Patients who have failed existing treatments for chronic hepatitis C virus (HCV) infection may soon have an effective new salvage option, according to results from POLARIS trials 1 and 4. Now under review by the US Food and Drug Administration, a three-drug pangenotypic regimen with sofosbuvir-velpatasvir-voxilaprevir followed for 12 weeks showed sustained virologic response rates of as much as 98% in refractory chronic HCV. The researchers published their findings online May 31 in the New England Journal of Medicine.
One daily treatment with the first single-pill three-drug combo proved effective in patients with any of the six HCV genotypes and with or without compensated cirrhosis who failed to show sustained virologic response after treatment with direct-acting antivirals (DAAs). DAAs included inhibitors of nonstructural protein 5A (NS5A), which plays a key role in HCV RNA replication. These patients are a continuing concern, as resistance-associated mutational substitutions in the viral genome selected by NS5A inhibitors can extend viral viability long after treatment failure.
“This population of patients has been underrepresented in clinical trials and has limited retreatment options,” Marc Bourlière, MD, chief of hepatogastroenterology, Hôpital Saint-Joseph in Marseille, France, and a group of international researchers conducting the POLARIS-1 and POLARIS-2 trials, write. POLARIS-1 and POLARIS-4 included 747 patients enrolled during 20015 to 2016 across 108 sites in Europe, North America, Australia, and New Zealand.
Although a substantial number of patients had worrisome resistance-associated viral substitutions at baseline, these had no effect on the rates of sustained virologic response to the triple regimen.
The mean age of patients across groups was similar, ranging from 57 to 59 years; more than 75% were men, and 43% had cirrhosis (46% in the active treatment groups).
POLARIS-1 included patients infected with genotype 1 (the most common in North America) and previously treated with an NS5A inhibitor. The researchers randomly assigned patients to receive the three-drug combo (n = 150 patients) or matching placebo (n = 150) once daily for 12 weeks. Those with other HCV genotypes (n = 114) were enrolled in the three-drug group. The three-drug combo consisted of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir.
POLARIS-4 included patients with HCV genotype 1, 2, or 3 previously treated with a DAA but not an NS5A inhibitor. The researchers randomly assigned patients to receive sofosbuvir-velpatasvir-voxilaprevir (n = 163) or the older combination sofosbuvir-velpatasvir (Epclusa, Gilead Sciences; n = 151) for 12 weeks. The study enrolled an additional 19 patients with genotype 4 in the three-drug group.
In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir-velpatasvir-voxilaprevir and 0% with placebo. In POLARIS-4, the rate of response was 98% with the triple regimen and 90% with two-drug therapy.
The most common adverse events in the POLARIS studies were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment because of adverse events was 1% or less.
“Most patients are cured with existing very potent regimens, but for the rare patient who has not responded, this regimen gives us a new option,” Andrew Aronsohn, MD, a hepatologist and an associate professor of medicine at the University of Chicago, Illinois, told Medscape Medical News. “Although this new regimen is more than what is needed for most patients, it’s closer than we’ve come in the past to a one-size-fits-all approach. But I suspect it is not something that you would give patients who have never been treated for HCV,” Dr Aronsohn said. Dr Aronsohn is a member of the HCV guidance committee of the American Association for the Study of Liver Diseases.
“These data are very interesting, but there are significant limitations to using this treatment,” David K. H. Wong, MD, an assistant professor of medicine at the University of Toronto, Ontario, Canada, and a hepatologist at Toronto General Hospital, Ontario, Canada, told Medscape Medical News. “If you use the older two-drug regimen, then the three-drug regimen is available for salvage in the few who fail. But if you start with the new triple regimen, there’s nothing left for those who fail. There’s no salvage option.” He added that the vast majority of those who fail treatment do so because they fail to take their medication.
Dr Wong noted that in contrast with older regimens that only work against genotype 1, the newer pangenotypic regimens eliminate the need for type and resistance testing.
The authors agree that the proportion of patients who fail to show sustained virologic with standard treatment is small, but as HCV affects as many as 150 million people globally, the actual numbers are high and will likely grow as more seek treatment. They stress that approved retreatment options for patients previously receiving an NS5A inhibitor are lacking and expect this new regimen will help fill that gap.
Earlier this year, Medscape Medical News reported on two other POLARIS trials, which found that triple therapy for 8 weeks was not as effective as a 12-week regimen. POLARIS-2 and POLARIS-3 included 941 and 219 patients, respectively, at 117 sites. Researchers randomly assigned patients with HCV who were previously unexposed to DAAs to receive the three-drug combination for 8 weeks or the two-drug combination for 12 weeks. A shorter course of treatment is considered desirable to maximize patient compliance with treatment.
Gilead Sciences funded the trials, and numerous authors report various financial ties with one or more of the following private sector companies/organizations: Gilead, Merck, Merck Sharp & Dohme, AbbVie, Bristol-Myers Squibb, Genfit, Intercept Pharmaceuticals, GlaxoSmithKline, Conatus Pharmacueticals, CymaBay, Exalenz, CVS Caremark, Amgen, Tibotec, Lupin, Shanghai Sundise Traditional Chinese Medicine Co, Novartis, Janssen, the Falk Foundation, Idenix Pharmaceuticals, Trek Therapeutics, Orasure Technologies, Discovery Life Sciences, Siemens, MedMira, Ortho Clinical Diagnostics, Johnson & Johnson, Vertex, Mallinckrodt Pharmaceuticals, Roche, Boehringer Ingelheim, Biotest Pharmaceuticals, and Trio Health. Dr Wong and Dr Aronsohn have disclosed no relevant financial relationships.
N Engl J Med. Published online June 1, 2017.
For more news, join us on Facebook and Twitter
Tidak ada komentar:
Posting Komentar