title: In vitro drug combination studies of Letermovir (AIC246, MK-8228) with approved anti-human cytomegalovirus (HCMV) and anti-HIV compounds in inhibition of HCMV and HIV replication.
abstract: Despite modern prevention and treatment strategies, human cytomegalovirus (HCMV) remains a common opportunistic pathogen associated with serious morbidity and mortality in immunocompromised individuals, such as transplant recipients and AIDS patients. All drugs currently licensed for the treatment of HCMV infection target the viral DNA polymerase and are associated with severe toxicity issues and the emergence of drug resistance. Letermovir (AIC246, MK-8228) is a new anti-HCMV agent in clinical development that acts via a novel mode of action and has demonstrated anti-HCMV activity in vitro and in vivo. For the future, drug combination therapies, including letermovir, might be indicated under special medical conditions, such as the emergence of multidrug-resistant virus strains in transplant recipients or in HCMV-HIV-coinfected patients. Accordingly, knowledge of the compatibility of letermovir with other HCMV or HIV antivirals is of medical importance. Here, we evaluated the inhibition of HCMV replication by letermovir in combination with all currently approved HCMV antivirals using cell culture checkerboard assays. In addition, the effects of letermovir on the antiviral activities of selected HIV drugs, and vice versa, were analyzed. Using two different mathematical techniques to analyze the experimental data, (i) additive effects were observed for the combination of letermovir with anti-HCMV drugs and (ii) no interaction was found between letermovir and anti-HIV drugs. Since none of the tested drug combinations significantly antagonized letermovir efficacy (or vice versa), our findings suggest that letermovir may offer the potential for combination therapy with the tested HCMV and HIV drugs.
authors.affiliation: AiCuris GmbH Co. KG, Wuppertal, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Wildum
authors.affiliation: AiCuris GmbH Co. KG, Wuppertal, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Zimmermann
authors.affiliation: AiCuris GmbH Co. KG, Wuppertal, Germany peter.lischka@aicuris.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Lischka
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects*; D004338:Drug Combinations; D024882:Drug Resistance, Viral; D006801:Humans; D011799:Quinazolines / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000085:Acetates; D019380:Anti-HIV Agents; D000998:Antiviral Agents; D004338:Drug Combinations; D011799:Quinazolines; C000588473:letermovir