AMSTERDAM — The benefits of both double and triple direct-acting antiviral therapy combinations depend on myriad patient and disease factors, according to findings presented at the International Liver Congress.
Jean-Michel Pawlotsky, MD, PhD, professor at the University of Paris-Est and director of the French National Reference Centre for Viral Hepatitis B, C and Delta, raised the question of whether three is, in fact, better than two, or whether they are more or less equal.
“There are a number of factors,” he said. “The potency of the individual drugs is important. Lack of resistance is important. Ribavirin increases the likelihood of curing infection during therapy.”
Regarding potency, Pawlotsky offered a realistic portrait of where the pipeline stands at the moment. “The potency of current and future HCV direct-acting antiviral therapies, and their potential for additive or synergistic effects, have been maximized already,” he said.
The main factor that muddies the picture is the impact of sensitive or resistant viral kinetics. “The same drug combination will have different effects on sensitive and resistant populations,” Pawlotsky said.
NS5A inhibitors comprise the backbone of the current armamentarium, according to Pawlotsky. “This is a completely original drug class for HCV,” he said.
Pawlotsky ran down a laundry list of agents in the pipeline, including NS5A inhibitors odalasvir (Achillion), pibrentasvir (AbbVie), and ruzasvir (Merck), and NS5B inhibitors AL-335 (Achillion), pibrentasvir (AbbVie) and uprifosbuvir (Merck). Although trials are currently underway, he suggested that ruzasvir has improved on previous compounds. “This drug has a virtually no resistance in vitro,” he said, noting that the resistance barrier was lower than Daklinza (daclatasvir, Bristol-Myers Squibb) or ledipasvir (Gilead). “You can see we’re making progress.”
Pawlotsky also reviewed findings and offered commentary on some of these new therapies as they function in double or triple combinations. “In one scenario, a doublet is optimal, with two drugs being enough to achieve 100% SVR,” he said. “In the other scenario, the addition of another drug, either another DAA with cross-resistance, or ribavirin, is optimal.”
The newest doublet is glecaprevir and pibrentasvir (AbbVie). “Pibrentasvir has a resistance profile that is much improved compared with previous therapies,” Pawlotsky said. “Theoretically, this combination should be effective. So far, data have shown us this, with high rates in genotypes 1 through 6 with or without cirrhosis.”
He noted that this combination can’t be used in decompensated cirrhotics, and that it remains to be determined if this can be used with SOF as a re-treatment regimen.
For triple regimens, Viekira Pak (ombitasvir/paritaprevir plus dasabuvir, AbbVie) has shown particular efficacy in genotype 1a, according to Pawlotsky. He added that Harvoni (ledipasvir/sofosbuvir, Gilead) is efficacious in genotype 1b, but that the efficacy drops with certain resistance variants. “You have to add ribavirin to get the SVR back to original levels,” he said.
Regarding Zepatier (grazoprevir/elbasvir, Merck), the effect can vary depending on the patient’s baseline viral load, according to Pawlotsky. “With a baseline load less than 800,000 IU/ml, there is no impact of RAS,” he said. “More than 800,000 IU/ml, SVR goes down with NS5A RAS.”
He added that 12 weeks of this doublet may be insufficient. “Adding ribavirin and slightly prolonging the duration of therapy will increase SVR rates,” he said.
Pawlotsky suggested that the combination of Epclusa (sofosbuvir/velpatasvir, SOF/VEL; Gilead) and the triple therapy of SOF/VEL/voxilaprevir present a complex picture. “The doublet is good regardless of NS5A RAS at baseline,” he said. “The problem here is genotype 3, which is associated with a slightly lower SVR rate. The addition of a third drug, either ribavirin or voxilaprevir, is recommended.”
It is noteworthy that voxilaprevir is not suggested for decompensated cirrhotics, he added.
In general terms, a third drug is required for patients with genotype 3 disease, those with decompensated cirrhotics and those with previous DAA exposure. “Triplets are not necessarily better than doublets or vice versa,” Pawlotsky said.
By Rob Volansky
Pawlotsky JM. Joint Workshop EASL/Viral Hepatitis Group. Presented at: International Liver Congress; April 19-24, 2017; Amsterdam.
Disclosure: Pawlotsky reports receiving grant and research support from AbbVie and Gilead; being on the advisory boards of AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Merck; and speaking and teaching with AbbVie, Bristol-Myers Squibb, Gilead, Janssen, and Merck. Please see the study for a list of all other researchers’ financial disclosures.