January 30, 2014

Gut

Zoe Mariño, Florian van Bömmel, Xavier Forns, Thomas Berg

Gut. 2014;63(2):207-215.

Introduction

Since the discovery of HCV in 1989, interferon α (IFNα)-based therapy has been the only treatment approach leading to HCV genotype-dependent sustained virological response (SVR) rates in a significant number of patients. However, the treatment uptake has been generally low due to numerous side effects and contraindications to IFNα-based regimens. Because of these limitations, the overall HCV-related health burden could only gradually be decreased, even though treatment efficacy was increased over recent years. [1,2]

The lack of cell culture systems to grow HCV had been a key limitation for the development of direct acting antivirals (DAAs). Nevertheless, in 1997, only a few years after the discovery of HCV, the first subgenomic HCV replicons were obtained allowing researchers to develop and assay DAAs with a robust methodology. [3–5] In 2004, the safety and efficacy of the first DAA, the protease inhibitor BILN2061, were assessed in a proof-of-concept clinical trial. [6] Now, a few years later, IFNα-containing or IFNα-free regimens based on DAAs showed the potential to cure HCV infection in very high percentages with overall good tolerability. [7]

DAAs targeting two major steps of the HCV life cycle have reached clinical development: (1) inhibitors of the NS3-4A protease, which block HCV polyprotein processing and (2) inhibitors of viral replication, including several drug families, such as nucleoside/nucleotide and non-nucleoside inhibitors of the RNA-dependent RNA polymerase (RdRp), and inhibitors of the NS5A viral protein which have a regulatory role in HCV replication. [8–12]

A perspective of the future treatment landscape for chronic HCV infection is depicted in figure 1. Peg-IFNα-containing regimens with second generation protease inhibitors like simeprevir and faldaprvir or the polymerase inhibitor sofosbuvir will become the first to be licensed for HCV type 1 infection. A significant number of different all oral IFNα-free regimens with pan-genotypic activity by combining different classes of DAAs have entered phase II and III and may become available in the near future (see figure 1).

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Figure 1. Selected treatment regimens for chronic hepatitis C infections which are expected to become available in the near future. Future treatments focus on interferon (IFN)α-free, direct acting antiviral-based combination regimens which have shown sustained virological response rates of around 90%. The displayed studies include predominantly patients without liver cirrhosis. (1) Submitted for approval in Japan in 2013; (2) approval expected in Japan and in the USA at the end of 2013; and (3) submission for approval expected in November 2013. NS3/4A PI=second generation protease inhibitor; NUC=nucleosidic polymerase (NS5B) inhibitor; NS5A=NS5A inhibitor; PI/r=ritonavir boosted PI; PR=pegylated-IFNα plus RBV; RBV=ribavirin.

Sofosbuvir is the first nucleotide polymerase inhibitor that will become licensed for the treatment of HCV infection as part of IFNα-containing and IFNα-free regimens. As other nucleoside/nucleotide inhibitors of the RdRp, it shows high antiviral activity against all HCV genotypes and a high barrier to resistance. [12] Sofosbuvir was shown to be safe and overall well tolerated, and no relevant drug–drug interactions (DDI) have to be expected. Due to this favourable pharmacological profile, sofosbuvir has a great potential to become a cornerstone in the management of HCV infection. Especially, the performance of sofosbuvir in IFNα-free treatment approaches may open a new and promising area in the treatment of hepatitis C.

The present article reviews the clinical current knowledge of sofosbuvir as part of IFNα-containing as well as IFNα-free treatment regimes, which have been published in phase II and III studies. We have further tried to estimate its possible use in patients who show difficult-to-treat characteristics. Finally, we were trying to give an outlook on the future role of sofosbuvir in the treatment of chronic HCV infection.

Current Standard of Care

The current standard of care for the treatment of chronic HCV infection is still based on a combination of pegylated (Peg)-IFNα and ribavirin (RBV) but includes a protease inhibitor (either telaprevir or boceprevir) for HCV type 1-infected patients. This triple regimen has increased SVR rates up to approximately 70% and also allows reducing treatment duration in approximately 50% of patients to 24 weeks. [12] However, the antiviral efficiency of triple regimens is low in previous null responders, especially in those with advanced fibrosis or cirrhosis and the addition of a protease inhibitor to the regimen led to a significant increase in the number of side effects. [8–11] Contraindications or status intolerance to IFNα or RBV further limits the number of patients who may benefit from this first generation protease inhibitor-based triple therapy.

Protease inhibitors are not licensed for the use in non-type-1-infected patients for whom the combination of Peg-IFNα and RBV remains the standard of care. After 48 weeks of treatment duration, SVR rates of around 60% can be achieved in HCV genotypes 4, 5 and 6 infection whereas up to 60%–80% of type 2 and 3-infected patients may be cured by a 24-week dual regimen. [13,14]

Pharmacology of Sofosbuvir

Sofosbuvir, a prodrug of 2'-deoxy-2'-fluoro-2'-C-methyluridine monophosphate, is a specific nucleotide analogue inhibitor of the HCV NS5B polymerase that acts as a false substrate for the RdRp, leading to chain termination after incorporation into the newly synthesised RNA chain. [15] The drug needs two additional phosphorylations to be activated. Sofosbuvir has a potent antiviral activity covering all HCV genotypes. [16] Dose findings studies showed optimal inhibition of HCV replication by a once daily dose of 400 mg. [17]

Sofosbuvir is a once-daily drug which can be taken with or without food. The drug traverses the GI tract and remains intact during absorption, resulting in high exposure in the liver. [15] It is absorbed rapidly with a median t max of 1 h (range 0.5–3.0 h). The elimination is rapid with median t½ in the range of 0.48–0.75 h. The active metabolite of sofosbuvir, GS-331007, exhibits a longer median t max of 4 h (range 1.5–8) and a half life ranging from 7.27 to 11.80 h. [17]

Sofosbuvir is mainly eliminated by the kidneys at a rate of 76%. Clearance of the drug is rapid, with median half life in the range of 0.48–0.75 h. [17] No dose adjustment seems necessary in patients with renal clearance >30 mL/min, whereas modification of doses or dosing intervals may be required in patients with moderate to severe renal impairment or haemodialysis. [18]

One of the additional advantages of sofosbuvir and other drugs of the same family is their low potential for DDI, because their metabolism is not linked to the CYP3A4 pathway. A recent study conducted in healthy volunteers assessed the potential for pharmacokinetic interactions between sofosbuvir and the immunosuppressants cyclosporine and tacrolimus and revealed that sofosbuvir did not affect the exposure to calcineurin inhibitors and only a slight increase in the concentration of sofosbuvir was observed in individuals who received cyclosporine. [19] In addition, no clinically significant interactions have been observed with methadone or with antiretroviral therapies in HCV/HIV co-infected patients such as the nucleosidic reverse transcriptase inhibitors tenofovir and emtricitabine, the non-nucleosidic reverse transcriptase inhibitors efavirenz and rilpivirine or the protease inhibitors darunavir or ritonavir. [20]

Sofosbuvir Development Programme

IFN-free Sofosbuvir Regimens in HCV type 1-infected Patients: Results From Phase II Trials

IFNα-free strategies have been evaluated in phase II studies in HCV type 1-infected patients which tried to define the efficacy of different treatment combinations for different treatment durations ranging from 8 to 24 weeks. [21–26] These regimens typically consist of combinations based on (1) sofosbuvir plus RBV, (2) sofosbuvir plus a second DAA or (3) sofosbuvir plus a second DAA in combination with RBV, summarised in figure 2A and B. Even though the numbers of type 1-infected patients included in the numerous different arms of the studies were quite often limited and to date not all patients have completed the observation period yet, interesting preliminary conclusions can already be extracted from the presented results.

