Sildenafil to Treat HIV-Associated Pulmonary Hypertension

All volunteer subjects must be at least 18 years of age and must be able to provide informed, written consent for participation in this study. Eligibility in the study is determined prior to enrollment on the basis of the following inclusion and exclusion criteria.

For Healthy Volunteers:

1. Males or females, 18 years of age or older.
2. No history of HIV infection.
3. EKG and echocardiogram with no evidence of clinical relevant heart disease (including TRV less than 2.5 m/s)
4. No history of causes of pulmonary hypertension such as collagen vascular disease, chronic liver disease with ALT or AST greater than 2 times the upper limit of normal or cirrhosis of the liver, chronic thromboembolic disease, congenital heart defects, or pulmonary parenchymal disease with hypoxemia.
5. No history of diseases thought to be related to development of endothelial dysfunction including systemic hypertension or diabetes requiring drug therapy, hypercholesterolemia and obesity.
6. No history of anemia, thrombocytopenia or coagulopathy.
7. No history of renal insufficiency.

8. No medical conditions requiring chronic medication use with the exception of:

   1. Heartburn, GERD
   2. Environmental allegeries, post nasal drip or non-allergic rhinitis
   3. Asthma with no history of oral steroid use, weekly inhaled steroids, or hospitalization for asthma exacerbation.
   4. Dermatologic conditions that do not require the use of oral steroids or other immunosuppressants.
9. No more than 20 cigarettes per year for the previous 2 years and no cigarette use for 30 days prior to the screening evaluation until completion of the study.

For HIV Positive Volunteers:

1. Males or females, 18 years of age or older.
2. Diagnosis of HIV infection.
3. Under the care of a primary care physician.
4. No history of other potential causes of pulmonary hypertension such as collagen vascular disease, chronic liver disease with ALT or AST greater than 2 times the upper limit of normal or cirrhosis of the liver, chronic thromboembolic disease, congenital heart defects, or pulmonary parenchymal disease with hypoxemia.
5. For stage 3 enrollment: symptomatic pulmonary hypertension with MPAP greater than or equal to 25 mmHg and six-minute walk distance between 150-450 m.

EXCLUSION CRITERIA:

For Healthy volunteers:

1. Current pregnancy, lactation or women not currently using medically acceptable birth control. (All women of childbearing age will be required to have a screening urine or blood pregnancy test)

2. Contraindication to MRI scanning including individuals with the following devices:

   A) Central nervous system aneurysm clips

   B) Implanted neural stimulator

   C) Implanted cardiac pacemaker or defibrillator prior to enrollment

   D) Cochlear implant

   E) Ocular foreign body (e.g. metal shavings)

   F) Insulin pump

   G) Metal shrapnel or bullet

3. Contraindications to MRI contrast agent administration:
4. Inability to provide informed written consent for participation in the study.
5. Chronic, medically refractory atrial tachyarrhythmias
6. Symptoms of heart failure
7. Mean PA greater than 25 mmHg or PVR greater than 1.5 wood units, or PCWP greater than 15 mmHg
8. History of recreational drug use with the exception of marijuana. No Marijuana use within 3 months of protocol screening through completion of the study.

Volunteers may be excluded if in the opinion of the study investigators they have a condition that may adversely affect the outcome of the study or the safety of the volunteer.

For HIV Positive Volunteers:

1. Current pregnancy, lactation or women not currently using medically acceptable birth control.
2. Active, untreated opportunistic infection with the exception of oral thrush or neoplasm with the exception of Kaposi's Sarcoma.

3. Any of the following medical conditions:

   A) Severe renal insufficiency (on hemodialysis or serum creatinine greater than 2.5 mg/dl) or (CrCl less than 20 ml/min).

   B) Severe coagulopathy (platelets less than 100,000, PT INR greater than 1.5, PTT greater than 40 s)

4. Chronic, medically refractory atrial tachyarrhythmias
5. Current recreational drug use or use within 4 weeks of protocol screening with the exception of marijuana

6. Contraindication to MRI scanning including individuals with the following devices:

   A) Central nervous system aneurysm clips

   B) Implanted neural stimulator

   C) Implanted cardiac pacemaker or defibrillator prior to enrollment

   D) Cochlear implant

   E) Ocular foreign body (e.g. metal shavings)

   F) Insulin pump

   G) Metal shrapnel or bullet

7. Contraindications to MRI contrast agent administration:

A) Individuals with hemoglobinopathies

Volunteers may be excluded if in the opinion of the study investigators they have a condition that may adversely affect the outcome of the study or the safety of the volunteer.