The purpose of this study is to compare the cardiovascular profiles of efavirenz and rilpivirine, which are two drugs used to treat HIV infection.

This is a randomized, controlled, open-label, single-center study comparing the effects of efavirenz (EFV) versus rilpivirine (RPV) on endothelial function in a total of 40 HIV-uninfected healthy volunteers (20 in each arm) at the Indiana University Medical Center. Enrolled subjects will have their brachial artery flow-mediated dilation (FMD), a measure of endothelial function, and other cardiovascular, inflammatory, and oxidative stress parameters measured at baseline and again after 4 weeks of study treatment.

Inclusion Criteria:

1. 18 years of age or older
2. Negative ELISA for HIV-1 or HIV-2 at screening
3. Negative hepatitis B surface antigen at screening
4. Negative hepatitis C antibody at screening
5. For women of reproductive potential, a negative urine pregnancy test at screening and willingness to use two forms of birth control during the course of the study
6. For men who are capable of impregnating a female sexual partner, a willingness to use condoms with spermicidal gel for all sexual contacts during the course of the study
7. No documented history of or receipt of medications being used to treat any psychiatric disorder, including (but not limited to) depression, dysthymia, mania, bipolar disease, schizophrenia, or previous suicidal ideation/attempts
8. No anticipated changes or additions to other medical therapies during the course of the study
9. No documented history of seizure disorder

Exclusion Criteria:

1. Inability to provide written, informed consent
2. Known allergy/intolerance to rilpivirine, efavirenz, or nitroglycerin
3. Absolute neutrophil count < 750cell/mL at screening
4. Hemoglobin < 11g/dL at screening
5. Platelet count < 100,000/mL at screening
6. Estimated creatinine clearance (per Cockcroft-Gault equation) < 55 mL/min at screening
7. Liver transaminases (AST or ALT) > 100 IU/mL or total bilirubin > 1.5mg/dL at screening
8. Serum glucose > 200mg/dL at screening
9. Serum total cholesterol > 190mg/dL at screening
10. Breastfeeding at screening or during the course of the study
11. Hypotension, defined as SBP < 90mmHg at time of each main study visit before brachial artery ultrasound measurements
12. Hypertension, defined as SBP > 160mmHg at time of screening
13. Receipt of investigational agents within 30 days of each screening visit or anticipated use during the trial
14. Receipt of cytotoxic chemotherapy within 30 days of each screening visit or anticipated use during the trial
15. Receipt of systemic glucocorticoids (> 10mg/day of prednisone or the equivalent), inhaled/nasal/topical fluticasone, or anabolic steroids within 30 days of each screening visit or anticipated use during the trial
16. Use of sildenafil (Viagra or Silagra), vardenafil (Levitra), or tadalafil (Cialis), within 72 hours (before or after) of brachial artery reactivity testing
17. Indwelling vascular catheters within any upper body vessel at time of brachial artery reactivity testing
18. Active drug or alcohol use or dependence that, in the opinion of the investigator or study personnel, would interfere with adherence to study requirements
19. Acute therapy for serious infection or other serious medical illnesses (in the judgment of the site investigator) requiring systemic treatment and/or hospitalization within 14 days prior to each screening and study visit
20. History of migraine headaches
21. History of Raynaud's phenomenon
22. History of cardiac arrythmias
23. History of hypothyroidism or hyperthyroidism that is untreated (defined as a TSH outside the normal range on most recent testing during normal clinical care)
24. History of carotid bruits
25. History of any tobacco use (cigarette smoking, cigar smoking, chewing tobacco) or nicotine replacement treatments (patch, gum) within 45 days of screening
26. Drugs/therapies with significant CYP 450 induction or inhibition potential at screening
27. Use of antacids, H2-blockers, or proton pump inhibitors within 30 days of screening or anticipated use of these drugs during the trial
28. Any history of injection or illicit drug use
29. Presence of fever, defined as an oral or tympanic temperature > 100.3F, at either the Entry or Closeout Visits
30. On the PHQ-9 depression questionnaire at screening, a total score of more than 9 or any score over 0 on question 9.

One month