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Figure 2. Phase II trials on sofosbuvir-containing interferon α-free treatments in (A) treatment-naive and (B) treatment-experienced patients with HCV type 1 according to present publication of sustained virological response (SVR) rates.21–26 The study arms were designed to examine the efficacy of sofosbuvir in combination with ribavirin (RBV) (highlighted in blue), in combination with a second direct acting antiviral (DAA) (highlighted in pink) or with both a second DAA and RBV (highlighted in purple) to examine the optimal treatment length, which could be between 8 and 24 weeks. Of note, only few patients in these trials had liver cirrhosis. *One patient was missing in the evaluation 12 weeks after the end of treatment. All patients remaining in the study showed SVR.

Sofosbuvir in Treatment-naive HCV Type 1-infected Patients

In the QUANTUM and ELECTRON studies, sofosbuvir was given for 12 weeks in combination with RBV to overall 50 treatment-naive patients with HCV type 1 infection. [23,27] SVR12 was observed in 56% and 88% of patients, respectively (mean of 70%). Prolongation of this dual combination treatment to 24 weeks seemed not implicitly to increase in SVR rates, as the overall SVR12 rate was 52% and 90%, respectively (mean 67%) in 35 patients of the QUANTUM and NIH SPARE studies. [23,25] These findings were surprising in view of the results from the phase III FUSION trial in HCV type 2 and 3 infection, where treatment extension from 12 to 16 weeks tended to improve SVR rates significantly from 56% to 73%. [28]

Combining sofosbuvir with a second DAA generally led to a much more robust treatment response with higher SVR rates as compared with the sofosbuvir plus RBV regimen, irrespective of whether RBV was added or not (figure 2A and B). [21–25]

The choice of the second DAA—either a non-nucleoside polymerase inhibitor or NS5A inhibitor—did not seem to impact the strength of the response, as far as it can be judged by the present results. A combination of sofosbuvir with another distinct nucleotide analogue (GS-0938) for 12 weeks resulted in SVR12 in 88% out of 25 patients. The SVR4 rates after 12 weeks of combination treatment with sofosbuvir and the NS5A inhibitors daclatasvir or ledipasvir (GS-5885) were as high as 98% and 100% in the 41 and 19 patients which were studied, respectively. [22,24] Whether a prolongation of this combination treatment beyond 12 weeks will be required to further increase the response rates is questionable, as treatment extension to 24 weeks with GS-0938 plus sofosbuvir showed an equally high SVR12 rate of 88%. [23] Even shorter treatment duration seems to be a realistic option, as sofosbuvir and ledipasvir given for 8 weeks already led to SVR8 in 95% of 20 patients in the LONESTAR trial. [22]

Sofosbuvir in Treatment-experienced Type 1-infected Patients

A 12-week sofosbuvir plus RBV regimen was evaluated in the multipart ELECTRON study in 10 HCV type 1-infected patients who previously showed null response to Peg-IFNα and RBV (figure 2B). [21] On treatment, complete suppression of hepatitis C viremia was achieved in all patients, but surprisingly all but one of these patients relapsed after treatment was stopped.

The limitations which sofosbuvir obviously had in these patients when combined with RBV were overruled when sofosbuvir was given with a second DAA for only 12 weeks in patients, which resulted in SVR rates between 90% and 100%. Regardless of the mode of action of the second DAA, being either the NS5A inhibitor ledipasvir or daclatasvir, the protease inhibitor simeprevir or the non-nucleoside polymerase inhibitor GS-9669 this regimen showed equally high SVR rates as in treatment-naive patients (figure 2B). [22,24,26]

Treatment extension to 24 weeks using a combination of sofosbuvir and the NS5A inhibitor daclatasvir was evaluated in the AI444-404 study in 41 patients who failed a previous protease inhibitor-based triple therapy. [24] This study was controlled for the effect of RBV by randomising patients to receive 1000–1200 mg RBV per day or placebo for 24 weeks. Irrespective of the addition of RBV, all patients who were followed for 12 weeks after stopping therapy achieved an SVR.

