ABSTRACT & COMMENTARY
Sofosbuvir and Ledipasvir combo Therapy for HCV: End game for interferon?
A sustained virological response even in patients with compensated cirrhosis
By Richard R. Watkins, MD, MS, FACP
Division of Infectious Diseases, Akron General Medical Center, Akron, OH; Associate Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH
Dr. Watkins reports no financial relationships in this field of study
SOURCE: Lawitz E, et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): An open-label, randomized, phase 2 trial. Lancet 2014;383:515-523.
Hepatitis C virus (HCV) infection is an important global health issue that affects approximately 184 million people. Conventional therapy for HCV with interferon and ribavirin is associated with high rates of virological failure and severe side-effects. The recently introduced HCV protease inhibitors (i.e. boceprevir and telaprevir) also cause a high rate of adverse events. Novel direct-acting antivirals (DAAs) have been developed that make it possible to give interferon-sparing regimens. One of these is sofosbuvir, a nucleotide analogue inhibitor of the HCV NS5B polymerase and another is ledipasvir, an HCV NS5A inhibitor. A previous pharmacokinetic analysis found no significant interactions between the two drugs. Therefore, Lawitz and colleagues at the Texas Liver Institute investigated the efficacy of a fixed-dose combination tablet of sofosbuvir and ledipasvir with and without ribavirin, for 8 weeks and 12 weeks in both treatment-naïve and protease-inhibitor treated patients who failed to achieve sustained virological response (SVR) including those with compensated cirrhosis.
Eligible patients were over 18 years of age and had chronic genotype 1 HCV infection with a serum RNA concentration of at least 10,000 IU/mL. Patients with hepatic decompensation, low body mass index, or co-infection with HIV and/or hepatitis B virus were excluded. The researchers included treatment naïve patients (cohort A, n=60) and treatment nonresponders or relapsers (cohort B, n=40). Cohort A patients were randomly assigned to receive sofosbuvir plus ledipasvir for 8 weeks (n=20); sofosbuvir plus ledipasvir and ribavirin for 8 weeks (n=21); or sofosbuvir plus ledipasvir for 12 weeks (n=19). Cohort B patients were randomized to receive sofosbuvir plus ledipasvir for 12 weeks (n=19); or sofosbuvir plus ledipasvir and ribavirin for 12 weeks(n=21). In cohort B 22 patients (55%) had compensated cirrhosis. Deep sequencing of the NS3 and NS5A regions of the HCV RNA was done initially on all patients, 9 of whom were found to harbor NS5A resistance-associated variants (RAVs) and 33 had NS3 RAVs. This testing was repeated on patients with virologic failure at the time the failure was detected. Patients were followed for a total of 24 weeks. The primary endpoint of the study was the proportion of patients who achieved SVR at 12 weeks.
The results of the study were impressive. SVR was achieved by 97 patients at both weeks 12 and 24. Only 2 patients had virological relapse after receiving a full course of treatment. Of the three patients who failed to achieve a SVR at 12 weeks, none received ribavirin. All 33 patients with NS3 RAVs achieved SVR while 7 of the 9 with NS5A RAVs did. Deep sequencing at the time of virological relapse in one patient showed 3 new NS5A RAVs (Y93H, Q30L and L31V), while the other patient had the same RAVs detected at baseline and at the time of relapse (Q30L and Y93H). Adverse events were common but generally mild with 48 of 100 patients reporting at least one during the study. The patients in the ribavirin groups had the highest rates of adverse events (57% in both groups). The most commonly reported were nausea, anemia, upper respiratory tract infections and headache and were most often rated mild by the treating physician. Anemia was seen in 4 patients receiving ribavirin. The only serious events were delirium, an exacerbation of peptic ulcer disease, a spinal compression fracture, and one patient had anemia and suicidal ideation. No patient in any group discontinued therapy because of an adverse event. The investigators reported no high grade liver chemistry abnormalities or increases in creatinine. Patients receiving ribavirin developed mild increases in total bilirubin.
The combination of sofosbuvir and ledipasvir demonstrated a very high SVR with a favorable adverse event profile. However, this was a small, single-center study with a relatively short follow up, making it difficult to generalize the results to other settings and patient populations. For example, future studies will need to include patients co-infected with HCV/HBV and HCV/HIV in order to determine if a similar SVR is attainable. Another significant issue with the new DAA drugs in general and sofosbuvir in particular is their high cost. Sofosbuvir alone costs $84,000 for a 12 week course. However, this needs to be balanced by the huge burden on the health care system that comes from decompensated cirrhosis, such as repeated hospitalizations and liver transplants. Indeed, further cost-benefit analyses need to be done to elucidate whether the upfront costs of these novel drugs are justified by potential savings in the future. A practical blueprint for these types of studies is already available from the HIV/AIDS epidemic, as are strategies for making the HCV DAAs available in resource-limited settings. It seems likely that interferon and probably ribavirin will go the way AZT has for treating HIV in the not too distant future.