Special Issue: Proceedings of the 7th Paris Hepatitis Conference International Conference of the Management of Patients with Viral Hepatitis, 13–14 January 2014, Paris, France. Guest Editors: Patrick Marcellin and Tarik Asselah. The publication of this supplement was supported by an unrestricted educational grant from Gilead, Janssen Therapeutics, Janssen, Bristol-Myers Squibb, Roche, Boehringer Ingelheim, Merck, AbbVie, Novartis, Idenix and Alios.
Volume 34, Issue Supplement s1, pages 79–84, February 2014
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Mitchell L. Shiffman1,2,*, Yves Benhamou1,2
Article first published online: 23 DEC 2013
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Keywords: chronic hepatitis C virus; faldaprevir; sofosbuvir; simeprevir
The treatment of chronic HCV is evolving rapidly. In 2014, three new oral antiviral agents, simeprevir, faldeprevir and sofosbuvir will become available for patients with HCV genotype 1. These agents have far less side effects than the first generation protease inhibitors telaprevir and boceprevir. Treatment will therefore be easier for patients to tolerate but still require peginterferon and ribavirin (PEGINF/RBV). The first IFN free therapy, sofosbuvir (SOF) and ribavirin (RBV), will also become available in 2014. This treatment is highly effective for patients with HCV genotype 2. However, SVR rates with SOF/RBV appear to be similar to that achieved with PEGINF/RBV in patients with HCV genotype 3. The first IFN-free all oral antiviral therapy combination for patients with HCV genotype 1 may be available late in 2014 or early 2015. The factors which should be considered when deciding whether to treat a patient with HCV now or to delay treatment until IFN free therapies are available is discussed.
The treatment of chronic hepatitis C virus (HCV) continues to evolve at a rapid pace. Since the 2013 Paris Hepatitis Conference 1 year ago several new direct acting antiviral (DAA) agents have completed the clinical trials process and data supporting their efficacy and safety has or will soon be presented to the USA Food and Drug Administration, the European Medicines Agency and the health regulatory agencies in several other countries. By the time this manuscript appears at the 2014 Paris Hepatitis Conference we expect that simeprevir (SIM) and sofosbuvir (SOF) will have been approved and available for HCV treatment in the USA. We anticipate that faldaprevir (FAL) will be available during the first several months of 2014. All three of these agents should also be available in many European countries during 2014.
SIM and FAL are potent protease inhibitors (PIs) [1-4]. Both bind to the same site and inhibit the same NS3-4 protease as telaprevir (TVR) and boceprevir (BOC) and have a high rate of resistance if utilized as monotherapy. Clinical trials of both agents have been conducted in combination with peginterferon (PEG-IFN) and ribavirin (RBV) and both will likely be approved for use in patients with HCV genotype 1 who are either treatment naïve or who have failed previous treatment with PEGINF and RBV. Both of these PIs will be utilized according to the concepts of response guided therapy; similar to the way TPV has been utilized since that agent became available in mid-2011 . SIM and FAL achieve high rates of rapid virological response (RVR) and this allows over 80% of patients to be treated for only 24 weeks. Sustained virological response (SVR) rates in the 75–85% range have been reported [1, 3]. SOF is a polymerase inhibitor and has antiviral activity against all HCV genotypes . It is anticipated that this agent will be approved and utilized with PEG-IFN and RBV for treatment naive patients with HCV genotypes 1, 4, 5 and 6. RVR occurs in virtually all patients treated with SOF, PEG-IFN and RBV and SVR rates of 90% or better have been observed with just 12 weeks of treatment .
In 2014, the standard of care for the treatment of chronic HCV genotype 1 will continue to be the combination of a single DAA plus PEG-IFN and RBV . The antiviral agent choices will include one of four protease inhibitors; TPV, BOC, SIM and FAL or the polymerase inhibitor SOF. The pharmacology, efficacy and side effect profile for each of these agents are detailed throughout this supplement to Liver International.