IFN-free Sofosbuvir Regimens in HCV Non-type 1-infected Patients: Results From Phase II Trials

To evaluate a possible benefit of adding Peg-IFNα to a 12-week combination treatment of sofosbuvir plus RBV in patients with HCV type 2 or type 3, four treatment arms including 12, 8, 4 weeks or no Peg-IFNα and sofosbuvir plus RBV were included in the phase IIa ELECTRON trial. [21] All patients who were treated for 12 weeks with sofosbuvir and RBV, with or without Peg-IFNα, showed SVR12 giving conclusive evidence that adding Peg-IFNα was not needed for these patients. Also patients who were treated with sofosbuvir as monotherapy for 12 weeks showed undetectable HCV RNA at the end of treatment; however, at week 4 post-treatment, four of the 10 patients had a virological relapse. As a result, in the following phase III studies, monotherapy with sofosbuvir was no longer considered.

Sofosbuvir as Part of Peg-IFNα-containing Regimens in HCV Type 1 and Type 4–6-infected Patients: Results From Phase II Trials

A strong efficacy of the combination treatment of sofosbuvir plus RBV and Peg-IFNα in patients with HCV type 1 was demonstrated in the PROTON and in the ATOMIC phase II studies. [29,30] The PROTON study, in which 400 mg sofosbuvir per day or placebo were given in combination with Peg-IFNα plus RBV for 12 weeks followed by an additional 12 or 36 weeks of Peg-IFNα and RBV, showed 91% SVR12 rates for the sofosbuvir group versus 40% for the placebo group. [29] In the ATOMIC trial, it was investigated whether maintenance treatment is necessary once a response was introduced by a 12-week sofosbuvir-containing triple regimen. Overall, 332 treatment-naive patients with HCV types 1, 4 and 6 without cirrhosis were treated with sofosbuvir 400 mg per day plus Peg-IFNα and RBV given for either 12 or 24 weeks. [30] In the 12-week arms, patients were randomised to either stop treatment or enter a maintenance phase with either sofosbuvir alone or in combination with RBV for additional 12 weeks. Regardless of the treatment arms, SVR rates between 90% and 94% were observed. Therefore, a 12-week combination treatment of sofosbuvir plus RBV and Peg-IFNα was chosen for the phase III NEUTRINO study. [31]

Sofosbuvir as Part of Peg-IFNα-containing Regimens in HCV Type 1 and Type 4–6-infected Patients: Results From the NEUTRINO Phase III Trial

In the NEUTRINO trial, 327 naive HCV type 1, 4, 5 and 6 patients were treated for 12 weeks in an open-label single-arm design with sofosbuvir 400 mg and RBV 1000–1200 mg per day as well as with Peg-IFNα 180 μg per week. [31] The result were compared with the historic SVR12 rates of treated cohorts with Peg-IFNα and RBV over 48 weeks which had a global SVR12 rate settled on 60%. The study included 291 patients with HCV type 1 (89%), and 35 with types 4, 5 and 6 (11%). The overall SVR12 rate was 90% (figure 3), 89% in HCV type 1, 96% in HCV type 4 and 100% in the seven patients with HCV types 5 and 6. Out of the 55 patients with cirrhosis, 80% achieved SVR12. No significant differences in SVR rates were found with respect to other baseline parameters, but slightly higher SVR rates were observed in patients with low viral load, favourable IL28B CC genotype and those being infected with HCV subtype 1a versus1b.

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Figure 3. Phase III trials on sofosbuvir-containing treatments in treatment-naive, treatment-experienced patients with contraindications to IFNα. The study arms were designed to examine the efficacy of sofosbuvir in combination with Peg-IFNα and ribavirin (RBV) given for 12 weeks (highlighted in blue) or for 24 weeks (highlighted in orange) in HCV types 1, 4, 5 and 6, and to examine the efficacy of sofosbuvir in combination with RBV (highlighted in light blue) in patients with types 2 and 3. 28,31

Sofosbuvir was well tolerated and did not add side effects to the expected safety profile of Peg-IFNα plus RBV. The rate of discontinuation related to adverse events was 2% which was significantly lower as in the historical controls. Even among patients with cirrhosis, serious adverse events were rare and only one patient had to discontinue treatment. [31]

Sofosbuvir as Part of Peg-IFNα-free Regimens in HCV Type 2 and 3-infected Patients: Results From the Phase III Trials FISSION, FUSION and POSITRON

Combination of sofosbuvir plus RBV given for 12 weeks in phase II trials had led to such convincing SVR rates in HCV type 2 and 3-infected patients that this regimen was further evaluated in phase III. According to prior treatment experience different treatment scenarios were explored in three different phase III trials—the FISSION, FUSION and POSITRON studies. [28,31]

The FISSION trial was designed to assess the efficacy of the combination of an IFNα-free regimen based on sofosbuvir plus RBV given for 12 weeks in 256 treatment-naive type 2 or 3-infected patients in comparison with combination of Peg-IFNα plus RBV given to 243 patients with types 2 or 3 for 24 weeks. [31] About 176 (72%) of the patients had HCV type 3, and 50 patients (21%) had cirrhosis. The rates of SVR were 67% in both arms, confirming the non-inferiority main endpoint of the oral regimen (figure 3). The response rates to the IFNα-free sofosbuvir plus RBV regimen were however significantly lower among patients with HCV type 3 than among those with type 2 (56% vs 97%, respectively; figure 4).

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Figure 4. Influence of liver cirrhosis on response to treatment with sofosbuvir plus ribavirin (RBV), and the effect of treatment prolongation from 12 to 16 weeks in treatment-experienced patients with HCV types 2 or 3, as observed in the phase III FUSION trial.28 Extending the treatment duration by 4 weeks increased sustained virological response (SVR) rates especially in patients with type 3 infection, but also in patients with type 2 infection and cirrhosis.

Presence of cirrhosis was another strong negative predictor of response. SVR rates were only 47% in patients with cirrhosis, which was similar to the 38% SVR in the control arm with standard treatment of Peg-IFNα plus RBV (figure 4). In terms of safety, the sofosbuvir plus RBV arm was associated with significantly fewer adverse events than the arm with Peg-IFNα plus RBV.

The FUSION trial aimed at investigating whether the combination treatment of sofosbuvir and RBV was more effective when given for 16 instead of 12 weeks. [28] The studied cohort was conducted in HCV type 2 and 3 patients who had failed previous Peg-IFNα-based therapies. Among these patients, 75% had suffered virological breakthrough or relapse, and 25% were defined as non-responders. [28] Patients were randomised 1:1 to receive either 12 weeks (n=103) or 16 weeks (n=98) treatment with sofosbuvir 400 mg plus RBV 1000–1200 mg per day. The overall SVR rates were 50% in the 12-week and 73% in the 16-week arms (p<0.001), both results comparing favourably with a 25% cure rate which has been estimated for a virtual control group expressing identical characteristics but being treated with Peg-IFNα plus RBV (figure 3). [28]

Again, HCV type 3 and presence of cirrhosis were the main predictors of poor outcome. However, in such cases, the extension of treatment duration from 12 to 16 weeks could improve the results considerably (see figure 4). No increase in adverse events was observed when treatment was extended to 16 weeks. [28]

In the POSITRON trial, the effectiveness of 12 weeks of combination of sofosbuvir and RBV was investigated in 278 patients with HCV type 2 or 3 being ineligible for Peg-IFNα-based therapies due to contraindications and/or unacceptable previous adverse events or unwillingness to receive Peg-IFNα therapy. [28] Patients were randomised 3:1 to receive either sofosbuvir 400 mg plus RBV 1000–1200 mg per day or placebo. Overall, 78% of patients in the treatment-arm and no patient in the placebo group achieved an SVR (figure 3). For HCV type 2 and 3-infected patients, SVR rates were 93% and 61%, respectively. Among the 44 patients with compensated cirrhosis, SVR rates were 94% in HCV type 2 but only 21% in HCV type 3 infections.

Sofosbuvir Resistance

HCV variants which cause resistance against sofosbuvir have been identified in vitro using the HCV replicon system. [32] In these assays, sofosbuvir showed a 9.5-fold increase in EC 50 if the S282T mutation was present. Infection models using HCV types 1a, 1b and 2 could also demonstrate a selection of this mutation in presence of sofosbuvir. In type 1a patients, additional variants as the mutation I434M were shown to be selected by sofosbuvir, although these variants only lead to a small loss of susceptibility.

