Downmodulating Monocyte Activation for HIV-1 Associated Neurocognitive Disorders (HAND)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01600170
Recruitment Status : Completed
First Posted : May 16, 2012
Last Update Posted : December 12, 2017
Information provided by (Responsible Party):
University of Pennsylvania

Brief Summary:

HIV associated neurological disorders (HAND), are a major problem even in ART treated people. HAND results from chronic inflammation which is largely attributed to expansion and activation of monocytes. These activated monocytes, some of which also carry virus to the brain, invade the CNS and release cytokines / chemokines resulting in further recruitment of monocytes, as well as release viral proteins which injure neurons and cause activation of other brain cells. Persistent monocyte/macrophage activation is thus a potential critical target for adjunctive therapy to treat or prevent HAND. The investigators therefore propose to study the effects of a statin drug (Atorvastatin), which has anti-inflammatory functions, on the monocyte activation status in vitro and in ART treated HIV+ individuals.

The investigators objectives are based on the hypothesis that Atorvastatin treatment will reduce the inflammatory and activated phenotype and function of monocytes which have been linked to HIV associated neuropathogenesis and occur in HIV infected subjects despite ART. In this study the investigators propose to

  1. determine how Atorvastatin modulates monocyte activation, intracellular signaling pathways and functions implicated in the pathogenesis of HAND in vitro
  2. define the effect of Atorvastatin on monocyte activation in HIV infected / ART treated subjects in a double blind, placebo controlled crossover study
  3. define gene expression patters of monocyte activation before and following statin treatment
  4. assess Atorvastatin effects on CNS immune activation markers and neurocognitive function in ART treated subjects.

Condition or disease Intervention/treatment Phase
HIV Dementia Drug: Atorvastatin (generic Lipitor) Drug: placebo Phase 4

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Statin Modulation of Monocyte/Macrophage Activation for HAND Treatment
Study Start Date : January 2013
Actual Primary Completion Date : October 2017
Actual Study Completion Date : October 2017

Arm Intervention/treatment
Active Comparator: Atorvastatin Drug: Atorvastatin (generic Lipitor)
Atorvastatin is an FDA approved prescription drug which is frequently used to lower cholesterol levels.It is available in the form of tablets ranging in dose from 10-80mg.

Placebo Comparator: Placebo Drug: placebo
A substance containing no medication and prescribed or given to reinforce a patient's expectation to get well.

Primary Outcome Measures :
  1. Effects of Atorvastatin on peripheral blood monocytes [ Time Frame: 4 years ]
    1. Peripheral blood monocyte surface markers CD16; CD14; CD163; CCR2;
    2. Plasma levels of monocyte associated inflammatory cytokines and chemokines: MCP-1; sCD14 and neopterin
    3. Monocyte gene expression patterns in ART treated HIV+ subjects.
    4. Monocyte / macrophage signaling pathways

Secondary Outcome Measures :
  1. Effects of Atorvastatin on T cell and CSF activation markers [ Time Frame: 4 years ]
    1. Immune activation markers in the CSF: MCP-1 and neopterin
    2. T cell activation markers: CD38 and CD25.
    3. Neurocognitive outcomes.

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Chronic HIV-1 infected individuals on HAART (with no change in treatment within 4 weeks of study entry) and willing to continue therapy for the duration of the study.
  2. HIV viral load less than 200 copies/ml for more than 6 months at time of screening.
  3. Nadir CD4 count less than 350 and current CD4 counts greater than 100 cells/ul.
  4. Hs-CRP levels above 2mg/L.
  5. Willingness to use a method of contraception during the study period.
  6. Willingness to comply with study evaluations for LP sub-study.
  7. Karnofsky performance score of 80 or higher.
  8. If female, willing to undergo pregnancy testing on a monthly basis and not breastfeeding.
  9. Hemoglobin greater than or equal to 9.0 g/dL for female and 10.0 g/dL for male subjects.
  10. men and women 18 years or older.

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 breastfeeding
  4. Active drug use or alcohol abuse/dependence which in the opinion of researchers will interfere with the patients' ability to participate in the study.
  5. Allergy or hypersensitivity to Atorvastatin 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 (nasal or inhaled) will be ineligible for 3 months after completion of therapy with the agent.
  8. History of inflammatory muscle disease such a 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 study period.
  11. CPK greater than 3 times the ULN.
  12. Known active liver disease or AST/ALT greater than 3 times the ULN.
  13. Renal insufficiency, indicated by serum creatinine greater than 2mg/dL.
  14. Absolute neutrophil counts less than 1000/ul; hemoglobin less than 10g/dL for males and less than 9g/dL for females; platelet counts less than 100,000/mm3.
  15. Documented HCV infection.
  16. NYHA class III or IV congestive heart failure.
  17. Active IV drug use within 1 year prior to entry.
  18. For LP sub-study, allergy to Lidocaine.
  19. Coronary artery disease or equivalent including Diabetes mellitus.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01600170

United States, Pennsylvania
University of Pennsylvania School of Medicine
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
University of Pennsylvania
Principal Investigator: Ronald G Collman, MD University of Pennsylvania

Responsible Party: University of Pennsylvania Identifier: NCT01600170     History of Changes
Other Study ID Numbers: IRB Protocol # 815512
First Posted: May 16, 2012    Key Record Dates
Last Update Posted: December 12, 2017
Last Verified: December 2017

Keywords provided by University of Pennsylvania:

Additional relevant MeSH terms:
HIV Infections
Neurocognitive Disorders
AIDS Dementia Complex
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Mental Disorders
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Atorvastatin Calcium
Anticholesteremic Agents
Hypolipidemic Agents
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors