January 7, 2014

Alimentary Pharmacology & Therapeutics

Early View (Online Version of Record published before inclusion in an issue)

Review Article

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R. S. Koff*

Article first published online: 6 JAN 2014
DOI: 10.1111/apt.12601
© 2014 John Wiley & Sons Ltd

Summary

Background

The treatment of chronic hepatitis C is changing rapidly.

Aim

To review clinical studies of the efficacy and safety of sofosbuvir-containing regimens in the treatment of chronic hepatitis C.

Methods

Using PubMed and search terms ‘sofosbuvir,’ ‘emerging HCV treatment,’ and ‘HCV polymerase inhibitor,’ literature on the clinical development of sofosbuvir, as well as abstracts presented at the November 2013 annual meeting of the American Association for the Study of Liver Diseases (AASLD), was reviewed. The last search was undertaken on 15 November 2014.

Results

In a dose of 400 mg once daily, the drug has been safe and generally well tolerated with most adverse reactions attributable to the concurrent use of ribavirin or peginterferon plus ribavirin. A high barrier to resistance has been demonstrated. In genotype 1 (G1) patients, the addition of sofosbuvir to peginterferon plus ribavirin yielded sustained virological response rates at week 12 after discontinuation of treatment (SVR12) of about 90% with slightly lower levels in G1b and in patients with cirrhosis, but with no major impact of IL28B genotype, high viral load, body mass index (BMI), alanine aminotransferase (ALT) or race/ethnicity. In genotype 2 (G2), sofosbuvir and ribavirin for 12 weeks also resulted in SVR12 of 90% or better with little effect from cirrhosis. In contrast, genotype 3 (G3) was less responsive to 12 weeks of sofosbuvir plus ribavirin, especially in the presence of cirrhosis.

Conclusions

The efficacy and safety of sofosbuvir-containing regimens with ribavirin alone or with peginterferon plus ribavirin signals a new era in treatment.

Introduction

The emergence of a new and novel treatment for chronic hepatitis C signals a major change in the standard of care. In addition, our understanding of the definition and benefits of effective treatment has recently expanded. The goal of treatment in all infected individuals, regardless of which of the six major genotypes (G1-6) are present, has been and continues to be the achievement of a sustained virological response (SVR) in which circulating HCV RNA is undetectable with the use of a highly sensitive assay following treatment. Initially, SVR was measured at 24 weeks (SVR24) after the end of treatment. In 2013, sufficient data from clinical trials were available to demonstrate that SVR measured at 12 weeks post-treatment (SVR12) showed a high concordance with SVR24. In the United States, the Food and Drug Administration (FDA) has indicated that SVR12 is an appropriate primary end-point for registration trials seeking FDA approval.[1] It should, nonetheless, be noted that because concordance between SVR12 and SVR24 is not perfect, in clinical practice, assessment of SVR24 would still seem reasonable. It is now generally accepted that achievement of a SVR is highly predictive of eradication of infection. Long-term follow-up studies indicate that disease progression is interrupted, histological, clinical and laboratory features of advanced disease may be reversed, and life-expectancy may return towards normal. Nevertheless, it is now clear that among patients with advanced hepatic fibrosis (defined as Metavir F3 and F4), a risk of hepatocellular carcinoma remains for several years after achievement of a SVR.[2]

In the early years of chronic hepatitis C management, treatment with nonpegylated interferons without and later with ribavirin resulted in low efficacy and was poorly tolerated. Between 2001 and 2011, the standard of care became a combination of pegylated interferon (peginterferon) plus ribavirin, and treatment duration was determined by genotype. In general, with 48 weeks of combination therapy in genotype 1 (G1), SVR rates varied from 40 to 50%. Subtype G1a appeared slightly more responsive than G1b.[3] For genotypes 2 and 3 (G2, G3), with 24 weeks of combination treatment, SVR rates were 70–80%. Although the tolerability of peginterferon was better than that for the nonpegylated forms, many patients were peginterferon intolerant, and ribavirin regularly induced a haemolytic anaemia and other adverse events. Concerns about ribavirin's teratogenicity also complicated patient management. In 2011, a new standard of care for genotype 1 patients, consisting of treatment with an NS3/4A HCV serine protease inhibitor (either telaprevir or boceprevir), received FDA approval for use in combination with peginterferon plus ribavirin. In many patients, treatment could be shortened, but because peginterferon and ribavirin were still required and the protease inhibitors dramatically increased the severity and rapidity of the onset of haemolysis and carried other adverse events (rash, neutropenia, etc.), tolerability (and safety) remained an issue. Discontinuation rates due to adverse events were approximately 15%. Furthermore, both protease inhibitors had to be given with food multiple times throughout the day, drug–drug interactions complicated therapy[5] and resistant HCV variants emerged in those failing to achieve a SVR. The protease inhibitor-containing regimens resulted in SVR rates of 65–75% in previously untreated patients in registration trials, and lower rates (58–61%) among naïve patients in clinical practice[6] and even lower rates (50–52%) in United States veterans.[4]

