Since the approval of the first direct-acting antivirals (DAAs) — telaprevir and boceprevir — for hepatitis C (HCV) in 2011, HCV treatment has continued to evolve at lightning speed. There has never been any area in medicine in which progress has been made at such a rapid pace and a cure so consistently achieved with a short course of well-tolerated therapy that is orally administered and in many instances as simple as one pill a day. At the time of writing, three protease inhibitors (simeprevir, paritaprevir and grazoprevir); five NS5A inhibitors (ledipasvir, ombitasvir, daclatasvir, elbasvir and velpatasvir); one nonnucleoside polymerase inhibitor (dasabuvir); and one nucleotide polymerase inhibitor (sofosbuvir) are approved by the U.S. Food and Drug Administration for treatment of HCV. The currently available DAA combinations can achieve sustained virologic response (SVR) rates of approximately 95 percent in most patients with compensated liver disease, including patient groups that were once considered to be difficult to treat. For most patients, these high rates of SVR can be accomplished with 12 weeks of DAAs that do not require ribavirin.
Many have wondered whether the end of HCV and the end of HCV research is here. It was gratifying that data from several new DAA-combination regimens were presented at The Liver Meeting in Boston, MA, in November 2016. These new regimens focused on pan-genotypic activity and improved SVR rates for genotype 3 cirrhosis (shorter duration of treatment), and rescue therapy for DAA failures.
Currently only one DAA combination therapy — sofosbuvir + velpatasvir (Epclusa) — has been approved for all genotypes. Three additional DAA combination therapies were shown to have pan-genotypic activity in phase 2/3 trials and will likely be approved in 2017 or shortly thereafter. They include: (a) sofosbuvir + velpatasvir + voxilaprevir (protease inhibitor); (b) MK-3682 (nucleotide polymerase inhibitor) + grazoprevir + ruzasvir (second-generation NS5A inhibitor); and (c) glecaprevir (second-generation protease inhibitor) + pibrentasvir ( second-generation NS5A inhibitor). The major advantage of combination therapies with pangenotypic activity is simplicity in selecting an appropriate treatment for the individual patient. This is particularly important in countries where HCV genotyping is not widely available.
During the era of interferon-based therapies, genotypes 2 and 3 were considered to be easy to treat compared to genotype 1. However, genotype 3 has proven to be difficult to treat in the DAA era, and until recently, SVR rates for genotype 3 cirrhosis, even with 24 weeks of sofosbuvir + ribavirin or 12 weeks of sofosbuvir + daclatasvir, were approximately 65 percent. In addition to sofosbuvir + velpatasvir approved in June 2016, the three new combinations described above can achieve SVR rates greater than 90 percent in this difficult-to-treat group.
A 12-week course of DAA suffices for the majority of patients with HCV and for treatment-naïve patients with genotype 1, no cirrhosis and low viral load, an eight-week course of sofosbuvir + ledipasvir has similar efficacy to a twelve 12- week course of the same drugs both in clinical trials and in clinical practice. Attempts to shorten the duration of treatment to four or six weeks have generally resulted in lower SVR rates, but eight weeks of treatment with sofosbuvir + velpatasvir + voxilaprevir or glazoprevir + pibrentasvir may suffice for selected groups of patients. An alternative is to combine DAAs with mir-122, which has been shown to be effective in blocking HCV replication when used as monotherapy.
DAA treatment is highly effective, but a minority of patients have failed to achieve SVR. Treatment failure is more common in patients with Child B/C cirrhosis who are most in need of a cure. Three new combination therapies: sofosbuvir + velpatasvir + voxilaprevir, glecaprevir + pirbrentasvir, and MK-3682 + grazoprevir + ruszasvir have been shown to achieve SVR rates greater than 95 percent in patients who had been previously treated with regimens that contained sofosbuvir +/- NS5A inhibitor.
While quantum jumps are not expected in 2017, new DAA combinations that will simplify HCV treatment, improve SVR rates for genotype 3 cirrhosis and offer rescue for DAA failures will come on the scene. Many have wondered when primary-care physicians will start treating HCV. Besides the high cost and the need to navigate insurance barriers, other new wrinkles will dampen their enthusiasm — foremost being the risks of DAA reactivating other chronic viral infections including hepatitis B and varicella zoster virus. Although the incidence of reactivating other viruses is unclear, severe sequelae (including deaths) have been reported, and recommendations for preventing these events have not been defined due to the scarcity of high-quality data. The notion that DAA therapies may increase the risk of hepatocellular carcinoma recurrence or lead to more aggressive tumors needs to be further studied. Major advances have been made in HCV treatment, but the work is not finished yet.
Dr. Lok is the current president of AASLD.