Can Valacyclovir Delay the Need for Initiation of Human Immunodeficiency Virus (HIV) Treatment in HIV-infected Individuals? (VALIDATE)

VALacyclovir In Delaying Antiretroviral Treatment Entry

This study is a multicentre, randomized, placebo-controlled, fully blinded, clinical trial of twice daily oral valacyclovir 500mg versus placebo with the goal of delaying the need for initiating HAART among HIV infected individuals who neither use nor require HAART, and who have not used chronic suppressive anti-HSV therapy for at least the 6 months prior to study initiation.

Study Overview

• Status: Completed
• Conditions: HIV Infections; HIV Infection; Herpes Simplex Type II
• Intervention / Treatment: Drug: Placebo; Drug: valacyclovir

• Study Type: Interventional
• Enrollment (Actual): 202
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1202ABB
    • Fundación Huésped
• Brazil
  • Rio de Janeiro, Brazil
    • Instituto de Pesquisa Clínica Evandro Chagas
  • Sao Paulo, Brazil, 04040-002
    • Ambulatorio de Infectologia da UNIFESP
  • Sao Paulo, Brazil, 04121-000
    • Centro de Referencia e Treinamento em DST/AIDS
• Canada
  • Quebec, Canada, G1V 4G2
    • Centre Hospitalier Universitaire de Quebec-Pavillon CHUL
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2C8
      • University of Alberta
  • British Columbia
    • VIctoria, British Columbia, Canada, V8W 1M8
      • Cool Aid Community Health Centre
    • Vancouver, British Columbia, Canada, V6H 1N1
      • B.C. Women's Hospital & Health Centre - Oak Tree Clinic
    • Vancouver, British Columbia, Canada, V6Z 2C7
      • Vancouver Infectious Disease Clinic
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • CDHA, QEII Health Sciences Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster University Health Sciences Centre
    • Ottawa, Ontario, Canada, K1N 6N5
      • University of Ottawa Health Services
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital, General Campus Divsions of Infectious Diseases
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
    • Toronto, Ontario, Canada, M5G 2N2
      • University Health Network
    • Toronto, Ontario, Canada, M5B 1L6
      • Maple Leaf Medical Clinic
    • Toronto, Ontario, Canada, M2N 3M5
      • Sunnybrook Health Science Centre
    • Toronto, Ontario, Canada, M4K 1N1
      • St. Clair Medical Associates
    • Windsor, Ontario, Canada, N8W 1E3
      • Windsor Regional Hospital
  • Quebec
    • Montreal, Quebec, Canada, H2X 2P4
      • Montreal Chest Institute
    • Montréal, Quebec, Canada, H2L 4M1
      • Centre Hospitalier de l'Universite de Montreal
• United Kingdom
  • Brighton, United Kingdom, BN2 1ES
    • Brighton & Sussex University Hospitals NHS Trust
  • London, United Kingdom, W2 1NY
    • St. Mary's Hospital
  • London, United Kingdom, SE1 7EH
    • Guy's and St. Thomas' NHS Foundation Trust
  • London, United Kingdom, SW10 9NH
    • St. Stephen's AIDS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• adult (aged 18 years or older or as per Local/Provincial Guidelines)
• documented HIV-1 infection (determined by EIA and Western blot, sites' standard assays are acceptable if approved in advance by the PIs for the study, Dr. Darrell Tan and/or Dr. Sharon Walmsley)
• no use of chronic anti-HSV therapy for the past 6 months, and not anticipated to require chronic anti-HSV therapy during the study
• antiretroviral naïve (no more than 14 days of total prior ARV exposure)
• CD4 count within the 400-900 cells/mm3 range (inclusive) on two consecutive occasions, with at least one measurement within 30 days of initiating trial (baseline visit)
• does not meet recommendations for initiating ARV therapy according to current guidelines

Exclusion Criteria:

