Can Valacyclovir Attenuate Inflammation in Antiretroviral-Treated HIV-Infected Individuals With Herpes Simplex Virus Type 2? (VALIANT Pilot)

VALacyclovir for Inflammation AttenuatioN Trial Pilot (VALIANT Pilot)

The purpose of this study is to compare the levels of immune and inflammatory markers among HIV-1, HSV-2 co-infected adults achieving plasma HIV RNA suppression to <50 copies/mL, between those randomized to valacyclovir and placebo, over a twelve-week intervention period.

Study Overview

• Status: Completed
• Conditions: Herpes Simplex; Human Immunodeficiency Virus
• Intervention / Treatment: Drug: Valacyclovir; Drug: Placebo

Detailed Description

Highly active antiretroviral therapy (HAART) has dramatically reduced HIV-1 infection (herein referred to as 'HIV') related morbidity and mortality, transforming an invariably fatal disease into a manageable, chronic condition. Yet even HAART-treated HIV infection is characterized by chronic systemic inflammation and immune activation. This systemic inflammatory response is composed of multiple components, and can be quantified by measuring markers of immune activation, inflammatory cytokines, acute phase reactants, endothelial activation markers, and markers of microbial translocation. This inflammation is clinically relevant, as it may contribute directly to HIV disease progression and non-AIDS related morbidity and mortality in HIV-infected patients. Because this inflammation persists even in the context of suppressive HAART, albeit at modestly decreased levels, adjunctive therapeutic strategies to attenuate this persistent inflammatory response are therefore needed. Herpes simplex virus type 2 is a common, clinically important co-infection seen in individuals living with HIV infection, and may contribute to this ongoing inflammation. This pilot trial will investigate whether short-term valacyclovir for HSV-2 suppression can decrease systemic inflammation in HAART-treated, HIV-1, HSV-2 co-infected individuals.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital, University Health Network

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• adult (aged 18 years or older)
• documented HIV-1 infection (determined by EIA and Western blot)
• documented HSV-2 seropositivity (determined by ELISA during screening)
• no use of chronic anti-HSV therapy for the past 6 months, and not anticipated to require chronic anti-HSV therapy during the study
• sustained plasma HIV RNA<50 copies/mL on HAART for at least 12 months
• no active opportunistic infection for at least 12 months

Exclusion Criteria:

• hepatitis C co-infection
• hepatitis B co-infection
• 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 any other interventional clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High dose valacyclovir; Valacyclovir 1g po BID	Drug: Valacyclovir; Valacyclovir will be used at two different dosages (1g po BID and 500mg po BID) to be used for 12 weeks. Supplied as 500mg caplets.; Other Names: Valtrex; Apo-Valacycyclovir
Active Comparator: Low dose valacyclovir; Valacyclovir 500mg po BID	Drug: Valacyclovir; Valacyclovir will be used at two different dosages (1g po BID and 500mg po BID) to be used for 12 weeks. Supplied as 500mg caplets.; Other Names: Valtrex; Apo-Valacycyclovir
Placebo Comparator: Placebo; Inert placebo	Drug: Placebo; Placebo, supplied as caplets identical in appearance, odour and taste to valacyclovir 500mg caplets.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage activated CD8+ T-cells	Percentage of CD8+ T-cells co-expressing CD38 and HLA-DR	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammatory markers	IL-6, hsCRP, sICAM-1, LPS	12 weeks
CD4 cell count	CD4 cell count (absolute and percentage)	12 weeks
Virologic blips	Plasma HIV RNA level >50 copies/mL but <1000 copies/mL, followed by a repeat plasma HIV RNA level <50 copies/mL.	12 weeks
Drug-related adverse events	Adverse events (AEs) are defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the study medication. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not it is related to the medication.	18 weeks
HSV reactivations	Clinical reactivations of herpes simplex virus. Simultaneous reactivations at more than one anatomic site will be counted as a single reactivation event.	12 weeks
Acyclovir-resistant HSV	Clinical reactivations of herpes simplex virus that are microbiologically confirmed to be caused by acyclovir-resistant virus.	18 weeks

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Collaborators: Canadian Institutes of Health Research (CIHR); University of Toronto
• Investigators: Principal Investigator: Darrell HS Tan, MD FRCPC, University Health Network, University of Toronto; Principal Investigator: Sharon L Walmsley, MD FRCPC MSc, University Health Network, University of Toronto

Publications and helpful links

General Publications

• Yi TJ, Walmsley S, Szadkowski L, Raboud J, Rajwans N, Shannon B, Kumar S, Kain KC, Kaul R, Tan DH. A randomized controlled pilot trial of valacyclovir for attenuating inflammation and immune activation in HIV/herpes simplex virus 2-coinfected adults on suppressive antiretroviral therapy. Clin Infect Dis. 2013 Nov;57(9):1331-8. doi: 10.1093/cid/cit539. Epub 2013 Aug 14.

Helpful Links

• Study Results

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): August 1, 2013

Study Registration Dates

• First Submitted: August 4, 2010
• First Submitted That Met QC Criteria: August 4, 2010
• First Posted (Estimate): August 6, 2010

Study Record Updates

• Last Update Posted (Estimate): May 12, 2016
• Last Update Submitted That Met QC Criteria: May 10, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; DNA Virus Infections; Skin Diseases, Infectious; Skin Diseases, Viral; Herpesviridae Infections; Slow Virus Diseases; HIV Infections; Inflammation; Acquired Immunodeficiency Syndrome; Herpes Simplex; Anti-Infective Agents; Antiviral Agents; Valacyclovir
• Other Study ID Numbers: VALIANT-001