• To evaluate the effect of valacyclovir 1 gram orally twice daily on prevention of days with genital herpes lesions compared with acyclovir 400 mg orally twice daily. [ Time Frame: 26 weeks ] [ Designated as safety issue: No ]
• To evaluate the safety of valacyclovir 1 gram orally twice daily in HIV-1 seropositive persons. [ Time Frame: 26 weeks ] [ Designated as safety issue: Yes ]

To compare the effect of daily valacyclovir 1 gram orally twice daily versus acyclovir 400 mg orally twice daily on the frequency of genital HSV reactivation and on plasma and genital HIV-1 levels among HSV-2/HIV-1 co-infected individuals. The investigators hypothesize that both treatments will reduce genital HSV and systemic and genital HIV-1.

We propose to conduct a randomized, open-label, cross-over study of 38 individuals who are HIV-1 seropositive and HSV-2 seropositive. Both men and women will be recruited for the study. Participants must not be on antiretroviral therapy and must not be planning to initiate antiretroviral therapy during the anticipated study period. Participants will be randomized 1:1 to receive acyclovir 400 mg twice daily or valacyclovir 1000 mg twice daily. After 12 weeks on the initial treatment, each participant will be crossed over to the alternative treatment arm for 12 weeks. The treatment periods will be separated by a 2-week washout period. During the first four weeks of each treatment period (i.e., Weeks 1-4 and Weeks 15-18), participants will provide self-collected genital swabs daily for HSV detection. Each week during the entire study period, participants will provide plasma and genital samples for HIV-1 detection.

Open-label acyclovir and valacyclovir will be used for this trial, as the primary outcome measures (genital HSV and plasma and genital HIV-1) are unlikely to be influenced by knowledge of treatment assignment. However, laboratory staff performing plasma and genital HIV-1 measurements will not be aware of treatment assignment.

• Genital Herpes
• HIV Infections

• Drug: valacyclovir
• Drug: acyclovir

• Experimental: valacyclovir 1 gram orally twice daily
• Active Comparator: acyclovir 400 mg orally twice daily

Inclusion Criteria:

• Age 18 years or older
• Documented HIV-1 seropositive
• Not on HIV-1 antiretroviral therapy nor planning to initiate antiretroviral therapy during the study period
• Detectable HIV-1 plasma viral load
• HSV-2 seropositive as determined by western blot
• Not intending to move out of the area for the duration of study participation
• Willing and able to provide independent written informed consent
• Willing and able to undergo clinical evaluations
• Willing and able to take study drug as directed
• Willing and able to adhere to follow-up schedule

Exclusion Criteria:

• Known history of adverse reaction to acyclovir, valacyclovir, or famciclovir
• Planned open label use of acyclovir, valacyclovir, or famciclovir
• History of evidence of CMV disease
• Known medical history of seizures
• Known renal insufficiency, defined as serum creatinine greater than 1.5 mg/dl
• AST or ALT greater than 3 times upper limit of normal
• Hematocrit less than 30 %
• Neutropenia, defined as absolute neutrophil count less than 1000
• Thrombocytopenia, defined as platelet count less than 75,000
• History of thrombotic microangiopathy
• For women, pregnancy as confirmed by a urine pregnancy test
• Any other condition which, in the opinion of the principal investigator, may compromise the ability to follow study procedures and complete the study