Indeed, in the ELECTRON trial, in one of the four patients who suffered a relapse after 12 weeks of sofosbuvir monotherapy, the S282T mutation could be detected after the relapse. Before treatment this variant had not been present in this patient. No mutations associated with resistance to sofosbuvir have been detected in patients who showed a relapse after sofosbuvir combination therapy with either RBV or a second DAA. [33] Moreover, no on-treatment resistance associated viral breakthrough has been observed in any of the patients treated with any sofosbuvir regimens and virtually all patients showed a robust and quite rapid response to the drug. Interestingly, in two patients who experienced a relapse in HCV replication after 12 weeks combination treatment with sofosbuvir and the protease inhibitor simeprevir, the mutation Q80K that is associated with simeprevir resistance was detectable at baseline. One of these patients gained the D168E and I170T simeprevir resistance mutations during combination treatment, but there were no emergent sofosbuvir resistance mutations detectable during the relapse. [34]

The high genetic barrier against resistance created by sofosbuvir may have different reasons. First, replication fitness of the sofosbuvir resistance associated variant S282T is significantly impaired as this mutation within the active site of the RdRp impairs polymerase activity decreasing the replication capacity by approximately 90% in HCV types 1a and 1b as compared with the wild type replicon. Second, the drug was able to suppress hepatitis C viremia to undetectable levels in virtually all patients within 4 weeks of treatment as has been demonstrated in all clinical trials so far. The shutdown of viral replication at these early stages on treatment limits the time for the selection of resistant variants which is in line with the concept: 'no replication=no resistance'.

Predictors of Response and the Problem of Relapse

A rebound of viral replication (a relapse) after stopping sofosbuvir-based therapy accounts for practically all failures to this treatment. The phenomenon that, in spite of fast suppression to undetectable HCV RNA levels in virtually all patients within the first 2–4 weeks of sofosbuvir treatment, HCV replication may relapse in some patients after stopping treatment is poorly understood.

Significant relapse rates (ie, greater than 10%) were however only seen in patients treated with either sofosbuvir alone or in combination with RBV, but not in those treated in combination with a second DAA or Peg-IFNα, and relapse rates were especially high in HCV type 1 and 3-infected patients with previous null response to Peg-IFNα and RBV therapy and those with cirrhosis (figure 4).

There are subtle hints that very early viral kinetics within the first days of treatment may differ between patients who are going to relapse and those achieving a sustained response (figure 5). [20] There remains, however, the intriguing question: why does prior response to a Peg-IFNα-based treatment influence the responsiveness to a IFNα-free regimen like sofosbuvir plus RBV? One might speculate that prior null response to Peg-IFNα and RBV might not only be driven by low IFNα susceptibility but also by non-responsiveness to RBV. According to this concept, re-treatment of these patients with sofosbuvir plus RBV may be basically equivalent to a functional sofosbuvir monotherapy which is not effective enough to eradicate the infection during a short treatment period. A genetic profile associated with an altered innate immune function (ie, IL28B non-CC genotype) predominates in patients showing non-responsiveness to Peg-IFNα and RBV, which also may contribute to the lower likelihood of viral eradication that can be induced during short-term blocking of viral replication by polymerase inhibitors. [35]

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Figure 5. Model of the early kinetics of HCV RNA levels including a subgroup of 20 treatment-naive patients with HCV type 1 infection receiving sofosbuvir plus ribavirin in the NIH SPARE study.25 Patients who achieved sustained virological response (SVR) showed a significantly faster decrease of HCV RNA to undetectable levels within the first 7 days of treatment as compared with patients who suffered a relapse after treatment.

