Purpose: To ascertain if dietary supplement(s) may improve blood lipid profile associated with antiretroviral therapy by reducing elevated LDL cholesterol. Secondary endpoints include the potential for such an intervention to induce a reduction in triglyceride level as well as an increase in HDL cholesterol.

Rationale: Abnormalities in lipid metabolism are a recognized side effect of the use of certain antiretroviral drugs such as protease inhibitors (PI) therapy and the use of the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz in HIV-infected patients. The use of hydroxymethylglutaryl coenzyme A reductase inhibitors ("statin) drugs are problematic for a variety of reasons including (a) interactions with ARV therapy; (b) serious, debilitating and potentially lethal side effects; and (c) cost. Other interventions may be as effective with significantly fewer side effects and lower risk.

Use of niacin in cholesterol management: there is a long history of use of Vitamin B3 in the management of dysregulated blood lipids. Niacin is one of the best-studied treatments for high cholesterol. However, it must be taken in fairly high doses (1,000 mg or more), which can cause flushing/reddening and itching. Studies have used high doses (from 1 to 10 grams). Most of the studies saw side effects (nausea, vomiting) with high doses. Work up dose slowly, increasing by 50 or 100 mg a week. Trial will consider1,000 -3,000 mg per day, bringing the dose up gradually (see below).

Use of IHN in cholesterol management: Inositol hexanicotinate (IHN, Nicolip), may be more effective in cholesterol lowering at much lower doses. A number of clinical studies have shown its benefit in conditions like intermittent claudication and Raynaud's disease, conditions where poor or disrupted circulation can impair walking in the case of claudication and cause damage to fingers, hands and toes in the case of Raynaud's disease. The evidence is somewhat mixed on its ability to lower LDL, VLDL cholesterol and triglycerides and increase HDL. One Italian study appeared to show only modest benefit with some exacerbation of other aspects of the lipid profile. Other studies have shown modest improvements. It may be worth a try if for no other reason than it does not have the same side effects of flushing, itching and nausea that are possible with niacin. Also may be helpful for various forms of acne.

Use of carnitine in cholesterol management: German researchers conducted a pilot study in twelve men with lipodystrophy-related body shape changes (increases and losses of fat). They used 1,000 mg of L-carnitine twice daily for 12 weeks (possibly not long enough or a high enough dose to show an effect on body distortions). No improvements in body shape changes were reported, but both total cholesterol and LDL dropped (LDL from a median of 177 mg/dl to 132 mg/dl). 1,000-2,000 mg three times per day (total 3-6 grams per day) is probably the best bet.

hawthorn - Intensively studied; can help the heart in numerous ways, including blood vessel dilation (like gingko); this helps assure that heart tissue is well-filled with blood and limbs have good blood supply. Its action is probably due to oligomeric proanthocyanidins (as found in grapeseed extract). Don't take with other heart medications (at least not without physician oversight; German studies show it enhances effects of cardiac glycosides and hawthorn can be used to reduce the toxic effects of those drugs). Don't overdose. Leaves and flowers are most commonly used. May reduce blood pressure. 1 tsp of chopped leaves (1.8 g) taken 2-3 times per day; also available in capsules: 80 mg standardized for OPC (oligomeric proanthocyanidins).

[POTENTIAL ALTERNATIVES TO HAWTHORN; CONSIDER RESVERATROL?]:

Use of guggul lipids in cholesterol management: The Indian herb, Commiphora mukul, should be found in products standardized to approximately 18?% guggulsterones. It is also known as gum guggulu and has been used to treat allergies and to reduce VLDL and LDL cholesterol and triglycerides. In 40 people administered 4.5 grams in two divided doses over a 16-week period, such reductions in lipid profiles were noted. (That's 9 tablets per day.) It may be helpful for blood lipid problems related to lipodystrophy. It also may stimulate thyroid activity. May promote menstrual flow. Do not use if pregnant. Should be standardized to 5% guggulsterone content. Do not use if pregnant (may induce menstruation or abortion). 2 capsules 2-3 times per day

lecithin - Phosphatidylcholine, a major component of lecithin, is widely used in Europe for the treatment of liver disease and elevated cholesterol levels. With high cholesterol, one suggested mechanism is that it helps the transport of cholesterol to the liver where it can be broken down. In the United States, phosphatidylcholine is regarded as a food supplement because no therapeutic claims are made by manufacturers. May need up to 20 grams/day of lecithin to treat cholesterol but as part of complete program; also good for the liver and for mental function/memory. 5-10 grams of 20% phosphatidylcholine.

