The authors of the article address concerns raised by Michael Eisenhut regarding the potential impact of acyclovir resistance on the effectiveness of herpes simplex virus (HSV) suppressive therapy in preventing HIV transmission. They argue that the occurrence of acyclovir-resistant HSV-2 strains has not increased over the past two decades, and resistance is not predictive of clinical failure. They also note that the slight increase in HIV plasma viral load in the placebo group is unlikely to be due to gastrointestinal diseases. The authors emphasize that valacyclovir and acyclovir have a long safety profile and that the primary outcome of genital HIV viral load showed little difference between the placebo and valacyclovir groups. They conclude that the potential benefits of HSV suppressive therapy on HIV-1 disease progression and transmission outweigh any concerns about resistance.The authors of the article address concerns raised by Michael Eisenhut regarding the potential impact of acyclovir resistance on the effectiveness of herpes simplex virus (HSV) suppressive therapy in preventing HIV transmission. They argue that the occurrence of acyclovir-resistant HSV-2 strains has not increased over the past two decades, and resistance is not predictive of clinical failure. They also note that the slight increase in HIV plasma viral load in the placebo group is unlikely to be due to gastrointestinal diseases. The authors emphasize that valacyclovir and acyclovir have a long safety profile and that the primary outcome of genital HIV viral load showed little difference between the placebo and valacyclovir groups. They conclude that the potential benefits of HSV suppressive therapy on HIV-1 disease progression and transmission outweigh any concerns about resistance.