Review Article

The Efficacy and Safety of Sofosbuvir, a Novel, Oral Nucleotide Ns5B Polymerase Inhibitor, in the Treatment of Chronic Hepatitis C Virus Infection

R. S. Koff

Disclosures

Aliment Pharmacol Ther. 2014;39(5):478-487. 

In This Article

Abstract and Introduction

Abstract

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.

Conclusion The efficacy and safety of sofosbuvir-containing regimens with ribavirin alone or with peginterferon plus ribavirin signal 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[4] 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[5] and even lower rates (50–52%) in United States veterans.[6]

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.

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