- Click here for explanation of classification scheme.

To determine the safety, tolerability, and efficacy of omega-3 fatty acid supplementation in HIV-infected subjects with hypertriglyceridemia who were receiving combination antiretroviral therapy.

• HIV-infected adults who had 8-h fasting serum TG levels of >200 mg/dL
• Receiving at least 3 antiretrovirals for >3 months
• Stable statin therapy ok

• Diabetes mellitus
• Heart disease with an American Heart Association classification of class 1 or greater
• Taking fibrates within 6 weeks prior to study entry

Recruitment Recruited from the University of North Carolina Infectious Diseases Clinic

 

Design Open label, randomized, controlled trial

 

Blinding used (if applicable)

 

Intervention (if applicable)

• Diet and exercise counseling
  • All subjects regardless of treatment assignment
  • Diet and exercise plan devised and reviewed in accordance to with American Heart Association recommendations
    • General information on strategies to reduce intake of overall dietary fat and trans fatty acid, to increase intake of fiber and how to adopt a daily aerobic exercise program
    • Increased intake of food rich in omega-3 fatty acid was discussed in general terms
    • Target weight and exercise goals were tailored to the needs and capabilities of each subject
• Subjects randomized to one of two intervention groups
  • Diet and exercise group
  • Fish oil group
    • Diet + exercise + 16 week course of omega-3 fatty acid supplementation
    • Coromega (1750 mg EPA +1150 mg DHA) taken daily with food.
      • Total dose is within the 2-4 gm of EPA and DHA per day recommended by the American Heart Association for patients who need to lower TG levels.
      • Liquid formulation
      • High-level bioavailability of EPA and DHA per manufacturer

 

Statistical Analysis

• Outcomes
  • Primary: to compare the mean change (defined as the week 4 value minus the entry value, divided by the entry value) in fasting TG levels from baseline to week 4 within and between the study arms.
  • Secondary:
    • Comparison of the 2 study arms with respect to the mean TG levels from baseline to week 16 and the change from study entry to weeks 4 and 8 in mean absolute change in TG levels
    • Change in weight
    • Change in the levels of total cholesterol, HDL-cholesterol, LDl cholesterol and lipoprotein A
    • Safety and tolerability of study medication
• Statistical tests
  • Paired Student's t tests were used for comparing the changes from baseline in lipid values, platelet function assay results and weight.
  • Wilcoxon rand sum test was used to analyze the absolute change in TG levels

 

Timing of Measurements

 

	Baseline	Week 4	Week 16
Diet/exercise counseling	x	x	x
Three day food record/24 hour recall	x	x	x
Physical activity questionnaire	x	x	x
Fasting TG	x	x	x
Cholesterol	x	x	x
HDL-cholesterol	x	x	x
LDL cholesterol	x	x	x
Lipoprotein A	x	x	x
Oral glucose tolerancetest	x	x	x
Platelet function analysis	x	x	x
Basic blood chemistries	x	x	x
Adverse clinical/lab events	x	x	x

Dependent Variables

• Lipids
  • Fasting TG 
  • Cholesterol
  • HDL-cholesterol
  • LDL-cholesterol
  • Lipoprotein A
• Two hour oral glucose tolerance test
• Platelet function analysis
• Adverse clinical/laboratory event grading: NIH Health Division of AIDS toxicity grading table
• Dietary/medication/supplement intake: three day food record or 24 hour recall if food record not available
• Physical activity questionnaire: self assessed using the Lipid Research Clinics questionnaire
• Adherence to study medication was assessed using the AIDS Clinical Trials group self-reported adherence measure

Independent Variables

 Diet + exercise vs Diet + exercise + fish oil

Control Variables

 

 

Initial N: N=52

• Diet + exercise: N=26  (92.3% male)
• Fish oil: N=26 (88.5% male)

Attrition (final N):

• At 4 week evaluation: N=44 (85% completed)
  • Diet + exercise: N=20
    • Disappointed not randomized to fish oil (6)
  • Fish oil: N=24
    • Discomfort of phlebotomy (1)
    • Lost to follow up (1)
• At 16 week evaluation: N=41 (79% completed)
  • Diet + exercise: N=19
    • Relocation to another state (1)
  • Fish oil: N=22
    • Toxicity (1)
    • Dislike of liquid fish oil formulation (1)
• No major differences in demographic characteristics or laboratory values among the subjects who withdrew from the study prior to the week 4 evaluation and those who continued.

