HIV Antiretroviral Drugs and Metabolism
| Status: | Completed |
|---|---|
| Conditions: | HIV / AIDS |
| Therapuetic Areas: | Immunology / Infectious Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/2/2016 |
| Start Date: | March 2004 |
| End Date: | December 2010 |
| Contact: | Carl Grunfeld, M.D., Ph.D. |
| Email: | carl.grunfeld@ucsf.edu |
| Phone: | 415-750-2005 |
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.
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.
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
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