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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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VALacyclovir for Inflammation AttenuatioN Trial Pilot (VALIANT Pilot)

Conditions
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Human Immunodeficiency Virus, Herpes Simplex

Intervention / Treatment
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* Drug: Valacyclovir
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High dose valacyclovir<br>Valacyclovir 1g po BID | Drug: Valacyclovir<br>* 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.<br>* Other names: Valtrex;|
| Active Comparator: Low dose valacyclovir<br>Valacyclovir 500mg po BID | Drug: Valacyclovir<br>* 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.<br>* Other names: Valtrex;|
| Placebo Comparator: Placebo<br>Inert placebo | Drug: Placebo<br>* Placebo, supplied as caplets identical in appearance, odour and taste to valacyclovir 500mg caplets.<br>|

What is the study measuring?
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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 |