Modulation of Monocyte Activation by Atorvastatin in HIV Infection

NCT01263938 | Completed Phase 4 Results DMC

• 2 other identifiers: IRB Protocol #: 812196P30AI045008
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

Activated monocytes play a key role in the pathogenesis of HIV-associated neurocognitive disorders (HAND). Individuals with HAND have expanded populations of activated monocytes. These monocytes are thought to emigrate into the CNS, where they produce neurotoxic proinflammatory factors, and also carry virus into the CNS. Statins are cholesterol lowering drugs with pleiotropic immunomodulatory / anti-inflammatory properties that are currently being explored for immunomodulation of T cell activation in several diseases, in addition to their established role to treat hyperlipidemia and atherosclerosis. The investigators in vitro data suggests that these drugs can downregulate monocyte activation patterns seen in HIV infection. No in vivo studies have yet been carried out to assess the effects of statins on the pro-inflammatory monocyte population in chronic HIV disease. This will be a pilot study of whether statin treatment will reduce the inflammatory monocyte phenotype and downregulate the inflammatory cytokines that have been linked to neuropathogenesis in HIV infection. If so, they may have potential as adjunctive therapy in HIV-associated neurological disease. The investigators propose to:

• Determine the effect of Atorvastatin on peripheral blood monocyte populations in a 12-week pilot study in chronically HIV-infected people on HAART therapy.
• Determine the relationship between changes in monocyte phenotype following Atorvastatin treatment, and soluble markers of activation/inflammation linked to neuropathogenesis, as well as activation status of T cells.

Conditions

HIV Dementia

Keywords

HIV; monocytes; CD16+; statins; mcp1; inflammation

Outcome Measures

Primary Outcomes (4)

• Change in Monocyte Surface Markers Expression (Expressed as Percentage), Following Treatment of Chronic HIV+/ HAART+ Subjects With Atorvastatin (T=12wks Versus T=0wk).

  Effects of Atorvastatin on immune activation associated surface markers (CD16, CD163 and CCR2) of monocytes were assessed in chronic HIV+/HAART+ subjects following 12 weeks of treatment. Whole blood drawn from these subjects were stained with fluorochrome tagged antibodies to the surface markers. Stained whole blood cells were then acquired on a flow cytometer and analyzed using the Flowjo software to determine the percentage of cells (monocytes) expressing the specific marker. This was done before starting and after completing drug treatment to assess the effect of drug.

  Subjects enrolled in the study following the screening visit were assessed for the primary outcome measures at T=0 (drug intervention begins); T=12wks (intervention ends)

• Change From Baseline in Levels of Plasma Inflammatory Marker MCP-1 of Chronic HIV+/ HAART+ Subjects.

  Monocyte specific inflammatory soluble factor MCP-1 was measured by ELISA in plasma of HIV+/HAART+ subjects at baseline and at 12 weeks following atorvastatin treatment.

  Subjects enrolled in the study following the screening visit were assessed for the primary outcome measures at T=0 (drug intervention begins); T=12wks (intervention ends)

• Change From Baseline in Levels of Plasma Inflammatory Marker sCD14 of Chronic HIV+/ HAART+ Subjects.

  Monocyte specific inflammatory soluble factor sCD14 was measured by ELISA in plasma of HIV+/HAART+ subjects at baseline and at 12 weeks following atorvastatin treatment.

  Subjects enrolled in the study following the screening visit were assessed for the primary outcome measures at T=0 (drug intervention begins); T=12wks (intervention ends)

• Change From Baseline in Levels of Plasma Inflammatory Marker sCD163 of Chronic HIV+/ HAART+ Subjects.

  Monocyte specific inflammatory soluble factor sCD163 was measured by ELISA in plasma of HIV+/HAART+ subjects at baseline and at 12 weeks following atorvastatin treatment.

  Subjects enrolled in the study following the screening visit were assessed for the primary outcome measures at T=0 (drug intervention begins); T=12wks (intervention ends)

Study Arms (1)

Atorvastatin

OTHER

Drug: Atorvastatin

Interventions

Atorvastatin DRUG

For subjects on PI-based HAART therapy: 10mg/day X 2weeks followed by 20mg/day. For subjects on non PI-based HAART therapy: 20mg/day X 2weeks followed by 40mg/day.

Also known as: Lipitor

Atorvastatin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Chronic HIV-1 infected individuals presently on HAART with no change in drug combination for at least 3 months at time of enrollment
• Plasma viral load \<200 copies / ml for at least 6 months prior to enrollment in the study
• CD4 T cell count more than 350/ul
• Willingness to use a method of contraception during the study period
• Willingness to have blood drawn
• If female, willingness to undergo pregnancy testing on a monthly basis and are not breastfeeding
• Ability to understand and willingness to sign the informed consent
• hs-CRP levels above the upper limit of normal (\>3mg/L)

You may not qualify if:

• Concomitant use of fibric acid derivatives or other lipid lowering agents including patients on statins and Ezetimibe
• Use of any anti-inflammatory drugs (OTC or prescription) on a daily basis
• Pregnancy or breast feeding
• Active drug use or alcohol abuse/dependence, which in the opinion of the investigators will interfere with the patient's ability to participate in the study
• Allergy or hypersensitivity to statins or any of its components
• History of myositis or rhabdomyolysis with use of any statins
• Patients who are on concurrent immunomodulatory agents, including systemic corticosteroids will be ineligible for 3 months after completion of therapy with the immunomodulating agents
• History of inflammatory muscle disease such as poly or dermatomyositis
• Serious intercurrent illness requiring systemic treatment and/or hospitalization within 30 days of entry
• Evidence of active opportunistic infections requiring treatment or neoplasms that require chemotherapy during the study period
• Creatine phosphokinase elevations (CPK) greater than 3 times the upper limit of normal
• Known active liver disease or AST/ALT greater than 2x the upper limit of normal
• Renal insufficiency, indicated by serum creatinine 2 mg/dl
• Absolute neutrophil count (ANC) 1000/mm3, hemoglobin \< 10.0 g/dL for males and \<9 g/dL for females, platelet count 100,000/mm

Sponsors & Collaborators

• University of Pennsylvania: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (1)

University of Pennsylvania School of Medicine

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Conditions

AIDS Dementia Complex; Inflammation

Interventions

Atorvastatin

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Neurocognitive Disorders; Mental Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids

Limitations and Caveats

This study had a very small sample size of 5 subjects. Therefore due to lack of power the data is inconclusive.

Results Point of Contact

• Title: Dr. Ronald Collman
• Organization: University of Pennsylvania School of Medicine

collmanr@pennmedicine.upenn.edu

215-898-0193

Study Officials

• Ronald G Collman, MD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 17, 2010
• First Posted: December 21, 2010
• Study Start: September 1, 2011
• Primary Completion: October 1, 2017
• Study Completion: October 1, 2017
• Last Updated: May 1, 2019
• Results First Posted: April 18, 2019

Record last verified: 2019-04

Locations

US (1)