RBV reduces in vivo the mRNA levels of a large number of Peg-IFNα-stimulated genes, particularly those which were found to be upregulated in non-responders to Peg-IFNα plus RBV. [36] These epigenetic re-programming properties of RBV could synergise with the potent antiviral activity of sofosbuvir to restore the host innate immunity responses. [37] Furthermore, HCV-specific immune modulation with IFNα-free DAA therapy may occur via inhibition of HCV replication that may be key in order to prevent relapses and induce an SVR. [38]

HCV RNA testing 4 weeks after stopping treatment already allows a high positive prediction of sustained response as it has been shown in both the QUANTUM and the ELECTRON studies. [23,21] SVR24 rates were 99% and 97.1%, respectively, in patients who showed undetectable HCV RNA levels at week 4 of the post-treatment follow-up. [39]

Safety Profile of Treatments Containing Sofosbuvir

Sofosbuvir was generally well tolerated when given alone, in combination with RBV or in combination with Peg-IFNα and RBV.

Sofosbuvir given in Peg-IFNα-free regimens has clearly improved tolerability over Peg-IFNα-based treatments. [40] In a meta-analysis of different studies comprising Peg-IFNα-free arms, the rate of severe adverse events (SAE) was between 4% and 6%, and none of these SAEs was related to sofosbuvir. [40] Only four of 331 patients (1.2%) who received sofosbuvir as monotherapy, in combination with RBV or in combination with the NS5A inhibitor ledipasvir and RBV, discontinued treatment due to adverse events. Also few laboratory abnormalities were found in these patients. In the phase II COSMOS trial, grade 3–4 pancreatic amylase or lipase elevations were observed in five out 52 patients (10%) who had been treated with sofosbuvir in combination with simprevir plus RBV, and in one out of 29 patients (3%) who received sofosbuvir plus simeprevir. However, these laboratory findings were transient and not associated with clinical symptoms. [37]

Safety profile did not differ in patients with well compensated liver cirrhosis who were included in the phase III sofosbuvir trials and no hepatic decompensation was observed while on any of the IFNα-free treatment arms. [27,31]

Sofosbuvir for Difficult-to-Treat Patients

Due to its high antiviral potency, even when given as monotherapy, the favourable safety profile and obvious lack of cumbersome DDIs, sofosbuvir represents a nearly ideal backbone for the treatment of patients who were up to now considered as difficult-to-treat, that is, patients with prior treatment failures to Peg-IFNα-based treatments (including those who failed triple therapy), patients being intolerant or ineligible to Peg-IFNα, patients with extra hepatic HCV manifestations or HCV/HIV co-infection, as well as those with decompensated cirrhosis or liver transplant recipients. [41]

Pilot studies in patients awaiting LT and in liver transplant recipients with aggressive HCV recurrence are currently ongoing to assess efficacy of sofosbuvir in this population (studies NCT01687270 and NCT01779518; for more information see: http://www.clinicaltrials.gov). Sofosbuvir plus daclatasvir combination proof-of-concept therapy was effective to cure a liver transplant recipient with severe recurrent cholestatic hepatitis C. [42] Preventing the infection of the graft by application of sofosbuvir either alone or in combination with a second DAA also appears to become a realistic scenario in the near future.

Treatment efficacy of IFNα-free sofosbuvir regimens in HCV type 1-infected patients with compensated cirrhosis has not been evaluated in a significant number of patients. However, a lower cure rate might be expected given the fact that in HCV type 2 and especially in type 3-infected patients cirrhosis was one of the main risk factors for reduced SVR rates (figure 4). The expected low SVR in these patients has influenced the design of the NCT01687257 in which patients infected with different HCV types who have compensated or decompensated liver cirrhosis receive an extended 48-week combined treatment of sofosbuvir plus RBV. One is inclined to argue that patients with decompensated HCV-induced cirrhosis may profit most from IFNα-free combinations with different DAAs. In some ongoing trials evaluating these treatments, patients with liver cirrhosis may be included; however, data on safety and efficacy are awaited.

Sofosbuvir is currently being investigated in patients with HCV/HIV co-infection in the PHOTON trial (NCT01783678). In this trial, the efficacy of the combination of sofosbuvir plus RBV is investigated over 12 weeks in HCV type 2-infected patients and for 24 weeks in HCV type 1, 2, 3 and 4-infected patients.