In 2014, an effective oral antiviral agent will for the first time be available for patients with HCV genotypes 2 and 3 . The combination of SOF and RBV represents the first interferon free treatment for patients with chronic HCV. In patients with genotype 2 this treatment is highly effective. Virtually all patients achieve RVR and SVR rates with just 12 weeks of treatment are superior to that achieved with 24 weeks of PEG-IFN and RBV [6, 9]. In patients with HCV genotype 3, 12 weeks of SOF and RBV appears to have similar efficacy as 24 weeks of PEG-IFN and RBV. Extending the duration of SOF and RBV to 16 weeks appears to increase SVR especially in patients who have previously failed treatment with PEG-IFN and RBV and in patients with cirrhosis. We anticipate that the regulatory bodies will recommend that patients with HCV genotype 3 be treated for 16 weeks with SOF and RBV.
Several pharmaceutical manufacturers have independently developed either a PI, an NS5A replication complex inhibitor, a nucleoside polymerase inhibitor and/or a non-nucleoside polymerase inhibitor. When various combinations of these antiviral agents were evaluated in phase 2 clinical trials, with or without RBV, HCV RNA became undetectable very rapidly, and high rates of SVR were observed without resistance [10-13]. The results of these trials are reviewed throughout this supplement of Liver International. Phase 3 clinical trials of several interferon free oral antiviral therapies will be complete later in 2014. Table 1 summarizes those regimens we anticipate being approved and available for treatment of HCV genotype 1 during 2015.
Table 1. Interferon free all oral therapies for patients with HCV genotype 1 drugs that are expected to be available in 2015
At the 2013 Paris Hepatitis Conference the authors debated whether patients with chronic HCV should be treated in 2013 or wait for either a PI with less toxicity (which would be utilized with PEG-IFN and RBV) or an interferon free all oral antiviral regimen. These arguments were summarized in our contribution to the 2013 supplement to Liver International . Frankly, the arguments to treat in 2014 or wait are not very different now than 1 year ago. The difference is that an interferon free therapy has arrived for patients with genotypes 2 and 3 and this is now only about 12–18 months away for patients with genotype 1. The current manuscript will re-evaluate the treatment landscape and provide arguments as to why some patients could be treated now and others could continue to defer therapy. These arguments should be considered by patients and physicians when deciding when to initiate HCV treatment.
There was great enthusiasm in 2011 when the first protease inhibitors, TPV and BOC, were approved for the treatment of patients with chronic HCV. These two PIs when combined with PEG-IFN and RBV offered significant improvements in SVR and for the first time more patients were being cured instead of failing therapy [15-18]. An improvement in SVR compared with PEG-IFN and RBV was observed in nearly every patient population (treatment naïve or prior PEG-IFN and RBV failure) and subpopulation (race, degree of fibrosis, viral load or IL28B status). Unfortunately, these PIs substantially increased the toxicity of treatment compared with PEG-IFN and RBV. The biggest and most difficult to deal with side effect of TPV and BOC is anaemia. This occurs in approximately 40–50% of all persons treated with these PIs and is even more common when treating patients with cirrhosis . Telaprevir also causes a rash in about 50% of patients [16, 18]. Although this is severe and progressive in only a limited number of patients several regulatory agencies insisted that physicians be informed of this potential toxicity and issued a ‘black box’ warning in 2012. Other side effects observed more frequently in patients treated with telaprevir include pruritus and gastrointestinal symptoms. TPV has to be taken with a high fat content meal or snack three times daily; although more recently data has demonstrated that this protease can be dosed twice daily without impacting efficacy . BOC is associated with dysgeusia and is dosed three times daily. Both TPV and BOC have strong drug-drug interactions and several medications need to be either discontinued before the PI is started or the dosage and/or blood level of the alternate drug has to be closely monitored.