Age: (mean years)

• Diet + exercise: 45.3 years
• Fish oil: 42.0 years

Ethnicity:

• Diet + exercise: 46.2% non white race
• Fish oil: 61.5% non white race

Other relevant demographics:

Anthropometrics No statistically significance differences between the arms in any characteristic at baseline.

	Diet + exercise	Fish oil
BMI	27.2	27.4
CD4 cell count, cell/µL	478	577
Plasma HIV RNA  level, copies/mL	30,454	38,618
Antiretroviral therapy, %
1 Protease inhibitor	12	15
2 protease inhibitors	15	8
1 non-cleoside reverse transcriptase inhibitor	8	31
Protease inhibitor+ nonnucleoside reverse transcriptse inhibitor	31	23
Only nucleoside reverse transcriptase inhibitors	0	4
Ritonavir-boosted protease inhibitor	35	19
Any of the above with stavudine	19	15
Any of the above with ritonavir	50	35

• In addition: the mean number of National Cholesterol Education Program-defined cardiovascular disease risk factors was 1.9 per subject.

Location: University of North Carolina, Chapel Hill

 

 Lipid End Points

	Mean value			Mean % change from baseline (95% CI)
	Baseline	Week 4	Week 16	Week 4	P, Baseline vs Week 4 (between grps)	Week 16	P, Baseline vs week 16 (between grps)
TG, mg/dl
Fish oil	461	306	304	-25.1 (-34.6 to -15.7)	0.0074	-19.5 (-34.9 to -4.0)	0.12
Diet/exercise	502	503	513	2.8 (-17.5 to 23.1)	0.0074	-5.7 (-24.6 to 13.2)	0.12
Total cholesterol, mg/dl
Fish oil	227	219	218	-3.1 (-8.9 to 2.7)	0.61	-0.31 (-10.4 to 9.8)	0.80
Diet/exercise	254	242	259	-5.1 (10.6 to 0.43)	0.61	-1.8 (-8.5 to 4.9)	0.80
Direct LDL cholesterol, mg/dl
Fish oil	110	126	136	15.6 (4.8 to 26.4)	0.14	22.4 (7.91 to 36.8)	0.73
Diet/exercise	116	113	131	(3.5 (-9.0 to 16.0)	0.14	18.4 (-0.6 to 37.4)	0.73
HDL cholesterol,mg/dl
Fish oil	40	38	40	-0.4 (-5.2 to 4.3)	0.28	-1.7 (-6.21 to 9.69)	0.41
Diet/exercise	43	41	42	-3.86 (-8.0 to 0.2)	0.28	-2.0 (-6.97 to 3.03)	0.41
Lipoprotein A, mg/dl
Fish oil	11	8	8	-2.88 (.36.7  to 31.0)	0.41	23.37 (-21.7to 68.4)	0.33
Diet/exercise	12	10	10	30.18 (-44.9 to 105.3)	0.41	-2.34 (-32.5 to 27.8)	0.33

1.  At week 4 there was a statistically significant mean decrease in fasting TG levels in the fish oil arm compared with the mean change in the diet/exercise arm.
2. After controlling for baseline TG levels, a significant difference in the change in TG remained (P=0.001).
3. The mean absolute change in TG levels was significantly different between study arms: -138.8 mg/dl in the fish oil group compared with -25 mg/dl in the diet/exercise group (P=0.03).
4. At week 4, the mean TG levels of the fish oil group were significantly lower than those of the diet/exercise group (P=0.03).
5. The percentage of subjects who achieved a TG level of <200 mg/dl at week 4 was 39.1% in the fish oil group and 10.0% in the diet/exercise group (P=0.04).
6. At study week 16, subjects in the fish oil group continued to have a statistically significant mean reduction in TG levels since study entry, while the diet/exercise group experienced a modest mean decline in TG levels from baseline, which was not statistically different from the mean level at study entry. However, the difference between the study groups was no longer statistically significant (P=0.12).
7. There was a trend toward lower mean TG levels in fish fish oil group compared with the diet/exercise group: 304±219 mg/dl vs 513±626 mg/dl; P=0.09).
8. The difference between study groups in the percentage of subjects with TG levels of <200 mg/dl became statistically insignificant at week 16 (31.8% for the fish oil gorup vs 22.2% for the diet/exercise group; P=0.50).
9. Total and HDl-cholesterol levels and lipoprotein A levels did not change significantly from baseline in either group.
10. LDL cholesterol levels did significantly increase in the fish oil group but not in the diet/exercise group.

Assessment of glucose tolerance, insulin resistance and BMI

	Mean value			Mean % change from baseline (95% CI)
	Baseline	Week 4	Week 16	Week 4	P, baseline vs week 4 (between grps)	Week 16	P, baseline vs week 16 (between grps)
Insulin, IU
Fish oil	11	17	10	82.6 (7.2 to 157.9)	0.06	24.3 (-20.6 to 69.5)	0.35
Diet/exercise	11	10	18	6.8 (-22.0 to 35.5)	0.06	119.8 (-88.1 to 327.8)	0.35
Glucose, mg/dl*
Fish oil	107	100	103	-3.7 (-12.7 to 5.4)	0.08	-1.0 (-9.1 to 7.2)	0.19
Diet/exercise	100	110	107	11.2 (-4.3 to 26.6)	0.08	11.1 (-6.1 to 28.2)	0.19

* Determined by 2-h oral glucose tolerance test.

1. Glucose tolerance did not change significantly in either group, and there were no differences in 2-h oral glucose testing results between study groups at any point in the study.
2. Significant increase from baseline in the mean insulin level in the fish oil group at week 4 (but not at week 16), and there was a trend toward a greater increase in the mean insulin level in the fish oil group than in the diet/exercise arm.
3. In the diet/exercise arm, BMI was stable at week 4 but had declined significantly by week 16 (mean change, -0.63; P=0.04).
4. The fish oil group experienced a significant mean reduction in BMI at week 4 (mean change, -0.24; P=0.02) but not at week 16.

Adherence to fish oil therapy

1. Subjects reported high levels of adherence to study medication: 83% of subjects at week 4 and 86% of subjects at week 16 stated they had not missed a dose within the prior 4 days.

Adherence to diet

	Mean value
	Baseline	Mean change from baseline	P	Week 16	P
Total calorie intake, kcal/day
Fish oil	2053	-206	0.90	-42	>0.05
Diet/exercise	2276	-227		-392
Total fat intake, g/day
Fish oil		-12.4	0.50	9.1	0.04
Diet/exercise		-3.2		-19.1

Adherence to exercise

1. At study entry 65% of the fish oil and 69% of the diet/exercise group had very low or low levels of physical activity.
2. In the diet/exercise group, the percentage of subjects with very low or low physical activity levels dropped to 52% at week 4 and to 32% at week 16.
3. In the fish oil group, very low or low activity levels were recorded for 82% of the subjects at week 4 and for 41% at week 16.

Safety and tolerability

1. One subject in the fish oil arm discontinued therapy after 8 weeks because of new grade 2 nausea and vomiting which remitted after the fish oil was discontinued.
2. No new grade >3 signs, symptoms or laboratory abnormalities in either study group.
3. No significant change in platelet function from baseline as assessed by the platelet frunction analysis assay in either group, and no reports of increased bleeding tendency were made by any subject.

 

Other Findings

1. No reports of discontinuation or modification of HIV therapy by any subjects.
2. None of the subjects initiated nonstudy lipid-lowering therapy and no subject in the diet/exercise group reported taking fish oil supplementation during the study.

 

• Daily administration of omega-3 fatty acids combined with a diet and exercise program was safe and well tolerated and reduced fasting TG levels among HIV-infected subjects receiving antiretroviral therapy.
• Increased in LDL cholesterol levels were consistently seen in subjects assigned to the fish oil arm. Further study of the effect of omega-3 fatty acid supplementation on cholesterol subsets is warranted.
• Diet and exercise counseling alone did not lead to significant improvements in TG levels or other lipid parameters.
• Atherotech and European Reference Botanical Laboratories supplied the study medication at no charge.
• Two of the authors (Wohl, Simpson) serve on the speakers' bureaus of various pharmaceutical companies and also receive grant support from these pharmaceutical companies.

 

University/Hospital:

University of North Carolina Center for AIDS Research

Small sample size, no sample size calculation; however this was a pilot study.

Subjects were not blinded to fish oil supplementation.

Subjects self-reported adherence to fish oil treatment.