Abstract
BackgroundAlthough 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/DesignThe 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/mm3 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.DiscussionAlthough 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.Trial RegistrationCurrent Controlled Trials ISRCTN66756285ClinicalTrials.gov NCT00860977
Highlights
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 highly active antiretroviral therapy (HAART) initiation an attractive goal
Study Objectives The primary objective of this trial is to compare the time from enrolment to the primary endpoint of either a CD4 cell count ≤ 350 cells/mm3 measured on two consecutive occasions at least 1 month apart, or initiation of HAART for any reason, between adults with both stable untreated HIV and herpes simplex virus type 2 (HSV-2) co-infection who are randomized to valacyclovir compared to those randomized to placebo
Given that herpes simplex virus (HSV)-2 is known to increase HIV viral load, that biological mechanisms of this interaction have been identified, and that pharmacologic suppression of HSV2 has been shown to cause reciprocal decreases in HIV viral load, the hypothesis underlying the VALIDATE trial is that valacyclovir 500 mg twice daily may attenuate HIV disease progression and delay the need for initiating HAART in HIV-1, HSV-2 co-infected adults
Summary
Given that HSV-2 is known to increase HIV viral load, that biological mechanisms of this interaction have been identified, and that pharmacologic suppression of HSV2 has been shown to cause reciprocal decreases in HIV viral load, the hypothesis underlying the VALIDATE trial is that valacyclovir 500 mg twice daily may attenuate HIV disease progression and delay the need for initiating HAART in HIV-1, HSV-2 co-infected adults. The primary endpoint of this study was intentionally designed as a composite of meeting the CD4 threshold of 350 cells/mm, and the initiation of HAART for any reason, including patient or provider preference for earlier treatment, whichever occurs first. Implementation of the VALIDATE intervention would not preclude bolstering of other interventions to curb the spread of HIV infection Further mitigating this concern is the hypothesis that HSV-2 suppression, if implemented using an appropriate regimen and/or in appropriate populations, could have meaningful effects on decreasing HIV transmission, even if existing acyclovir-based clinical trials have been unsuccessful far [88,89]. Valacyclovir for HSV-2 suppressive therapy is an attractive potential intervention for patients with HIV-1, HSV-2 co-infection at early stages of HIV disease, and the VALIDATE trial is hypothesized to validate this potential for clinical benefit
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