Trial to Study the Effect of Dose of Herpes Simplex Virus-2 (HSV-2) Suppressive Therapy on HSV and HIV

A Randomized, Open-label, Crossover Trial of the Effect of Dosing of Daily HSV-2 Suppressive Therapy on HSV Reactivation and Plasma HIV-1 Levels Among HIV-1/ HSV-2 Co-infected Persons

To compare the effect of high-dose valacyclovir (1 gram orally twice daily) versus standard-dose acyclovir (400 mg orally twice daily) on the frequency of genital HSV reactivation and on plasma HIV-1 levels among HSV-2/HIV-1 co-infected individuals. The investigators hypothesize that high-dose valacyclovir will result in greater reduction in plasma HIV-1 and genital HSV reactivation.

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 DNA quantification. Each week during the entire study period plasma samples will be collected from participants for HIV-1 RNA quantification.

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

Optional Sub-Study A: Sub-study A will be offered to study participants. The purpose of sub-study A is to measure the effect of valacyclovir twice daily on plasma HIV-1 replication.

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