice, has generated a corresponding proportion of patients with HCV variants resistant to NS3–4A protease inhibitors. With the introduction of IFN-based or IFN-free regimens with new generation DAAs the presence of patients with multidrug resistant viral populations is expected. Thus, the clinical relevance of response to other antiviral strategies has not been sufficiently studied and data are limited. However, the lower SVR rates observed in HCV-1a patients with the Q80K substitution treated with SIM-based therapy suggests that this issue must be carefully evaluated.[9,10]

Observational data on the failure of first generation PI have shown that viral populations resistant to NS3-4A protease inhibitors progressively decline, replaced by wild-type viruses within a few months after treatment withdrawal. These encouraging experimental results were confirmed clinically in a preliminary study showing high SVR rates in patients who did not respond to TVR or BOC TT when there were retreated with IFN-free regimens. Specifically, a 24-week course of SOF/DAC with/without RBV resulted in an SVR in 40/41 patients who failed TVR-based TT.[23] The LONESTAR-1 study[27] tested the effectiveness of 12 weeks of SOF/LED with/without RBV in 40 HCV-1 CHC patients who did not respond to first generation PI, 22 of them with cirrhosis. The authors reported SVR rates of 95% and 100% in the arms without and with RBV respectively.

Results in patients who did respond to IFN plus new generation DAAs vary. Nineteen HCV-1 patients from the ELECTRON-1 study who relapsed after SOF TT were retreated with 12 weeks of SOF/LED and all of them achieved an SVR.[26] On the other hand, HCV-1 patients who did not respond to PEG-IFN/RBV + an investigational PI with/without LED or tegobuvir, achieved an SVR rate of 74%.[28] Most of these patients (90%) carried at least 1 resistance associated variant.

Finally, clinical trials have shown that IFN-free regimens combining more DAAs are highly effective, and that virological failures because of breakthrough or relapse with resistant viruses are rare due to the high resistance barriers. Nevertheless, it should be remembered that: (i) viral populations harbouring resistance to NS5A protease inhibitors may persist for many years after treatment is discontinued and that the clinical significance of this is unknown for new combinations; (ii) the development of viral strains resistant to DAAs is expected to increase in clinical practice because of cases of suboptimal adherence to therapy; and (iii) until now studies evaluating escape strategies for unsuccessful IFN-free regimens have not been performed.

Although results are encouraging and suggest that IFN-free regimens are highly effective in cases of failure with BOC or TVR, further efforts are needed to identify standardized or personalized approaches in patients who do not achieve an SVR even with IFN-based or IFN-free new generation DAA combinations. For this, different approaches should be tested, such as careful assessment of virological strains, extending therapy, and/or adding PEG-IFN and/or RBV to modulate the immune system.

The issue of the cost: careful cost-effectiveness analyses needed

The rapid change in the landscape of antiviral therapy has resulted in an increase in the number of available molecules and significantly better results as well as a significant increase in the cost of drugs. Specifically, the cost of one course of antiviral therapy increased from approximately €10 000–15 000 for DT, to €30 000 for IFN-based first-generation PI therapy and €60 000 with SOF TT. In particular pricing of IFN-free regimens is not yet available, but the cost of the combination of SOF with SIM is approximately €120 000. This raises the key question of whether the application of a universal IFN-free strategy by national healthcare systems is viable in all HCV-1 CHC patients. To answer this question, assessment of the price of a course of antiviral therapy must take into account the cost of drugs, the effectiveness of the treatment strategy, and both direct and indirect costs of the management of side-effects related to drugs. In this way, we can accurately calculate the real cost of achieving an SVR. However, to assess the cost-effectiveness of a therapeutic strategy, its impact on the natural history of the disease and on the costs of managing the disease over time must also be evaluated. For this, the incremental cost-effectiveness ratio for life-years gained or for quality adjusted life years are the markers used. Two recent cost-effectiveness analyses of IFN-free regimens were published for CHC patients with contrasting results.[29,30] Differences in the results of these analyses were due to the estimated pricing of IFN-free regimens and the different comparison arms. Younossi et al.[29] simulated an unrealistic scenario in which the price of the IFN-free regimen was the same as IFN-based first-generation PI which generated a universal cost-effectiveness of IFN-free therapy. On the other hand, Deuffic-Burban et al.[30] developed a more realistic model in which IFN-free treatment was twice as expensive as IFN-based second generation DAAs. This model resulted in the lack of cost-effectiveness of a full IFN-free scenario. However, although the proposed analyses are useful for decision-making and for negotiation of the price of newer IFN-free regimens, the clinical value and ethical impact of treatment should not be unduly influenced by an economic analysis. In other words, availability of highly effective, short duration well tolerated treatment regimens, make them preferable for all patients, from those with advanced disease to those with mild liver damage. Although pricing and cost-effectiveness analyses provide information on IFN-free cost-effectiveness in all clinical scenarios, they cannot determine which patients should receive IFN-free and IFN-based strategies. In resource-limited settings a priority-based treatment plan must be designed where patients at high risk of the complications of liver disease are treated first while those with milder disease can be deferred while undergoing periodic re-evaluation of liver damage.