Patients with histologically advanced disease had lower response rates. The protease inhibitors were ineffective in genotypes other than G1 and response rates were somewhat lower in G1a compared with G1b.

Although the introduction of the serine protease inhibitors for G1 resulted in incremental increases in efficacy in G1, even in this, the most common genotype, their anti-viral activity was limited. As a consequence, research efforts have sought viral and host targets other than the serine protease. These include the NS5B protein and the NS5A replication protein, both of which are essential for HCV replication. Both nucleos(t)ide and nonnucleoside NS5B inhibitors are under study. Because the catalytic site of the NS5B protein is highly conserved across all genotypes, the nucleos(t)ide inhibitors are active against all genotypes, although the in vitro and in vivo data on G5 and G6 are limited. The nucleotide inhibitors also have a higher barrier to resistance than do the nonnucleoside NS5B inhibitors. This review is focused on a single nucleotide NS5B inhibitor – sofosbuvir. It will be the first of the NS5B inhibitors to become commercially available in early 2014. In addition to studies of sofosbuvir in combination with peginterferon and ribavirin or with ribavirin alone, a handful of studies combining sofosbuvir with NS3/4A protease inhibitors or NS5A inhibitors will be briefly reviewed.

Sofosbuvir background information

Originally termed PSI-7977, sofosbuvir is a prodrug of a uridine nucleotide analogue inhibitor of the NS5B polymerase protein. In vivo, it is converted to the 5′-triphosphate derivative, which targets the catalytic site of NS5B and serves as a non-obligate chain terminator.[7]Following treatment with sofosbuvir plus ribavirin, levels of the triphosphate well above the inhibition level have been found in human livers.[8] Studies in replicon cells containing different HCV genotypes indicated that sofosbuvir demonstrated broad genotype coverage. However, cross-resistance studies indicated that sofosbuvir treatment of replicon cells selected the S282T change in G1b cells.[9]Although this reduced sofosbuvir activity, such mutants also had reduced replicative capacity, compared with wild-type-containing replicons.[10] Sofosbuvir activity was not reduced in replicons with mutations in NS3/4A or NS5A. In an analysis of patients who failed to achieve a SVR with sofosbuvir-containing regimens, the S282T substitution was not detectable at baseline or later, although other NS5B substitutions were rarely detected.[11]

These data indicate that sofosbuvir-containing regimens have a high barrier to resistance and that substitutions in the NS5B gene do not affect SVR rates. This observation suggested that sofosbuvir might be an effective anti-viral agent in patients with pre-existing or treatment-emergent NS3/4A or NS5A mutations when combined with other classes of inhibitors. It should not be used as monotherapy.

The pharmacokinetics of single- or multiple-dosing of sofosbuvir has been reviewed elsewhere.[7, 12, 13] In early studies, it was shown that sofosbuvir was rapidly absorbed and eliminated. The triphosphate metabolite of sofosbuvir was largely excreted in urine and no significant accumulation of sofosbuvir or its metabolites was observed. No dose modifications were needed for patients with mild-to-moderate renal impairment. For patients with creatinine clearances less than 30 mL/min and for those on dialysis, sofosbuvir is contraindicated. No dose modification was necessary in patients with impaired liver function or with compensated cirrhosis. No data are available for patients with decompensated cirrhosis as such patients were excluded from participation in clinical trials. Because the metabolism of sofosbuvir does not involve cytochrome P450 3A/4 (CYP3A/4), drug–drug interactions are not anticipated. In fact, no drug–drug interactions with a variety of drugs, such as cyclosporine, tacrolimus, drugs used in the treatment of HIV infection, methadone, or combined oral contraceptives containing ethinyl estradiol and norgestimate, have been identified to date.

