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HIV Antiretroviral Drugs and Metabolism

The recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.
Verified March 2011 by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
Recruitment status was:  Recruiting
Sponsor:
ClinicalTrials.gov Identifier:
NCT00525239
First Posted: September 5, 2007
Last Update Posted: March 16, 2011
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.
Information provided by:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  Purpose

Hypothesis 1: Ritonavir-based regimens increase triglycerides and VLDL by both increasing VLDL production and decreasing VLDL clearance.

Specific Aim 1A: To quantify the effect of ritonavir on VLDL production and clearance using stable isotope turnover and other clearance methods.

Specific Aim 1B: To determine the composition of the triglyceride rich particles.

Protocol 1: The effects of ritonavir-based regimens on VLDL production, VLDL clearance and triglyceride-rich lipoprotein composition in healthy normal volunteers. HIV-seronegative volunteers will be studied before and at the end of four weeks of taking ritonavir, lopinavir/ritonavir or atazanavir/ritonavir.

Hypothesis 2: NNRTI drugs do not increase HDL by increasing apo AI production, but rather by decreasing apo AI clearance, prolonging time in circulation.

Specific Aim 2A: To determine the composition of HDL before and after NNRTI and assess its function.

Specific Aim 2B: To quantify the effect of NNRTI on apo AI production and clearance using stable isotopes.

Specific Aim 2C: To determine if the NNRTI induced increase in HDL is accompanied by improvement in flow mediated vasodilation and circulating markers of endothelial function Protocol 2A: The effects of efavirenz on HDL composition, HDL function, apo AI production, apo AI clearance, flow mediated vasodilation and circulating markers of endothelial dysfunction in healthy normal volunteers. HIV-seronegative volunteers will be studied before and at the end of six weeks of taking efavirenz.

Protocol 2B: The effects of starting an efavirenz-based regimen on HDL composition, HDL function, apo AI production, apo AI clearance, flow mediated vasodilation and circulating markers of endothelial dysfunction in patients with HIV infection. HIV-infected patients whose care providers have prescribed an efavirenz-based regimen will be studied before and after six weeks of starting efavirenz.

Hypothesis 3: Ritonavir-based PI regimens impair insulin secretion. Specific Aim 3: To determine which ritonavir-based PI regimens alter insulin secretion.

Protocol 3: The effects of ritonavir-based regimens on insulin secretion in healthy normal volunteers. HIV-seronegative volunteers will be studied before and at the end of four weeks of taking ritonavir, lopinavir/ritonavir or atazanavir/ritonavir.


Condition Intervention
HIV Infections Drug: ritonavir, lopinavir/ritonavir, atazanavir/ritonavir, efavirenz

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)

Resource links provided by NLM:


Further study details as provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Primary Outcome Measures:
  • Effect of HIV Protease Inhibitors on Glucose Metabolism by Hyperglycemic Clamp [ Time Frame: 4 weeks ]

Secondary Outcome Measures:
  • Effect of HIV Protease Inhibitors on Oral Glucose Tolerance Test [ Time Frame: 4 weeks ]

Estimated Enrollment: 60
Study Start Date: March 2004
Estimated Study Completion Date: December 2010
Estimated Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1: Ritonaivr
Pre and post ritonavir, lopinavir/ritonavir or atazanavir/ritonavir
Drug: ritonavir, lopinavir/ritonavir, atazanavir/ritonavir, efavirenz
100 mg, twice daily, for four weeks

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Protocols 1, 2A and 3 HIV negative, healthy normal volunteers, age > 18 years old.

Protocol 2B HIV-infected subjects, age > 18 years old and documented to have HIV-1 infection for ≥ 6 months, being started on efavirenz by their health care provider.

Exclusion Criteria:

Protocols 1, 2A and 3 Coronary artery disease, peripheral vascular disease, impaired fasting glucose (glucose > 100 mg/dl), obese (BMI > 30), dyslipidemia (triglycerides > 190 mg/dl, LDL-C > 190), anemia (Hct < 39), hypertension (BP> 140/90 mmHg or on medication), blood pressure <100 mmHg, renal disease (creatinine > 1.6), LFT > ULN, or use within 30 days of systemic glucocorticoids, anabolic steroids, growth hormone, niacin, antipsychotics, or lipid lowering medications. Women will be tested for pregnancy immediately prior to each inpatient study and excluded if pregnant. For Specific Aim 2, additional exclusion criteria include history of depression requiring treatment, psychosis, hallucinations or delusions; use of cGMP specific phosphodiesterase 5 inhibitors (e.g., sildenafil) within 7 days of study; or history of adverse reaction to nitrates.