Summary and Future Directions

The approval of sofosbuvir can be regarded as a first step towards a radical change in the antiviral management of chronic HCV infection. For the first time, we are about to hold a DAA in our hands that covers all genotypes and shows robust antiviral response in virtually all patients due to high intrahepatocellular concentrations. No viral breakthrough as a consequence of drug resistance has been observed, even when sofosbuvir was given as monotherapy. The excellent safety profile and the lack of significant DDIs will allow the broad use of the drug also in more difficult-to treat situations like co-infections, cirrhosis and the liver transplant setting.

For HCV type 1, 4, 5 and 6 infection, a triple combination containing sofosbuvir plus Peg-IFNα and RBV given for a fixed duration of only 12 weeks will be licensed in the close future that obviously is able to cure 90% of the patients without any response guided modifications. However, Peg-IFNα-containing regimens can be regarded only as a brief 'footnote' in the history of the sofosbuvir development programme, as IFNα-free regimens are close to becoming the standard in HCV type 1 infection.

For HCV type 2 and 3-infected patients, an IFNα-free regimen containing sofosbuvir plus RBV has been established by three different phase III trials showing cure rates that were at least comparable with those observed in dual therapy with Peg-IFNα plus RBV.

As virological relapses account for practically all sofosbuvir treatment failures, the main unresolved issues are now (1) how long the duration of treatment has to be and (2) how many DAAs have to be combined in order to prevent a virological relapse. Also, the role of RBV in the setting of multiple DDA regimens remains uncertain.

For HCV type 2-infected patients, a 12-week sofosbuvir plus RBV regimen may soon become the standard of care, whereas in HCV type 3 as well as in type 1-infected patients and in patients with cirrhosis, the high relapse rates that have been seen after this regimen certainly claim for individualised treatment adaptations. Prolonging treatment duration to 16 weeks helped to reduce the relapse rates in HCV type 3. Whether prolongation of sofosbuvir and RBV to 24 weeks may further increase cure rates is currently being evaluated in the ongoing European Valence Study (GS-US-34–0133) in HCV type 3 infection. An alternative approach which is now studied in phase II trials aims to shorten treatment to 12 or even 8 weeks by applying different regimens including either Peg-IFNα and RBV or a second DAA—the NS5A inhibitor ledipasvir or the non-nucleoside inhibitor GS-9669 in combination with sofosbuvir (NCT01260350).

For HCV type 1-infected patients, the combination of sofosbuvir plus a second DAA will probably represent the most promising approach. Gilead Sciences is currently evaluating the combination treatment with its own NS5A inhibitor ledipasvir (formerly GS-5885) in three different phase III trials (ION studies). [43] The ION-1 trial is designed to evaluating a once-daily fixed-dose combination of sofosbuvir plus ledipasvir with or without RBV for 12 or 24 weeks among 800 treatment-naive HCV type 1 patients. The ION-2 is evaluating sofosbuvir with ledipasvir and RBV for 12 weeks or sofosbuvir plus ledipasvir with or without RBV for 24 weeks among 400 treatment-experienced type 1 HCV patients who previously failed to respond to a triple therapy with Peg-IFNα, RBV and either boceprevir or telaprevir. The ION-3 trial is designed to evaluate 8- and 12-week courses of therapy with the combination of sofosbuvir and ledipasvir with or without RBV in 60 treatment-naive non-cirrhotic patients (NCT01851330).

In summary, a 12-week IFNα-free regimen may become the skeletal structure of the future sofosbuvir-based treatment algorithms. Depending on certain host and viral factors, like HCV type, prior treatment experience or presence of cirrhosis, a second DAA, RBV or both will need to be added. Also, shortening or extending treatment duration may become part of the new individualised treatment approach. It is likely that the availability of these Peg-IFNα-free antiviral regimens will lead to a similar shift in the treatment paradigms and outcomes as has been observed when the first polymerase inhibitors became available for patients with chronic HBV infection. However, we have to be aware that the number of treated patients with more 'difficult-to-treat' characteristics is limited, especially of those with cirrhosis who have been successfully cured with the new treatment regimens. Therefore, that a broader use of these new DAAs in the 'real-world' will probably face unprecedented safety and resistance issues cannot be ruled out.

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