It should be noted that in the discussion that follows both SVR12 and SVR24, data have been utilised in determining the efficacy of sofosbuvir-containing regimens. In fact, available data indicate a concordance of greater than 99% in studies of sofosbuvir. Hence, relapse alone, after SVR12 is achieved, is exceedingly rare.[14]

Genotype 1 Studies

Phase 2 Studies

Short-term (28 days), dose-ranging studies of treatment-naïve genotype 1 patients with sofosbuvir plus peginterferon and ribavirin suggested that a dose of 100 mg sofosbuvir was associated with virological breakthroughs on continuing treatment with peginterferon plus weight-based ribavirin after discontinuing sofosbuvir.[12] In these initial studies, viral suppression was greater in the sofosbuvir, peginterferon and ribavirin combination compared with peginterferon and ribavirin with placebo and occurred more rapidly. Furthermore, resistance monitoring failed to identify the S282T mutation either at baseline or during treatment, and sequencing of the entire NS5B protein failed to reveal any mutations that had been associated with resistance to nonnucleoside NS5B inhibitors. Adverse events were similar in frequency in the sofosbuvir-containing regimen compared to peginterferon plus ribavirin. Fatigue, nausea, headache, chills and arthralgias were the most frequently reported. No adverse events led to discontinuation of sofosbuvir.

Subsequently, the 200 mg sofosbuvir dose has been compared to the 400 mg dose, as neither was associated with virological breakthroughs. In one of these phase 2 studies,[15] 90% of G1 patients receiving the 200 mg dose achieved SVR12 with triple therapy for 12 weeks followed by 12 or 36 more weeks of peginterferon and ribavirin. The SVR12 for the 400 mg dose regimen was 91%. In comparison, SVR12 for patients receiving a sofosbuvir placebo with peginterferon plus ribavirin was 58%, significantly lower than for sofosbuvir-containing regimens. Although no patient experienced virological breakthrough while on sofosbuvir, 6% of patients who had received the lower 200-mg sofosbuvir dose experienced breakthrough while still on peginterferon and ribavirin. These findings support the notion that the 400-mg sofosbuvir dose provides more effective viral suppression. The 400-mg dose has been utilised in a number of phase 2 trials.[16, 17] In the open-label, multi-part ELECTRON trial, a small number of treatment-naïve and treatment-experienced patients were given a peginterferon-free regimen of sofosbuvir and ribavirin for 12 weeks.[16] In the treatment-naïve group, HCV RNA was undetectable by week 4 of treatment in 100%. SVR12 and SVR24 were identical at 84%. In contrast, among the treatment-experienced patients, only 10% had SVR12 and SVR24. These data suggested that for treatment-experienced G1 patients, peginterferon or the addition of another direct anti-viral agent would be required to achieve higher efficacy. In another phase 2 trial of sofosbuvir with peginterferon and ribavirin (ATOMIC) for new to treatment noncirrhotic G1 patients, the efficacy of sofosbuvir (400 mg daily) with peginterferon plus ribavirin given for 12 or 24 weeks was assessed.[17] In some patients who received 12 weeks of the combined treatment, the efficacy of an additional 12 weeks of sofosbuvir monotherapy or sofosbuvir plus ribavirin was evaluated. A SVR24 of 89% was achieved with 12 weeks of combination treatment with no additional benefit of treatment extension.

Patients with predictors of treatment failure, based on studies with peginterferon and ribavirin without or with protease inhibitors, had been largely excluded from these early trials. In one small-scale, randomised, open-label phase 2 trial, treatment-naïve G1 patients with unfavourable features of treatment success (African-American descent, high BMI, low frequency of IL28B CC genotype, high HCV RNA level and advanced liver disease) were treated with sofosbuvir and weight-based (1000–1200 mg daily) or low-dose (600 mg daily) ribavirin for 24 weeks.[18] Among patients with early-to-moderate hepatic fibrosis, SVR24 was 90%. Among patients with the full spectrum of hepatic fibrosis, viral suppression was achieved in 96% at week 4 of treatment. However, SVR24 rates were 68% in the ribavirin weight-based group and 48% in the ribavirin low-dose group due to high frequencies of relapse. These observations also support the need for the use of additional agents with sofosbuvir and ribavirin for some G1 patients.

