title: Can herpes simplex virus type 2 suppression slow HIV disease progression: a study protocol for the VALacyclovir In Delaying Antiretroviral Treatment Entry (VALIDATE) trial.
abstract: BACKGROUND
  Although highly active antiretroviral therapy (HAART) has dramatically decreased HIV-related morbidity and mortality, the associated costs, toxicities, and resistance risks make the potential delay of HAART initiation an attractive goal. Suppression of herpes simplex virus type 2 (HSV-2) may be a novel strategy for achieving this goal because HSV-2 is associated with clinically significant increases in HIV viral load, the primary driver of HIV disease progression.
  
  
  METHODS
  The VALacyclovir In Delaying Antiretroviral Treatment Entry (VALIDATE) trial is a multicentre, randomized, fully blinded, clinical trial of twice daily valacyclovir 500 mg versus placebo for delaying the need for initiating HAART among HIV-1, HSV-2 co-infected HAART-naïve adults. 480 participants from Canada, Brazil and Argentina will undergo quarterly clinical follow-up until reaching the composite primary endpoint of having a CD4+ T-cell count ≤ 350 cells/mm(3) or initiation of HAART for any reason, whichever occurs first. The primary analysis will use a proportional hazards model, stratified by site, to estimate the relative risk of progression to this endpoint associated with valacyclovir. Secondary analyses will compare the rates of change in CD4 count, median log10 HIV viral load, drug-related adverse events, frequency of HSV reactivations, rate of acyclovir-resistant HSV, and quality of life between study arms.
  
  
  CONCLUSIONS
  Although HIV treatment guidelines continue to evolve, with some authorities recommending earlier HAART among asymptomatic individuals, the potential delay of HAART remains a clinically relevant goal for many. If shown to be of benefit, implementation of the VALIDATE intervention will require careful consideration of both individual patient-level and public health implications.
  
  
  BACKGROUND
  Current Controlled Trials ISRCTN66756285. ClinicalTrials.gov NCT00860977.
authors.affiliation: University Health Network, 585 University Ave., 13N-1323, Toronto, Ontario, M5G 2N2 Canada. darrell.tan@gmail.com
authors.forename: Darrell H S
authors.initials: DH
authors.lastname: Tan
authors.forename: Janet M
authors.initials: JM
authors.lastname: Raboud
authors.forename: Rupert
authors.initials: R
authors.lastname: Kaul
authors.forename: Beatriz
authors.initials: B
authors.lastname: Grinsztejn
authors.forename: Pedro
authors.initials: P
authors.lastname: Cahn
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Walmsley
mesh_terms: D000212:Acyclovir / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use*; D002985:Clinical Protocols; D018450:Disease Progression; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects*; D018258:Herpesvirus 2, Human / Q000187:drug effects*; D006801:Humans; D000077483:Valacyclovir; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir