The combination of the two antiviral medications glecaprevir and pibrentasvir (Mavyret) is linked to improved symptoms in posttraumatic stress disorder (PTSD), new research suggests.
A national cohort study of US Department of Veterans Affairs patients included more than 250 participants with PTSD and comorbid hepatitis C virus.
Results showed the glecaprevir/pibrentasvir (GLE/PIB) combo was more strongly associated with PTSD symptom improvement than other antiviral combinations tested in the study, including ledipasvir/sofosbuvir.
“While there are great treatments available for PTSD, there’s a lot of desire in the field to find a new medication that will be helpful,” lead author Brian Shiner, MD, acting associate chief of staff for research, VA Medical Center, White River Junction, Vermont, told Medscape Medical News.
“We had a great opportunity to use a novel data mining method to look in a wonderful database for a new treatment and we found something very promising,” said Shiner, who is also an associate professor of psychiatry at the Geisel School of Medicine at Dartmouth in Hanover, New Hampshire.
The findings were published online recently in the American Journal of Epidemiology.
Common Psychiatric Disorder
PTSD is one of the most common psychiatric disorders, with an estimated lifetime prevalence of 6.4% in the United States. Yet only two drugs, the selective serotonin reuptake inhibitors sertraline (Zoloft) and paroxetine (Paxil), have been approved by the US Food and Drug Administration (FDA) to treat PTSD.
The VA recommends trauma-based psychotherapy, such as prolonged exposure and cognitive processing therapy, as first-line treatments for PTSD. However, not all patents respond to or have access to these approaches, said Shiner.
The investigators wanted to examine whether existing medications might reduce PTSD symptoms. Their previous exploratory study used “data mining” of national VA medical records.
Results from that study showed the three hepatitis C antivirals of GLE (an NS3/4A protease inhibitor), PIB (a NS5A protein inhibitor), and velpatasvir (another NS5A protein inhibitor) were associated with more than double the expected number of patients experiencing a clinically meaningful improvement in PTSD symptoms.
Sertraline was associated with only a slightly higher than expected improvement.
“SSRIs are effective, better than placebo, but the effects are not as good as we would hope,” Shiner said.
He noted that GLE and PIB are always prescribed together (Mavyret), whereas velpatasvir is commonly prescribed with the NS5B polymerase inhibitor sofosbuvir under the brand name Epclusa. Sofosbuvir is also commonly prescribed with the NS5A protein inhibitor ledipasvir under the brand name Harvoni.
The new study included 253 VA users with a diagnosis of PTSD and hepatitis C. Of these, 54 were receiving GLE/PIB, 145 were receiving ledipasvir/sofosbuvir, and 54 were receiving sofosbuvir/velpatasvir.
Researchers compared the groups with respect to change over 8-12 weeks on the PTSD Checklist (PCL), a 20-item self-report scale.
In adjusted analyses, the largest mean improvement on the PCL was 14.9 points for the GLE/PIB group and the smallest adjusted mean improvement on the PCL was 7.5 points for the ledipasvir/sofosbuvir group (mean difference, 7.34 points; 95% CI, 1.05 – 13.63).
The adjusted proportion of patients improving by 15 points or more on the PCL was highest for the GLE/PIB group at 43.6% and lowest for the ledipasvir/sofosbuvir group at 26.3%.
Even when accounting for patients receiving trauma-based therapy or SSRIs, “it still looks like there’s a strong association of the hepatitis C antivirals with PTSD symptom improvement,” said Shiner.
Researchers also carried out a sensitivity analysis among only patients who were cured of HCV (over 90% of the total sample), defined as having an undetectable HCV viral load up to a year after completion of therapy. The analysis showed PTSD outcomes were still superior for participants receiving GLE/PIB.
“The sensitivity analysis was not that robust because almost everyone was cured, so it included almost everybody, but it didn’t point us away from the possibility of an off-target effect,” Shiner said.
Why antivirals may improve PTSD symptoms is not clear, but they may affect the immune response in patients with hepatitis C — and there may also be an immune response in PTSD, he noted. “Some of those factors may be shared, and that could explain some of the off-target effect,” said Shiner.
However, he noted the GLE/PIB drug combination is costly and patients with PTSD can probably access it only through enrolling in a study.
“We are not recommending that people go out and purchase this very expensive drug to treat their PTSD at this point,” Shiner said.
He added that the research team has now received funding from the Department of Defense to conduct a randomized, placebo-controlled trial of GLE/PIB as a potential treatment for PTSD.
Promising Potential Treatment
Commenting for Medscape Medical News, PTSD expert Elspeth Cameron Ritchie, MD, chief of psychiatry at Medstar Washington Hospital Center, Washington, DC, said the results suggest GLE/PIB is a promising potential treatment for PTSD.
“I definitely think this should be looked at further,” said Ritchie, who was not involved with the research.
She noted that current PTSD therapies have drawbacks. SSRIs have side effects, the most “troubling” being sexual dysfunction. And although cognitive behavioral therapy is effective, “people have to stick with it” and studies show about two thirds of patients drop out, she said.
Potentially effective PTSD treatment approaches include “self-soothing” or “self-regulating” techniques such as exercise, meditation, yoga, and working with animals, she added.
Ritchie pointed out the numbers of participants in the study were relatively small, including two groups that had only 54 patients each.
And while the GLE/PIB combination should be explored further, cost, availability and side effects of this medication need to be taken into consideration, she said.
Ritchie added she is not overly concerned that the mechanism of action for the combination on PTSD may not be well understood. She noted several psychiatric medications fall into that category, including electroconvulsive therapy and lithium.
“When lithium was first found to be effective against bipolar disorder, we had no clue why,” she said. “So I would not discount the antiviral based on us not knowing how it works.”
However, “we’re a long way off” from starting a patient with PTSD on an antiviral, said Ritchie, adding there are “a lot of steps to go through” to get FDA approval.
The study was funded by the National Institute of Mental Health. The cohort used for this study was developed through support from the Department of Defense. Shiner is a co-inventor on a provisional patent application covering the use of glecaprevir, pibrentasvir, and velpatasvir for PTSD and other psychiatric indications. Ritchie has reported no relevant financial relationships.
Am J Epidemiol. Published online June 11, 2022. Abstract