When first approved, the combination of TPV and BOC were disproportionately utilized in patients who had failed previous treatment with PEG-IFN and RBV and in patients with cirrhosis. In several centres treatment was even initiated in patients with cirrhosis and prior hepatic decompensation. In the largest cohort where this experience was described high rates of anaemia, significant morbidity and several mortalities were observed. The SVR observed in this cohort of patients with prior non-response and/or cirrhosis was only 41% [19, 22].
The two newer PIs, SIM and FAL and the PI SOF will also be utilized with PEG-IFN and RBV in patients with HCV genotype 1. However, these agents offer significant advantages over TPV and BOC. The most important of these is that none of these three agents cause additional anaemia compared with PEG-IFN and RBV [1-4, 6]. All of these agents are dosed as a single once daily tablet, no special diet is required during dosing and no significant drug-drug interactions have been observed. Neither SIM nor SOF were noted to have any adverse events with greater frequency than PEG-IFN and RBV [1, 2, 6]. FAL was noted to have a slightly higher incidence of rash [3, 4]. However, the rash was graded as only mild or moderate in all cases and no grade 3 rashes were observed. FAL was also associated with a mild increase in total bilirubin without elevations in liver transaminases or alkaline phosphatase.
Controlled clinical trials comparing the various antiviral agents utilized for treatment of patients with HCV genotype 1 have not been conducted. As such, no direct comparison regarding the relative effectiveness of these agents can be made. Both SIM and FAL triple therapies were evaluated against a placebo control with PEG-IFN and RBV. As a result, the improvement in SVR with the PI over control could be compared for TPV, BOC, SIM and FAL [1, 3, 15, 16]. Such a comparison suggests that the RVR and SVR rates might be slightly higher in patients treated with SIM and FAL compared with telaprevir and boceprevir. The high RVR rates observed with SIM and FAL allowed over 80% of patients to be treated for only 24 weeks according to response guided therapy guidelines.
The success of treatment in patients treated with SIM and FAL, like the other PIs, is dependent upon an effective interferon response and this is modulated by IL28B genotype. The SVR exceeds 90% in patients with IL28B genotype CC and declines in patients with the CT and TT haplotypes [1, 3]. SIM and FAL have also been studied in patients who failed to achieve SVR with PEG-IFN and RBV [2, 4]. In general the SVR rates observed during retreatment follow a similar trend as reported for TPV and BOC and decline according to interferon responsiveness as defined by the previous treatment response. Patients with prior relapse had the highest SVR rates regardless of which PI was utilized. Patients with prior null response had the lowest SVR rates.
SOF, PEG-IFN and RBV is administered for only 12 weeks and in the phase 3 trial no placebo control was utilized . Virtually all patients treated with SOF triple therapy achieved a RVR and the overall SVR rate was 89%. In patients with cirrhosis the SVR rate was 80% . SOF triple therapy has not been evaluated in patients who failed either PEG-IFN and RBV or triple therapy with a PI [23, 24].
There is no doubt that the newer antiviral agents SIM, FAL and SOF will be easier to tolerate and they appear to be more effective than TPV and BOC. The major impediment to their widespread use will be that these agents will still require PEG-IFN. Many patients, particularly those with less fibrosis may therefore choose to delay therapy and opt for a future all oral antiviral regimen which is anticipated to be available by late 2014 or in 2015. In contrast, patients with cirrhosis will be more likely to seek treatment, and physicians will be more likely to treat these patients now with an interferon containing regimen that appears safer and is perceived to be superior. We fully expect that SOF, SIM and/or FAL triple therapy will be widely utilized in patients with cirrhosis in much the same manner as TPV and BOC were soon after these agents became available several years ago. The CUPIC study and other studies in patients with advanced cirrhosis clearly demonstrated that treating such patients with an interferon containing regimen is associated with significant morbidity and yields an SVR rate far below that observed in phase 3 clinical trials [19, 22]. We would expect somewhat similar results when SOF, SIM and/or FAL triple therapy are utilized in this population as well.