The safety of sofosbuvir-containing regimens was studied in these phase 2 trials. Adverse events were common in all studies and were consistent with those associated with peginterferon plus ribavirin treatment. Major reported events included fatigue, headache, nausea, chills, insomnia and arthralgias. Most were considered by the investigators to be mild to moderate and most resolved. Drug discontinuations due to adverse events were rare and were generally associated with peginterferon plus ribavirin rather than with sofosbuvir. Similarly, rates of neutropenia, thrombocytopenia and anaemia were consistent with those seen in patients treated with peginterferon and ribavirin.

Phase 3 Studies

The principal phase 3 trial of sofosbuvir treatment of new to treatment G1 patients was termed NEUTRINO.[19] In this open-label, multicentre trial, 89% of patients had genotype 1; 9% had G4; and just 2% were G5 or G6. G1a was the predominant G1 subtype. Mean age, BMI, sex and self-reported race or ethnic group were typical of chronic hepatitis C patients. HCV RNA levels of 800,000 IU/mL or higher were found at baseline in 82%, and the unfavourable IL28B TT and TC genotypes were present in 71%. Approximately 50% of patients had ALT levels more than 1.5 times the upper limit of normal (ULN). Cirrhosis was present in 17%. All patients received 400 mg sofosbuvir, with peginterferon plus weight-based ribavirin for 12 weeks. SVR12 was defined as an HCV RNA level below the lower limit of quantification (25 IU/mL). Although it would have been of interest to have a control group comprising a serine protease inhibitor with peginterferon and ribavirin, this was not included. Rapid viral suppression was evident by week 2 of treatment with 91% of patients having undetectable HCV RNA, and by week 4 of treatment, 99% were HCV RNA undetectable. SVR12 was 90% and no virological breakthroughs occurred during treatment. SVR12 was higher in G1a at 92% vs. G1b at 82%. As shown in Table 1, efficacy rates were also high in populations with less favourable host and viral characteristics. As expected, SVR12 was reduced in patients with cirrhosis (79%) compared with those without cirrhosis (92%). SVR12 rates were highest in those with minimal fibrosis (F0–F2), lower in those with bridging fibrosis (F3) and lowest in cirrhosis (F4). Similarly, patients with the unfavourable non-CC IL28B genotypes had a lower SVR12 (87%) than those with the CC genotype (98%). SVR12 rates did not differ fundamentally when race or ethnicity was considered. Similarly, BMI, viral load and alanine aminotransferase (ALT) elevations did not importantly influence SVR-12 rates.

Capture

Among patients who relapsed after end-of-treatment, both population and deep sequencing studies failed to detect resistance-associated variants. Although 95% of patients experienced an adverse event, discontinuation of treatment as a result of adverse events occurred in just 2%. Adverse events occurring with a frequency of more than 20% included fatigue, headache, nausea, insomnia and anaemia. Haemoglobin levels below 10 g/dL were found in 23%, and neutropenia levels below 500/mm3 were seen in 15%.

Genotype 2 and 3 Studies

Although trials of treatment with interferons with or without ribavirin often considered HCV G2 and G3 patients as one group, a large body of observations indicated that response to treatment was lower in G3. Studies of sofosbuvir-containing regimens support the notion of a differential response rate in some G3 patients, particularly prior null responders and those with cirrhosis. (Table 2)

Capture

Phase 2 Studies

In a phase 2b trial of sofosbuvir with peginterferon plus ribavirin given for 12 weeks to a total of 25 naïve, noncirrhotic G2 and G3 patients, 95% were HCV RNA undetectable at week 4 of treatment and SVR24 was achieved in 23 of the 25 (92%).[15, 20] No virological breakthrough or relapse was reported. The two patients who did not achieve a SVR included one lost to follow-up and one in whom a nonprotocol HCV RNA assay was utilised. In a component of the phase 2a ELECTRON trial, 18 noncirrhotic treatment-naïve G2 and 42 noncirrhotic treatment-naïve G3 patients were randomised to receive sofosbuvir plus ribavirin for 12 weeks either without peginterferon or with peginterferon for 4, 8 or 12 weeks.[16] A fifth group received 12 weeks of sofosbuvir alone and a sixth group received 8 weeks of treatment with sofosbuvir, ribavirin and peginterferon. All groups were small with only 9–11 patients per arm. SVR12 and SVR24 was 100% in all arms receiving peginterferon and in one arm of sofosbuvir with ribavirin in the absence of peginterferon. However, monotherapy with sofosbuvir for 12 weeks reduced the SVR12 and SVR24 to 60%. In that group, 2 G2 and 2 G3 patients relapsed but only one, a G2b patient, had the S282T mutation.

Phase 3 Studies

In the phase 3 FISSION non-inferiority trial, nearly 500 of 527 screened, new to treatment G2 and G3 patients were randomised to treatment with either 400 mg of sofosbuvir plus weight-based ribavirin for 12 weeks or peginterferon plus 800 mg of ribavirin for 24 weeks.[19] Approximately 20% had cirrhosis; 87% were white; mean BMI was 28; 43% had IL28B CC genotype; and 57% had serum levels exceeding 1.5 × the ULN. Viral suppression was more rapid in the sofosbuvir and ribavirin group. At week 2 of treatment, 92% had undetectable HCV RNA compared with 32% of those receiving peginterferon and ribavirin. Overall, SVR12 was 67% in both groups, indicating non-inferiority of the two treatment regimens. For G2 patients receiving sofosbuvir plus ribavirin, the overall SVR12 was 97% vs. 78% for those receiving peginterferon plus ribavirin. However, in G2 patients receiving sofosbuvir and ribavirin without cirrhosis, SVR12 was 97%; in those with cirrhosis, it was 91%. In contrast, in G3 patients receiving sofosbuvir plus ribavirin, SVR12 was 61% in those without cirrhosis and 34% in those with cirrhosis, significantly lower rates. Resistance-associated variants were not detected in any of the patients who relapsed. Adverse events and haematological abnormalities were less frequent in the sofosbuvir plus ribavirin group compared with the peginterferon plus ribavirin group. The discontinuation of treatment rate due to adverse events was also lower in recipients of sofosbuvir plus ribavirin (1%) than in recipients of peginterferon plus ribavirin (11%).

G2 or G3 patients in whom treatment with peginterferon was not an option because of unacceptable side effects, or were deemed peginterferon ineligible because of concurrent medical conditions, or refused peginterferon were evaluated in a phase 3 trial called (POSITRON).[21] In this blinded, placebo-controlled study, sofosbuvir plus weight-based ribavirin given for 12 weeks was compared to a matching placebo. About 92% of patients were white; about 75% had high viral loads; about 45% had IL28B CC genotype; and 15% had cirrhosis at baseline. SVR12 was 78% in the sofosbuvir plus ribavirin group and 0% in the placebo group. As in the FISSION study, SVR12 was higher in G2 patients at 93% compared with 61% in G3. Among G2 patients without cirrhosis, the SVR12 was 92% vs. 94% of those with cirrhosis. In contrast, among G3 patients without cirrhosis, the SVR12 was 68%, but only 21% in those with cirrhosis.

In the phase 3 FUSION trial, treatment-experienced G2 and G3 patients were treated with sofosbuvir plus ribavirin for either 12 or 16 weeks.[21] In G2 patients without cirrhosis, the SVR12 after 12 weeks of treatment was 96%; for G2 patients with cirrhosis, SVR12 was 60%. SVR12 after 16 weeks of treatment in G2 patients yielded a rate of 100% in those without cirrhosis and 78% in those with cirrhosis. In sharp contrast, 12 weeks of treatment of G3 patients without cirrhosis resulted in a SVR12 of 37%; in those with cirrhosis, the rate was just 19%. SVR12 after treatment of G3 patients without cirrhosis for 16 weeks revealed a SVR12 of 63% and for those with cirrhosis 61%. These observations indicate that for treatment-experienced G3 patients with cirrhosis, sofosbuvir plus ribavirin treatment duration may need to be extended or the addition of other direct anti-viral agents or peginterferon may be necessary.

The efficacy and safety of extending treatment with sofosbuvir plus weight-based ribavirin in G3 patients for longer than 12 or 16 weeks was assessed in the phase 3 VALENCE study[22] The original treatment protocol, which included G2 and both treatment-naïve and treatment-experienced patients, was amended to permit extending treatment to 24 weeks in G3 patients. In G2 patients treated for 12 weeks, the overall SVR12 was 93%. In the treatment-naïve group, it was 97%. In the treatment-experienced group, SVR12 was 91% in the noncirrhotic patients and 88% in cirrhotic patients. Twelve weeks of sofosbuvir plus ribavirin was given to a small group of G3 patients before the protocol was amended. In this group, the SVR12 was just 27%. Among G3 patients treated for 24 weeks, the overall SVR12 was 85% and but was higher in treatment-naïve patients without or with cirrhosis (94% vs. 92%). Treatment-experienced noncirrhotic G3 patients treated for 24 weeks had a SVR-12 of 87%, whereas those with cirrhosis had a SVR12 of 60%. The drugs were well tolerated for 24 weeks and the safety profile was consistent with that for ribavirin. Furthermore, discontinuations due to adverse events occurred in less than 1% of those treated for 24 weeks. No evidence of resistance was identified in any patient in whom relapse occurred. These observations confirm the notion that for G3 treatment-experienced patients and especially for those with cirrhosis, 24 weeks of treatment with sofosbuvir plus ribavirin is optimal.

Genotype 4 studies

The NEUTRINO study, described above under G1 phase 3 trials, also included 28 patients with G4 infection, treated with triple therapy for 12 weeks.[19] In this small group, SVR12 was 96%. In a phase 2 study, 60 treatment-naïve and -experienced G4 patients were randomised to treatment with sofosbuvir plus ribavirin without peginterferon for 12 or 24 weeks.[23] Baseline viral load was high, as were BMIs; the majority of patients had unfavourable IL28B genotypes, and nearly 25% had cirrhosis. At week 4 on treatment, 98% had undetectable HCV RNA and 100% were undetectable at the end of treatment. In the treatment-naïve patients treated for 12 weeks, the SVR measured at 4 weeks post-treatment (SVR4) was 79%. Longer treatment for 24 weeks resulted in a SVR4 of 100%. In the treatment-experienced group, SVR4 was 59% for the 12-week regimen and 93% for the 24-week regimen. SVR12 data had not yet been report

Genotypes 5 and 6 studies

Data on the efficacy of sofosbuvir-containing regimens in G5 and G6 patients are exceedingly limited. In the NEUTRINO study, only 2% of patients were G5 or G6.[19] SVR12 was achieved with 12 weeks of treatment with sofosbuvir and peginterferon plus ribavirin in the single patient with G5 and in all 6 patients with G6. Larger studies will be needed to confirm these promising observations.

Sofosbuvir in combination with other direct anti-viral agents

The combination of sofosbuvir with NS5A inhibitors (either daclatasvir or ledipasvir) has been recently studied. Daclatasvir with sofosbuvir with or without ribavirin given for 12 weeks appeared to result in high SVR rates in noncirrhotic, naive G1 and G1-3 patients in early studies.[24, 25] In a phase 2 trial, termed ELECTRON, a fixed dose combination of 400 mg of sofosbuvir and 90 mg of ledipasvir for 12 weeks has been studied with or without ribavirin in a small number of G1 prior null responders with compensated cirrhosis and in naïve, noncirrhotic patients.[26] Among the 10 cirrhotic patients treated with the fixed dose combination plus ribavirin, the SVR12 was 100%, whereas in the absence of ribavirin, the SVR12 was 70%. In G1 previously untreated, noncirrhotic patients, 6 weeks of the fixed dose combination with ribavirin yielded a SVR12 of 68%. Treatment for a longer period, 8 weeks, yielded a SVR12 of 100%. These observations indicate that 6 weeks of treatment is inadequate. Of interest, the addition of a nonnucleoside NS5B inhibitor (GS-9669) to sofosbuvir permitted a ribavirin-free regimen that induced a SVR12 of 100% in patients with advanced hepatic fibrosis.

Another phase 2 evaluation of the fixed dose combination of sofosbuvir/ledipasvir with or without ribavirin was termed LONESTAR.[27, 28]In this study of a limited number of treatment-naïve, noncirrhotic G1 patients, treatment with 8 weeks of the combination without ribavirin was compared with 8 weeks of combination therapy with ribavirin. In a third arm, the combination without ribavirin was given for 12 weeks. Most (87%) of the patients were G1a. SVR12 was achieved in 95% of patients getting the 8-week fixed dose without ribavirin and 100% in those treated for 8 weeks with the fixed dose plus ribavirin. In the group treated for 12 weeks without ribavirin, the SVR12 was 95%. An additional group of patients who had been nonresponders to protease inhibitor regimens and in whom 55% had cirrhosis were treated with the fixed dose combination with or without ribavirin for 12 weeks. SVR12 and SVR24 was 100% for the group receiving ribavirin and 95% for the group not receiving ribavirin. Of interest, most of the protease inhibitor treatment-experienced patients had the Q80K variant, a polymorphism of G1a, along with other protease inhibitor resistance-associated variants; baseline NS5A resistance-associated variants were also found but in a lower frequency.[29] Despite these variants, the efficacy of sofosbuvir/ledispavir with or without ribavirin was not impaired. A phase 3 study is underway.

Preliminary data from a phase 2a randomised, open-label trial combining sofosbuvir with the once-a-day NS3/4A serine protease inhibitor – simeprevir – with or without ribavirin (the COSMOS study) suggest that this interferon-free and ribavirin-free regimen may be efficacious in G1 patients.[30] Noncirrhotic and cirrhotic, treatment-naïve and prior null responder patients were treated with 400 mg of sofosbuvir plus 150 mg of simeprevir with or without ribavirin for 12 or 24 weeks. Just over 75% of the patients were G1a and about 50% of these had the baseline Q80K polymorphism, which has been reported to reduce responsiveness to macrolide NS3/4A protease inhibitors such as simeprevir. SVR12 in prior null responders with F0-F2 fibrosis were 93% whether treated for 12 or 24 weeks with sofosbuvir plus simeprevir. No additional benefit was achieved with the use of ribavirin. All patients completing treatment were HCV RNA undetectable at the end of treatment and virological breakthroughs were not seen while on treatment. Among patients with advanced hepatic fibrosis, either treatment-naïve or prior null responders, SVR4 was achieved in 100% with sofosbuvir plus simeprevir for 12 weeks. Although SVR12 data for all treated cohorts are not yet available, the high efficacy of this combination in G1 patients without either peginterferon or ribavirin denotes a major advance in treatment.

Specific populations

Liver transplant recipients

Recurrence of HCV infection in liver transplant recipients in whom HCV RNA is detected at the time of transplantation has been nearly universal, and in a significant proportion of patients, recurrent HCV infection leads to cirrhosis and reduced survival within 5 years of transplantation. In a small phase 2 study of patients who were candidates for transplantation for hepatocellular carcinoma, and in whom cirrhosis was well compensated, the efficacy of pre-transplant treatment with sofosbuvir and ribavirin for as long as 48 weeks in an attempt to prevent recurrence was assessed.[31] A total of 41 patients, with any genotype, were HCV RNA undetectable at the time of transplant and 64% of these achieved SVR12. The longer the period on treatment with HCV RNA undetectability before transplant, the lower the relapse rate observed. The lowest relapse rates were seen in patients who had been HCV RNA negative for more than 30 days prior to transplantation. Treatment was well tolerated in these compensated cirrhosis patients and drug interactions with anti-rejection drugs were not observed.

Among mainly G1 patients with severe HCV recurrence or with fibrosing cholestatic hepatitis following liver transplantation, early initial data from a compassionate use program in which sofosbuvir was combined with ribavirin with or without peginterferon, the latter at the discretion of the treating physician, have been reported for the first 44 patients.[32] Clinical improvement was noted in 64% of patients and liver chemistry abnormalities also improved. Overall SVR12 was 56%; in those receiving sofosbuvir plus ribavirin, it was 60% and in those receiving triple therapy, it was 50%.

In a prospective, multicentre trial of sofosbuvir plus ascending doses of ribavirin (400–1000 mg daily) given for 24 weeks to patients with recurrent HCV infection after liver transplantation, 100% of patients had undetectable HCV RNA levels at week 4 of treatment.[33] HCV RNA undetectability at end-of-treatment was 100% and SVR4 was 77%. SVR12 data were not yet available. No net change in immunosuppression dose requirements was found.

To date, no studies of nonliver organ transplant recipients with chronic hepatitis C have been reported.

