EAL

H/A: Hyperlipidemia (2009)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

A pilot study was conducted to determine the safety, tolerability and efficacy of omega-3 fatty acid supplementation in HIV-infected patients with hypertriglyceridemia who were receiving combination antiretroviral therapy.

Inclusion Criteria:

HIV-infected adults who had eught-hour fasting serum TG levels of more than 200mg per dL and had been receiving at least three antiretrovirals for more than or equal to three months
Patients receiving stable statin therapy were eligible.

Exclusion Criteria:

Subjects were excluded if they had diabetes mellitus or heart disease with an American Heart Association classification of class I or greater
Patients who had taken fibrates within six weeks prior to study entry were excluded.

Description of Study Protocol:

Recruitment

Subjects recruited from the University of North Carolina Infectious Diseases Clinic
Methods not specified
Open-label.

Design

Randomized controlled trial; subjects were assigned to one of two intervention groups: Diet and exercise arm and fish oil arm.

Intervention

Group 1: Diet and exercise arm, all subjects regardless of treatment received diet and exercise counseling from a research assistant in accordance with AHA recommendations; then upon group assignment, the nutritionist met with each participant one-on one at entry and week four for 30 to 45 minutes, where a diet and exercise plan devised and renewed
Group 2: The fish oil arm received, in addition to the standard diet and exercise counseling program, a 16-week course of omega-3 fatty acid supplementation consisting of 1,750mg EPA and 1,150mg DHA taken with food.

Statistical Analysis

Paired student's T-test was used for comparing changes from baseline in lipid values, platelet function assay results and weight
Wilcoxon rank sum test was used to analyze the absolute change in TG levels
Descriptive statistics.

Data Collection Summary:

Timing of Measurements

Baseline (entry), weeks four and 16 after randomization.

Dependent Variables

Triglyceride levels, total and HDL cholesterol levels, direct LDL-C and lipoprotein A levels. Cholesterol levels were determined using VAP test.
Oral glucose tolerance test
Platelet function analysis
Weight changes.

Independent Variables

Fish oil supplementation
Diet and exercise
Concomitant medications and supplements taken were recorded
Adherence to study medication was assessed using the AIDS clinical trials group self-reported adherence measure.

Control Variables

Standard diet using a three-day food record or 24-hour recall if food record was absent
Exercise: Self assessment using Lipid Research clinic questionnaire.

Description of Actual Data Sample:

Initial N

52 participants enrolled (47 males, five females).

Attrition (Final N)

By week four: N=44 (85%); six participants from the diet and exercise group left due to assignment, two from the fish arm left due to discomfort and were lost to follow-up
By week 16; N= 41 (79%); one from diet and exercise group and two from fish oil left due to toxicity, after taste and relocation.

Age

Mean: 42.0 years for the fish oil group
Mean: 45.3 years for the diet and exercise.

Ethnicity

28 Non-white race
24 white race.

Other Relevant Demographics

CD4 levels
Antiretroviral therapy

Anthropometrics

BMI: Mean 27.4kg/m² for fish oil group; 27.2 kg/m² for the diet and exercise group
There were no statistically significant differences between groups at baseline.

Location

University of North Carolina Infectious Diseases Clinic.

Summary of Results:

Variables

Treatment Group (Fish Oil)

Measures and Confidence Intervals

Control Froup (Diet and Exercise)

Measures and Confidence Intervals

Statistical Significance of Group Difference

Mean TG levels

Week four

Week 16

306mg per dL

Mean change from baseline = -25.1%; (95% CI = -34.6% to -15.7%)

304mg per dL; change = -19.5%; CI = -34.9 to -4.0%

403mg per dL

Mean change from baseline = +2.8% 95% CI = -17.5% to 23.1%)

513mg per dL; change = -5.7% CI = -24.6% to 13.2%

Difference in change between groups:

P=0.0074

P=0.12

Absolute change in TG

-138mg per dL

-25mg per dL

P=0.03

Other Findings

Total and HDL cholesterol as well as lipoprotein A levels did not change significantly from baseline in either group
LDL-C levels increased significantly in the fish oil group, but not in the diet and exercise group
Glucose tolerance did not seem to change significantly in either group and there were no differences in two-hour oral glucose testing results between study groups at any point in the study
A significant increase from baseline in mean insulin level was observed in the fish oil group at week four, but not week 16, and there was a trend toward greater increase in the mean insulin level in the fish oil group than in the diet and exercise group (P=0.06)
In the diet and exercise group, BMI was stable at week four but declined significantly by week 16 (mean change = -0.63; P=0.04). In contrast, the fish oil group experienced a significant mean reduction in BMI at week four (mean change = -0.24; P=0.02), but not at week 16.
Subjects reported high levels of adherence to study medication: 83% of subjects at week four and 86% at week 16 did not miss a dose within four days prior.
At baseline, total mean calorie intake for the diet and exercise group was 2,276kcal per day and 2,053kcal per day for fish oil group; calorie intake declined in both groups at week four (mean change = -227kcal per day vs. -206kcal per day (P=0.90) ; at week 16, change = -392kcal per day vs. -42kcal per day; P>0.05)
Total fat intake also declined: Week four = -3.2g per day (diet and exercise) and -12.4g per day in fish group; (P=0.50). At week 16, fat intake decreased in diet and exercise group (mean change = -19.1g per day) and increased in fish oil group (mean change = +9.1g per day; P=0.04).
Changes in low physical activity levels: At baseline, 69% of diet and exercise group and 65% of fish oil group have very low or low levels of PA. The percentage of particpants in the diet and exercise group with low or very low PA levels declined to 52% at week four to 32% in week 16. In the fish oil group, PA levels were recorded at 82% week four and 41% for week 16.
Fish oil was well tolerated.

Author Conclusion:

Found that daily administration of omega-3 fatty acids combined with diet and exercise program was safe and well-tolerated and reduced fasting TG levels among HIV-infected patients receiving antiretroviral therapy
Unexpectedly, increases in LDL cholesterol levels were consistently seen in patients assigned to the fish oil group
Further study of the effect of omega-3 fatty acid supplementation on cholesterol subsets is warranted in light of the increases observed in LDL-C
Diet and counseling alone did not lead to significant improvements in TG levels or other lipid parameters
Given the benefits of omega-3 fatty acid in reducing CVD risk in HIV-uninfected populations and the increasing concern regarding cardiovascular complications of antiretroviral therapy, expanded study of omega-3 fatty acid supplementation in the treatment of HIV-infected indiviudals with hypertriglyceridemia is justified.

Funding Source:

University/Hospital:	University of North Carolina
Other:	Lab support provided by UNC general Research Center (RR00046)

Reviewer Comments:

Although this study was a pilot study, it was well designed and executed. Attrition at 16 months was moderately strong (79%), which could have impacted the significance of outcomes.
Main concern is the issue of blinding: At week four, six participants dropped out because they were not on the fish oil treatment group; to me, that is significant and should indicate to the authors that blinding especially between groups is highly necessary
More research is needed to address the increase found in LDL with the treatment group
Maybe statistics accounting for confounders may provide answers with a larger sample.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	No
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	No
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		No
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	No
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	No
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	Yes
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	???
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	No
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		No
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	No
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	No
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes