William F. Balistreri, MD
December 03, 2013
Aiming for the Ideal Strategy
In 2011, the American Association for the Study of Liver Diseases (AASLD) issued an updated version of its practice guidelines for the treatment of chronic genotype 1 hepatitis C virus (HCV) infection. The current standard-of-care regimens include a protease inhibitor -- telaprevir or boceprevir -- in combination with pegylated interferon (PEG-IFN) and ribavirin. Protease inhibitor-based strategies for patients with genotype 1 HCV have led to high rates of sustained virologic response (SVR); however, there are several recurring concerns.
The disadvantages of IFN treatment are well known. Moreover, this strategy presents a complex and prolonged therapeutic course (24-48 weeks), low tolerability, a low barrier to resistance, and reduced efficacy in prior null responders or cirrhotic patients. These regimens are not an option for many patients because of contraindications or intolerability to IFN.[2-7]
To address these concerns, there has been a massive effort to create the ideal agent or strategy for use in updated therapeutic efforts. The pace of discovery has been unprecedented, and several agents are in the later phases of development. The approach has been to discover drugs that directly target various aspects of the HCV life cycle -- hopefully leading to combinations of agents that will more effectively treat patients, while minimizing intolerable side effects or adverse events.
Sofosbuvir Enters the Fray
The latest drug to emerge from this effort is sofosbuvir. In late October, an FDA advisory panel recommended the approval of sofosbuvir for the treatment of 2 groups of patients with chronic HCV: previously untreated adults with genotypes 1 and 4 infections (in combination with PEG-IFN and ribavirin) and adults with genotype 2 and 3 infections (in combination with ribavirin alone), which would allow an all-oral, IFN-free treatment for these 2 genotypes.
Sofosbuvir, an orally administered nucleotide analogue inhibitor of the HCV NS5B polymerase, exerts potent antiviral activity against HCV genotypes 1 through 6. This drug is meant to be taken once daily at a dose of 400 mg. Sofosbuvir has been extensively studied in various patient populations in combination with PEG-IFN/ribavirin, as well as with other direct-acting antiviral agents in treatment-naive patients with genotype 1 HCV infection.[8-12]
The FDA advisory committee reviewed primary efficacy and safety data from a series of clinical trials. The data supported the possibility of effectively treating HCV infection with a brief, well-tolerated, all-oral, once-daily regimen that has no known safety issues and no resistance development. Phase 3 trials of sofosbuvir in treatment-naive patients with hepatitis C virus genotypes 1 through 6 demonstrated that patients with genotype 1 infection have excellent treatment response that is superior overall to published response rates for combination therapy and currently available triple therapies. For patients with genotypes 2 and 3, efficacy was similar between an IFN-free sofosbuvir regimen and a standard PEG-IFN/ribavirin regimen.
Evidence for Sofosbuvir
Numerous studies have emerged; a brief overview of a few representative studies of sofosbuvir in combination with other direct-acting antiviral agents is offered here:
- Sofosbuvir was combined with simeprevir with and without ribavirin; SVR rates of 93%-96% were reported.
- Sofosbuvir plus the NS5A inhibitor daclatasvir led to SVR at 12 weeks (SVR12) rates of 86%-100%.
- Ledipasvir is a novel HCV NS5A inhibitor that has shown potent antiviral activity against genotypes 1a and 1b HCV infection.[14,15] It is active against HCV with the S282T mutation, the only variant known to reduce susceptibility to sofosbuvir. All treatment-naive patients and prior null responders (noncirrhotic) who received 12 weeks of sofosbuvir and ledipasvir plus ribavirin achieved high SVR12 rates (95%-100%). Patients treated for 12 weeks had a similar response to patients who received 8 weeks of therapy, suggesting that this shorter treatment strategy might be sufficient for noncirrhotic patients who have not previously been treated for HCV.
In all of these studies, sofosbuvir was well tolerated, with a low incidence of adverse events. In conjunction with the suggested brief duration of this regimen, this indicates that drug combinations should improve treatment adherence compared with IFN-based treatment. Traditional predictors of response, such as IL28B genotype and baseline viral load, do not seem to affect response rates. Other large multicenter trials are under way, designed to address the optimal treatment combination and duration, the need for ribavirin, and the efficacy in patients with compensated cirrhosis in both treatment-naive and previously treated patients.
Data on the Drug
Presentations offered at the AASLD's Liver Meeting 2013 abetted the data submitted to the FDA. Several studies reported pan-genotypic efficacy and safety of sofosbuvir, as well as other potential uses for this agent in various drug combinations and in various populations, including the following:
- In a phase 3 trial, 12 weeks of sofosbuvir plus ribavirin demonstrated high SVR rates in a predominantly treatment-experienced patient population with genotypes 2 and 3 HCV infection, with higher response rates in patients infected with genotype 2 than in those infected with genotype 3 HCV.
- In a phase 2, randomized, open-label study, the combination of sofosbuvir plus simeprevir plus ribavirin for 12 or 24 weeks in patients with HCV genotype 1 infection resulted in high SVRs. This study included null responders and patients with cirrhosis.
- Sofosbuvir plus ledipasvir given in a fixed combination elicited a rapid decline in HCV RNA levels in all patient populations, with no viral breakthrough. In treatment-naive patients with genotype 1 infection and without cirrhosis, a reduction in duration of therapy from 12 to 6 weeks increased the rate of relapse.In genotype 1-infected patients who were prior null responders and had cirrhosis, the addition of ribavirin to sofosbuvir and ledipasvir reduced the rate of relapse.
- Treatment-naive patients with HCV genotype 2 and 3 who were coinfected with HIV achieved high SVR12 rates with an IFN-free, oral regimen of sofosbuvir plus ribavirin. The SVR12 rates were 76% among patients with HCV genotype 1, 88% among those with genotype 2, and 67% among those with genotype 3; these are similar to the rates observed for patients infected with HCV only. These preliminary data suggest that sofosbuvir plus ribavirin treatment was well tolerated and safe, even with the coadministration of multiple antiretroviral drugs.
A Markov model, developed to evaluate the long-term outcomes of sofosbuvir-based therapy for HCV infection, indicated that regimens incorporating this agent are highly effective in preventing progression to advanced liver disease.
New Opportunities Bring New Challenges
Recurrence of HCV infection is the most common cause of graft loss and mortality in HCV-infected liver transplant recipients. IFN-based post-transplantation antiviral regimens, including those using protease inhibitors, are poorly tolerated and achieve SVRs that are lower than those in nontransplant patients.
Administration of sofosbuvir plus ribavirin after liver transplantation in the setting of established HCV recurrence was well tolerated, and approximately 80% of patients achieved an early SVR at 4 weeks. There were no episodes of rejection or drug interaction, and there was no apparent effect of sofosbuvir on serum levels of immunosuppressive medications, offering the potential for an all-oral therapy for treatment of HCV infection after liver transplantation. Sofosbuvir and ribavirin may, in fact, be used in the pretransplant phase to prevent recurrence of HCV infection after transplantation.
In summary, 2 novel direct-acting antiviral agents -- sofosbuvir and simeprevir -- target various components of the HCV genome. Advantages of these drugs include a high barrier to viral resistance, a shorter duration of treatment, once-daily dosing, absence of food restrictions, few clinically significant drug interactions, and similar efficacy in all genotypes. This will offer clinicians new options as well as new challenges. A recent review addressed some of these anticipated issues, such as the off-label use of HCV medications and the roles of the FDA, consumer pressure, medical society guidelines, and third-party payers.
The availability of these agents will provide unprecedented opportunities for off-label use of these therapies in many patients, including those with decompensated cirrhosis or chronic kidney disease, pediatric populations, and those with HIV coinfection. Because many of these populations represent relatively small numbers of patients with HCV, it may be difficult to accumulate the requisite data and possibly cost-prohibitive for manufacturers to apply for FDA approval.
The bottom line is that simpler, shorter, and safer strategies for treatment of patients infected with HCV are at hand.