Modulation of Monocyte Activation by Atorvastatin in HIV Infection

HIV Dementia Clinical Trial

Official title:

Pilot Study to Evaluate Effects of Atorvastatin on Monocyte Activation in HAART-treated HIV Infected Individuals

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01263938
• Other study ID #: IRB Protocol #: 812196
• Secondary ID: P30AI045008
• Status: Completed
• Phase: Phase 4
• Start date: September 2011
• Est. completion date: October 2017

Study information

• Verified date: April 2019
• Source: University of Pennsylvania
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5
• Est. completion date: October 2017
• Est. primary completion date: October 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Chronic HIV-1 infected individuals presently on HAART with no change in drug combination for at least 3 months at time of enrollment

2. Plasma viral load <200 copies / ml for at least 6 months prior to enrollment in the study

3. CD4 T cell count more than 350/ul

4. Willingness to use a method of contraception during the study period

5. Willingness to have blood drawn

6. If female, willingness to undergo pregnancy testing on a monthly basis and are not breastfeeding

7. Ability to understand and willingness to sign the informed consent

8. hs-CRP levels above the upper limit of normal (>3mg/L)

Exclusion Criteria:

1. Concomitant use of fibric acid derivatives or other lipid lowering agents including patients on statins and Ezetimibe

2. Use of any anti-inflammatory drugs (OTC or prescription) on a daily basis

3. Pregnancy or breast feeding

4. 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

5. Allergy or hypersensitivity to statins or any of its components

6. History of myositis or rhabdomyolysis with use of any statins

7. Patients who are on concurrent immunomodulatory agents, including systemic corticosteroids will be ineligible for 3 months after completion of therapy with the immunomodulating agents

8. History of inflammatory muscle disease such as poly or dermatomyositis

9. Serious intercurrent illness requiring systemic treatment and/or hospitalization within 30 days of entry

10. Evidence of active opportunistic infections requiring treatment or neoplasms that require chemotherapy during the study period

11. Creatine phosphokinase elevations (CPK) greater than 3 times the upper limit of normal

12. Known active liver disease or AST/ALT greater than 2x the upper limit of normal

13. Renal insufficiency, indicated by serum creatinine 2 mg/dl

14. Absolute neutrophil count (ANC) 1000/mm3, hemoglobin < 10.0 g/dL for males and <9 g/dL for females, platelet count 100,000/mm

Related Conditions & MeSH terms

• AIDS Dementia Complex
• HIV Dementia

Intervention

Drug:
• Atorvastatin
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.

Locations

Country	Name	City	State
United States	University of Pennsylvania School of Medicine	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
University of Pennsylvania	National Institute of Allergy and Infectious Diseases (NIAID)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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)
Primary	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)