Genotypes 4, 5 and 6
Genotype 4 is the most common genotype of HCV in Egypt and many other middle eastern countries [23, 24]. HCV genotype 5 is most prevalent in South Africa and HCV genotype 6 is most common in Vietnam and its neighbouring countries. In the USA and many European countries genotype 4 accounts for a small, but not insignificant percentage of patients with HCV whereas HCV genotypes 5 and 6 appear limited to those persons who emigrated from areas of the world where these genotypes of HCV are more common. SOF, PEG-IFN and RBV is highly effective in patients with HCV genotypes 4, 5 and 6. Although only 35 patients with genotypes 4–6 were included in the single arm phase 3 trial, 96% of patients with genotype 4, and all 7 patients with genotypes 5 and 6 achieved an SVR .
It is currently unknown if the interferon free oral antiviral regimens being developed for HCV genotype 1 would also be effective in patients with genotypes 4, 5 and 6. These genotypes were not included in the ongoing phase 3 clinical trials and it would therefore be very unlikely that these first generation interferon free regimens would be approved for use in patients with these other genotypes. For this reason it seems logical to proceed with treatment in all patients with genotypes 4, 5 and 6 now utilizing SOF triple therapy.
SOF and RBV yield superior SVR rates compared with PEG-IFN and RBV in patients with HCV genotype 2. In treatment naïve patients 12 weeks of SOF and RBV achieved SVR rates of 91 and 98% in patients with and without cirrhosis respectively [6, 8]. In patients who had previously failed PEG-IFN and RBV SVR rates of 96 and 60% were observed with 12 weeks of treatment . Why the SVR rate with 12 weeks of SOF and RBV was lower in patients with cirrhosis who previously failed PEG-IFN therapy compared with a treatment naïve population remains unclear. Extending the duration of SOF from 12 to 16 weeks did increase the SVR in this subgroup of patients with cirrhosis and prior PEG-IFN non-response to 78% . Given these results in the absence of PEG-IFN there appears to be no good reason why treatment with SOF and RBV should not be initiated in any patient with HCV genotype 2. Although 12 weeks of treatment will be sufficient in the majority of patients, this should probably be prolonged to 16 weeks in patients with cirrhosis and prior PEG-IFN non-response. Whether the regulatory bodies make this recommendation remains to be seen.
Genotype 3 is now the most difficult of all the HCV genotypes to cure. The reasons for this remain unclear, but could be related to the much higher percentage of hepatic steatosis associated with this type of HCV . The same is true when these patients are treated with SOF and RBV. The SVR rate observed with 12 weeks of SOF and RBV were only 34 and 61% for patients with and without cirrhosis and very similar to that observed with PEG-IFN and RBV [6, 8]. Prolonging the duration of SOF and RBV to 16 weeks increased the SVR rate in all patients with this genotype to 63–61% . We expect the regulatory authorities will recommend that patients with HCV genotype 3 be treated with SOF and RBV for 16 weeks. Given that the SVR rates with SOF and RBV are suboptimal and either similar to or only marginally higher than observed with PEG-IFN and RBV the main reason to select the all oral combination is to avoid the side effects associated with PEG-IFN and RBV.
Additional DAA agents, which could be utilized with SOF and RBV, are currently being evaluated for patients with HCV genotype 3. Until these agents are shown to be effective and approved it is very reasonable to defer treatment in patients with genotype 3 and mild fibrosis. In contrast, patients and their physicians will be more likely and willing to use SOF and RBV, despite a suboptimal SVR, in patients with cirrhosis. It is rationale to assume that adding PEG-IFN to SOF and RBV would elevate the SVR rate in patients with genotype 3. A small preliminary study suggests this may be correct; 20/24 (83%) patients including 10/12 (83%) with cirrhosis achieved SVR following 12 weeks of treatment with SOF, RBV and PEG-IFN . Until larger studies confirm these findings it is unclear if regulatory bodies and insurance carriers would approve and fund this combination, SOF triple therapy in patients with HCV genotype 3.