Protocols 1, 2A and 3 Currently on an NNRTI, coronary artery disease, peripheral vascular disease, recent opportunistic infection (within two months), impaired fasting glucose (glucose > 100 mg/dl) or diabetes, anemia (Hct < 39), hypertension (BP > 140/90 mmHg or on medication), blood pressure <100 mmHg, renal disease (Creatinine > 1.6), LFT > 2x ULN, use of cGMP specific phosphodiesterase 5 inhibitors (e.g., sildenafil) within 7 days of study, history of adverse reaction to nitrates, use within 30 days of anabolic steroids, systemic glucocorticoids, growth hormone, niacin, antipsychotics, or lipid lowering medications. Women will be tested for pregnancy immediately prior to each inpatient study and excluded if pregnant

  Contacts and Locations
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 ClinicalTrials.gov identifier (NCT number): NCT00525239


Contacts
Contact: Carl Grunfeld, M.D., Ph.D. 415-750-2005 carl.grunfeld@ucsf.edu
Contact: Mae Pang, R.N. M.S.N 415-750-2005 miyin.pang@ucsf.edu

Locations
United States, California
Department of Veterans Affairs Medical Center Recruiting
San Francisco, California, United States, 94121
Contact: Mae Pang, RN, MSN    415-750-2005    miyin.pang@ucsf.edu   
Contact: Lyda Galvez    415-750-2005    lyda.galvez@va.gov   
Sponsors and Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
Principal Investigator: Carl Grunfeld, M.D., Ph.D. Northern California Institute for Research and Education
  More Information

Publications:
Noor MA, Lo JC, Mulligan K, Schwarz JM, Halvorsen RA, Schambelan M, Grunfeld C. Metabolic effects of indinavir in healthy HIV-seronegative men. AIDS. 2001 May 4;15(7):F11-8.
Noor MA, Seneviratne T, Aweeka FT, Lo JC, Schwarz JM, Mulligan K, Schambelan M, Grunfeld C. Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study. AIDS. 2002 Mar 29;16(5):F1-8.
Lee GA, Seneviratne T, Noor MA, Lo JC, Schwarz JM, Aweeka FT, Mulligan K, Schambelan M, Grunfeld C. The metabolic effects of lopinavir/ritonavir in HIV-negative men. AIDS. 2004 Mar 5;18(4):641-9.
Lee GA, Mafong DD, Noor MA, Lo JC, Mulligan K, Schwarz JM, Schambelan M, Grunfeld C. HIV protease inhibitors increase adiponectin levels in HIV-negative men. J Acquir Immune Defic Syndr. 2004 May 1;36(1):645-7.
Schwarz JM, Lee GA, Park S, Noor MA, Lee J, Wen M, Lo JC, Mulligan K, Schambelan M, Grunfeld C. Indinavir increases glucose production in healthy HIV-negative men. AIDS. 2004 Sep 3;18(13):1852-4.
Lee GA, Rao MN, Grunfeld C. The effects of HIV protease inhibitors on carbohydrate and lipid metabolism. Curr HIV/AIDS Rep. 2005 Feb;2(1):39-50. Review.
Lee GA, Lo JC, Aweeka F, Schwarz JM, Mulligan K, Schambelan M, Grunfeld C. Single-dose lopinavir-ritonavir acutely inhibits insulin-mediated glucose disposal in healthy volunteers. Clin Infect Dis. 2006 Sep 1;43(5):658-60. Epub 2006 Jul 26.
Lee GA, Rao M, Mulligan K, Lo JC, Aweeka F, Schwarz JM, Schambelan M, Grunfeld C. Effects of ritonavir and amprenavir on insulin sensitivity in healthy volunteers. AIDS. 2007 Oct 18;21(16):2183-90.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Carl Grunfeld, M.D., Ph.D., Principal Investigator, Northern California Institute for Rerseach and Education
ClinicalTrials.gov Identifier: NCT00525239     History of Changes
Other Study ID Numbers: DK66999
First Submitted: September 4, 2007
First Posted: September 5, 2007
Last Update Posted: March 16, 2011
Last Verified: March 2011

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):
Lipids
lipoproteins
VLDL
triglycerides
apo B100
HDL
apo A1
endothelial dysfunction
insulin secretion
hyperglycemic clamp
HIV-seronegative Volunteers
HIV-infected subjects starting an efavirenz-based regimen
Treatment Experienced

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Ritonavir
Lopinavir
Atazanavir Sulfate
Efavirenz
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP3A Inducers


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