CMX001 Potentiates the Efficacy of Acyclovir in Herpes Simplex Virus Infections

Although acyclovir (ACV) has proven to be of value in the therapy of certain herpes simplex virus (HSV) infections, there is a need for more effective therapies, particularly for serious infections in neonates and immunocompromised individuals, where resistance to this drug can be problematic. CMX001 is an orally bioavailable lipid conjugate of cidofovir that is substantially less nephrotoxic than the parent drug and has excellent antiviral activity against all the human herpesviruses. This compound retains full antiviral activity against ACV-resistant laboratory and clinical isolates. The combined efficacy of CMX001 and ACV was evaluated in a new real-time PCR combination assay, which demonstrated that the combination synergistically inhibited the replication of HSV in cell culture. This was also confirmed in murine models of HSV infection, where the combined therapy with these two drugs synergistically reduced mortality. These results suggest that CMX001 may be effective in the treatment of ACV-resistant HSV infections and as an adjunct therapy in individuals with suboptimal responses to ACV. Effective therapies are available for the management of both genital herpes (23) and herpes labialis (1). Acyclovir (ACV) can inhibit the replication of both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) (6), and its oral prodrug, valacyclovir, is well tolerated and suitable for long-term suppressive therapy (38). Prophylactic therapy in individuals with frequent or severe symptoms can reduce the frequency of lesions by 80% to 95% (19) and can also reduce significantly, although not eliminate, asymptomatic virus shedding (8, 11) and transmission of the virus (5). Resistance to the drug is observed infrequently in the general population, even after long-term prophylactic therapy (38), and resistance occurs in immunocompetent individuals at a very low frequency (0.5%) (17). However, resistance to the drug has been reported to arise in up to 7% of immunocompromised hosts (38). Drug-resistant isolates selected by ACV therapy are also generally crossresistant to famciclovir, and secondary therapies such as cidofovir (CDV) and foscarnet are associated with significant toxicities. Thus, there is a clear need for improved therapies for herpes infection in immunocompromised hosts (21, 42).