Decompensated cirrhosis and renal failure

Data on the efficacy and safety of sofosbuvir-containing regimens in decompensated cirrhosis or renal failure, with or without dialysis, are not available and for the latter, treatment is now considered contraindicated.

HIV/HCV coinfected

The efficacy and safety of sofosbuvir plus ribavirin, in the absence of peginterferon, has been assessed in human immunodeficiency virus (HIV) coinfected patients with HCV G1-3 in a preliminary study.[34] In this nonrandomised open-label trial, in which all patients were HIV stable and nearly all were on antiretroviral therapy (ART) for HIV, 63% of patients were G1. Multiple ART regimens were permitted, but relatively few patients had cirrhosis. Patients with G1 were treated with sofosbuvir plus ribavirin for 24 weeks, whereas those with G2 or G3 received the combination for 12 weeks. Treatment was completed in 90% of patients. At week 4 of treatment, 96–100% of patients had undetectable HCV RNA. SVR12 was 76% in G1, 88% in G2 and 67% in G3. SVR12 rates were higher in patients with G1a at 82% than with G1b at 54%. Response rates were lower in patients with cirrhosis. HCV virological breakthrough was identified in only one patient in whom non-adherence was documented. HIV breakthrough occurred in two patients, one with non-adherence. The other HIV breakthrough occurred in a patient who regained HIV control without a change in therapy. Regardless of genotype, all relapses occurred by week 4 after ending treatment. Sofosbuvir plus ribavirin was well tolerated. Additional studies of sofosbuvir-containing regimens, with peginterferon or direct anti-virals, will be necessary to determine the optimal management strategy for HIV-coinfected patients.

Paediatric

No studies in children have been reported to date.

Discussion

Sofosbuvir has now been studied in over 3000 patients and is generally safe and well tolerated. In addition to its favourable pharmacology profile, and the absence of evidence of drug–drug interactions, no effect of food on pharmacokinetics has been found. It is formulated as a 400-mg tablet, which can be given once-daily, by mouth. As is the case with other HCV NS5B polymerase inhibitors, HCV NS3/4A protease inhibitors and NS5A replication protein inhibitors, it should not be used as monotherapy. In combination with ribavirin or with peginterferon plus ribavirin, virological breakthrough is rare and resistance-associated variants are not seen. Viral suppression is so rapid that little benefit can be gained by early monitoring of viral load, except where noncompliance is suspected.[35] Initially, 12 weeks of treatment with sofosbuvir combined with ribavirin will be the new standard of care for both new-to-treatment and treatment-experienced G2 patients. For G3 patients, 12 or 16 weeks of sofosbuvir plus ribavirin does not seem optimal. Better results, particularly in treatment-experienced G3 patients, can be achieved with a 24-week course of therapy. The addition of peginterferon or another direct anti-viral may also be necessary for these difficult-to-treat patients. At least initially, G1 patients will be treated with sofosbuvir, ribavirin and peginterferon. As more information becomes available about the efficacy and safety of combining sofosbuvir with the NS3/4A protease inhibitor simeprevir or the NS5A inhibitor ledipasvir or daclatasvir, management strategies are likely to change.

Many questions remain unanswered. So few G5 or G6 patients have been studied to date that recommendations for use of sofosbuvir-containing regimens cannot be made with much confidence. Similarly, additional studies are needed to assess the efficacy, safety and optimal sofosbuvir regimens for the prevention and for the treatment of recurrent HCV infection in the liver transplant recipient and for HCV infection in nonliver organ transplant recipients. Whether sofosbuvir-containing regimens will be safe and effective in patients with decompensated cirrhosis remains to be determined.

More data on the efficacy and safety of sofosbuvir in HCV/HIV-coinfected patients are necessary to confirm the promising early results. The management of chronic hepatitis C in the dialysis patient will remain an issue because of sofosbuvir's renal excretion, and studies in paediatric populations would seem reasonable. In addition, long-term follow-up studies are necessary to confirm the durability of viral eradication in patients who achieve SVR12 and SVR24.

Authorship

Guarantor of the article: R. S. Koff.

Author contributions: The author approved the final version of the manuscript.

Acknowledgement

Declaration of personal interests: R. S. Koff had served as a speaker for Vertex Pharmaceuticals and Gilead Sciences.

Declaration of funding interests: None.

References

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