Interventions: The study will investigate the use of niacin or inositol hexanicotinate (IHN), with or without carnitine and/or guggul lipid formula. Dietary intake will be assessed via a daily log.

Study Design: Participants will be randomized in a factorial design to receive:

Primary Endpoint: LDL

Secondary Endpoints: HDL; triglycerides; CD4 count; viral load; VLDL; C-reactive protein?

Inclusion Criteria: HIV+ men and women over the age of 18

Exclusion Criteria: Active opportunistic infection

Severe diarrhea

Prior Medication Excluded: Investigational, prescription, and over-the-counter medications within 14 days of study entry with the following exceptions: aspirin, acetaminophen, diphenhydramine, a daily multivitamin (each participant should take a daily multivitamin?). Participation in any investigational drug studies within 30 days prior to study entry. [?]

Concurrent Medication Prohibited: Use of hydroxymethylglutaryl coenzyme a reductase inhibitors ("statin) drugs. Other investigational, prescription, and over-the-counter medications, unless otherwise permitted.

Co-Existing Conditions or Diseases: Volunteers with the following conditions are excluded: 1. severe cardiovascular, renal, gastrointestinal, or endocrine(?), disease(s). This is inclusive of chronic illnesses such as hypertension, coronary artery disease, arthritis, diabetes, any chronic gastrointestinal conditions that might interfere with drug absorption, a history of depression, and past use of antidepressant medications. 2. Allergy/sensitivity to study drugs or their formulations. 3. Any medical condition that, in the opinion of the investigator, would interfere with the volunteer's ability to participate in this protocol. 4. Inability to maintain their usual diet throughout the study or inability to record food intake prior to study visits. 5. Urinalysis with clinically significant abnormalities, such as findings consistent with urinary tract infections, glomerular disease, and renal stones.

Condition(s) Studied: ARV-related hypercholesteremia

Expected Enrollment: 240

Currently Enrolled: 0/240

Trial Duration: 6 months

Hospitalization? Both Inpatient and Outpatient; overnight fasting cholesterol once per month? (every 2 weeks?)

Trial ID Numbers: FIAR-001

Drugs Used in this Trial Generic/Code Name:

Trade/Brand Name: Niacin (To be determined).

Dosage Mode: Oral.

Dosage Schedule: Arm A: 500 mg tid on Days 4-16. (Day 1, 500 mg; Day 2, 500 mg; Day 3, 1,000 mg); or Dosing of niacin will be increased gradually over one week from 100 mg to 1.5 g? or as below to 3,000 mg?

DOSAGES: In the Niacin and IHN arms, the dose would escalate gradually. In the Niacin arm, from 500 mg/day to 3,000 mg/day and IHN from 1,500 mg/day to 3,000 mg per day.

Trade/Brand Name: Inositol hexanicotinate (Nicolip).

Dosage Mode: Oral.

Dosage Schedule: Arm B: IHN five 800 mg tablets in divided doses taken at meal time. [confirm dosing

schedule]

Trade/Brand Name: Carnitine (Carnitor bran? To be determined).

Dosage Mode: Oral.

Dosage Schedule: 1,000 mg tid. (or 990 mg tid if using 330 mg Carnitor tablets)

Trade/Brand Name: Hawthorn

Dosage Mode: Oral.

Dosage Schedule: (To be determined).

Trial Sites/Contacts: To be determined.

Content Last Updated: May 5, 2002

Notes: Analyze data stratified by age; intent-to-treat analysis.

Include?:

Concurrent Medication Permitted: 1. All Arms: Aspirin or acetaminophen (up to 650 mg every 4 hours) as an analgesic, diphenhydramine (25 mg at bedtime) as a sleeping aid, daily multivitamin and mineral supplements, and hormone replacement therapy for postmenopausal women. 2. Loperamide or prochlorperazine in accordance with protocol guidelines, and hormonal contraception for women of reproductive potential, provided a second method of birth control is used during, and for 10 days after, NFV administration.