Anti-HCV drugs interact with evening dosing of HIV-1 protease inhibitors

Last Updated: 2016-01-19

By Will Boggs MD

NEW YORK (Reuters Health) - The three-drug direct-acting antiviral (DAA) regimen used to treat hepatitis C virus (HCV) infection is not recommended with evening administration of two HIV-1 protease inhibitor regimens, according to the results of five pharmacokinetic studies in healthy volunteers.

The three-drug (3D) regimen of ombitasvir, paritaprevir, and dasabuvir for HCV infection is commonly coadministered with various dosing schemes of HIV-1 protease inhibitors darunavir, atazanavir, and lopinavir.

Dr. Amit Khatri and colleagues from AbbVie, North Chicago, Illinois, investigated the safety and pharmacokinetics of the 3D regimen coadministered with various label-recommended regimens of those HIV-1 protease inhibitors in 144 healthy male and female volunteers.

The 3D regimen decreased the plasma trough concentration (Ctrough) of darunavir by 43% to 48%, increased the Ctrough of atazanavir by 68% with the evening-dosing regimen (but not the morning-dosing regimen), and increased the Ctrough of lopinavir by 218% with the once-daily regimen (but not with the twice-daily regimen).

Ombitasvir and dasabuvir pharmacokinetics varied by 27% to 53% when coadministered with protease inhibitors, according to the January 5 online report in Clinical Infectious Diseases.

Paritaprevir pharmacokinetics, however, were strongly affected by evening dosing of atazanavir plus ritonavir (increases of up to 1,095%) and lopinavir/ritonavir once-daily dosing (Ctrough increases of 723%).

Evening dosing of darunavir/ritonavir or atazanavir/ritonavir with the 3D regimen significantly increased the Ctrough of ritonavir (by 1,315% and >20-fold, respectively).

Adverse events did not differ significantly between study regimens.

"Data from these studies indicate that no dosage adjustments should be required for darunavir regimens or morning administration of atazanavir in combination with the 3D regimen, a conclusion supported by available data from the TURQUOISE-I trial," the authors wrote. "In contrast, the atazanavir plus ritonavir evening-administration regimen is not recommended in combination with the 3D regimen due to increased paritaprevir exposures."

"Although short-term coadministration of lopinavir/ritonavir regimens with the 3D regimen posed no interaction or safety concerns, this combination is not recommended due to the possibility of gastrointestinal side effects during extended (12- to 24-week) treatment," the researchers added. "Future results from TURQUOISE-I will further elucidate the viability of protease inhibitor/3D regimen combinations. Until these data are available, clinicians are urged to follow the prescribing information of these drugs when considering concomitant treatment in patients with comorbid HIV-1 and HCV infection."

Dr. Marina Klein, from McGill University, Montreal, Quebec, Canada, and colleagues, in another January 5 Clinical Infectious Diseases report, suggest that DAA results from clinical trials have limited generalizability to real-life clinical practice.

Dr. Klein told Reuters Health by email, "Using the Canadian Co-Infection Cohort as a representative population, we found the vast majority of patients (56-94%) in care would have been excluded from participating in these trials meaning that those studied really didn't represent our patients at all. Additionally, the most common reasons for exclusion were characteristics that define this population i.e., cART regimens and active illicit drug use. Even among the most inclusive trial (ALLY-2), there was no evidence that this trial actually ended up enrolling any subjects that would be generalizable to HIV-HCV co-infected patients."

"This means that the exceptionally high rates of cure seen in clinical trials may not be found when treatments are rolled out into the real world," she concluded. "Co-infected patients starting DAAs may need close monitoring and support during treatment to achieve cure rates seen in trials. It may be that the type of care provided in these trials could serve as an excellent model for clinical practice."

Dr. Khatri did not respond to a request for comments.

AbbVie sponsored the research and employed all authors of the first study. The Canadian Institutes of Health Research supported the second study; no authors reported any conflict of interest with this study.

SOURCE: http://bit.ly/1QlbZDR and http://bit.ly/1Kp8gyp

Clin Infect Dis 2016.