Mixing and matching antiviral agents
In 2014, both SIM and SOF will have been approved and available for use in the USA and many European countries. Both agents are highly effective against HCV genotype 1. In a small pilot study of patients with HCV genotype 1 and prior non-response all patients treated with the combination of SIM and SOF for 12 weeks achieved SVR . To our knowledge, no additional formal studies utilizing these two agents is planned by their respective manufacturers. It is therefore unlikely that regulatory authorities and payers will authorize payment for this combination. However, if such approval could be obtained the combination of SIM and SOF would appear to be an excellent and safe combination with which to treat all patients with HCV genotype 1, especially those with advanced cirrhosis.
A few thoughts about cost
It is relatively intuitive that patients would rather be treated and physicians would rather prescribe several non-toxic oral DAAs than deal with the side effects of a PEG-IFN containing regimen. This is especially true if the SVR rates for the two regimens are similar. There is no doubt that a therapy that cures more patients with HCV can be shown to be more cost effective than a treatment with a lower cure rate. However, the payer, whether a private insurance carrier or a government entity may not will be willing to pay a substantially higher cost for medication that yields a similar SVR even though the more economical choice is associated with a higher side effect profile. There are many patients with chronic HCV that already have favourable response profiles. This includes a low serum HCV RNA level, mild fibrosis, prior relapse and IL28B genotype CC. The later patients already enjoy an SVR rate of over 90% and both retrospective and prospective data strongly suggest that this high SVR rate can be preserved with just 12 weeks of TPV triple therapy [28, 29]. Waiting for an interferon free all oral regimen may yield an easier treatment, but it is unlikely that this would be associated with any higher chance of SVR in certain subpopulations. Health care dollars are becoming more limited and tailoring treatment to each patient's response characteristics may be a more rational approach than treating all HCV patients with a more costly albeit easier regimen.
Continued improvement in our ability to ‘cure’ HCV has been made within the past year when we last reviewed the reasons to treat or wait in patients with mild fibrosis. Two new PIs and a polymerase inhibitor are now or will soon be available. In patients with genotypes 2 and 3 an interferon free all oral treatment is already or will soon be available. In patients with genotype 1 these new agents will still be utilized with PEG-IFN; but an IFN-free all oral option appears to be only another 12–18 months away.
This manuscript has summarized our current treatment for HCV and provided reasons for treating now as well as reasons why patients with mild fibrosis should continue to defer treatment. These reasons are summarized in Table 2. The vast majority of patients can be cured of HCV with our current PEG-IFN containing therapies and the only reason to wait is to avoid the side effects of IFN. However, as the duration of therapy is reduced to as little as 3 months the concern for interferon side effects becomes less of an issue. No two patients are the same and in the end it all comes down to presenting the patient with their choices and proceeding with what the patient is most comfortable doing.
|Treat now||Delay treatment|
|Genotype 4, 5 and 6||All patients without cirrhosis and stable cirrhosis||Decompensated cirrhosis|
|Genotype 2||All patients|
|Genotype 3||All patients with bridging fibrosis and cirrhosis||Patients with mild fibrosis|
MLS is an advisor for Abbvie, Achillion, Boehringer-Ingelheim, Bristol-Myers-Squibb, Gen-Probe, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis and Roche/Genentech; speaks on behalf of Bayer, Boehringer-Ingelheim, Gilead, Janssen, Merck, Roche/Genentech and Vertex and receives grant support from Abbvie, Achillion, Beckman-Colter, Bristol-Myers-Squibb, Boehringer-Ingelheim, Gilead, Idenix, Intercept, Merck, Novartis and Vertex. YB has no conflicts of interest to declare.