• pregnancy or actively planning to become pregnant
• receiving chemotherapy, chronic steroid therapy or other immunomodulatory medications (e.g. interferon, azathioprine, methotrexate, TNF-alpha antagonists, etc.)
• Estimated creatinine clearance <30 mL/min
• Other medical condition likely to cause death within 24 months
• Enrolled in a therapeutic HIV vaccine or immunotherapy trial
• Enrolled in another trial investigating the impact of another intervention on HIV disease progression
• HIV elite controller (EC), phenotypically defined here as documented duration of HIV infection of ≥5 years, a persistent CD4 cell count ≥500 cells/mm3, and a persistent plasma HIV viral load of <1000 copies/mL in the absence of antiretroviral therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; Odourless placebo tablet identical to valacyclovir in appearance and taste, to be taken twice daily	Drug: Placebo; Odourless placebo tablet identical to valacyclovir in appearance and taste, to be taken twice daily
EXPERIMENTAL: Valacyclovir; oral valacyclovir 500mg twice daily	Drug: valacyclovir; oral valacyclovir 500mg twice daily; Other Names: Valtrex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
annual rate of change in CD4 count, calculated as the slope of participants' CD4 count change / time.	up to 5 years

Secondary Outcome Measures

Outcome Measure	Time Frame
time from baseline until reaching the composite 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, whichever occurs first.	up to 5 years
Annual rate of change in the CD4 cell count percentage, calculated as the slope of the participants' CD4 count percentage change over time	up to 5 years
Log10 plasma HIV viral load at 12, 24 and 36 months of follow-up	up to 5 years
Treatment-emergent adverse events and laboratory abnormalities (CBC, serum creatinine)	up to 5 years
Frequency of episodes of HSV reactivations at any anatomic site	up to 5 years
Proportion of microbiologically confirmed flares of HSV during the trial that are caused by laboratory-confirmed acyclovir-resistant HSV	up to 5 years
Overall quality of life as measured by the MOS-HIV questionnaire at each 6-monthly time point	up to 5 years

Other Outcome Measures

Outcome Measure	Time Frame
analysis of inflammatory markers in HIV disease progression, HIV Resistance Mutations and other herpesvirus serologies	up to 6 years
genetic testing of HLA-B*5701 and HLA-B*5703 status, and future genetic markers related to HIV disease progression and the impact of herpes and valacyclovir	up to 5 years

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Collaborators: CIHR Canadian HIV Trials Network
• Investigators: Principal Investigator: Sharon L Walmsley, MD FRCPC MSc, University Health Network, Toronto; Principal Investigator: Darrell HS Tan, MD FRCPC, University Health Network, Toronto

Publications and helpful links

General Publications

• Tan DH, Raboud JM, Kaul R, Grinsztejn B, Cahn P, Walmsley SL. Can herpes simplex virus type 2 suppression slow HIV disease progression: a study protocol for the VALacyclovir In Delaying Antiretroviral Treatment Entry (VALIDATE) trial. Trials. 2010 Nov 24;11:113. doi: 10.1186/1745-6215-11-113.

Helpful Links

• CIHR Canadian HIV Trials Network - CTN 240

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2010
• Primary Completion (ACTUAL): August 1, 2015
• Study Completion (ACTUAL): August 1, 2015

Study Registration Dates

• First Submitted: March 11, 2009
• First Submitted That Met QC Criteria: March 11, 2009
• First Posted (ESTIMATE): March 13, 2009

Study Record Updates

• Last Update Posted (ACTUAL): March 6, 2018
• Last Update Submitted That Met QC Criteria: March 2, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: HIV; Treatment Naive; Genital herpes; Herpes simplex virus type II
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Disease Attributes; DNA Virus Infections; Skin Diseases, Infectious; Skin Diseases, Viral; Herpesviridae Infections; Slow Virus Diseases; HIV Infections; Infections; Communicable Diseases; Acquired Immunodeficiency Syndrome; Herpes Simplex; Anti-Infective Agents; Antiviral Agents; Valacyclovir
• Other Study ID Numbers: CTN 240; ISRCTN66756285