HIV Antiretroviral Drugs and Metabolism

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.


Eligibility 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