Abstract

Hypertriglyceridemia is common in antiretroviral therapy-treated patients and Omega 3 fatty acids are being used as a intervention in reducing serum triglycerides (TG) in these patients. The objective of this study is to evaluate the effectiveness of the use of Omega 3 in the treatment of hypertriglyceridemia in HIV/AIDS patients on antiretroviral therapy. This study is a systematic review with meta-analysis of randomized clinical trials. Electronic databases – PubMed, Cochrane and Lilacs were researched. Fifty one articles were encountered. Nine were added to the meta-analysis. The reduction of triglycerides level was -77.55 mg (IC of -121.85 to -33.25) in Omega 3 groups. The analysis considering trials with more than 1000 mg of EPA/DHA included seven studies and the heterogeneity dropped to 0%.The reduction of combined averages was -101.56mg (IC of -145.76 to -57.37). The analysis considering trials with patients that had more than 200 mg/dL of initial triglycerides included also seven trials and the heterogeneity dropped to 0%. The reduction of combined averages was -114.15 mg (IC of -162.34 to -65.97). EPA/DHA supplementation reduces serum triglycerides levels in patients with HIV/AIDS-associated hypertriglyceridemia in stable use of antiretroviral therapy.

HIV; HAART; Triglycerides; Omega 3 and fish oil

Resumo

A hipertrigliceridemia é comum em pacientes tratados com terapia antirretroviral e os ácidos graxos ômega 3 estão sendo usados como uma intervenção na redução triglicérides séricos (TG) nesses pacientes. O objetivo deste estudo é avaliar a eficácia do uso do ômega 3 no tratamento da hipertrigliceridemia em pacientes com HIV/Aids em terapia antirretroviral. Este estudo é uma revisão sistemática com metanálise de ensaios clínicos randomizados. As bases de dados eletrônicas – PubMed, Cochrane e Lilacs foram pesquisadas. Cinquenta e um artigos foram encontrados. Nove incluídos na metanálise. A redução do nível de triglicerídios foi -77.55 mg (IC de -121,85 a - 33,25) no grupo com Omega 3. A análise considerando ensaios com mais de 1000 mg de EPA/DHA incluiu sete estudos e a heterogeneidade caiu para 0%. A redução das médias combinada foi -101.56 mg (IC de -145,76 a -57,37). A análise considerando ensaios com doentes que tinham mais do que 200 mg/dL, de triglicéridos iniciais incluiu também sete ensaios e a heterogeneidade caiu para 0%. A redução das médias combinada foi -114.15 mg (IC de -162,34 a -65,97). A suplementação de EPA/DHA reduz níveis de triglicérides séricos em pacientes com hipertrigliceridemia associada ao HIV/AIDS em uso de terapia antirretroviral estável.

HIV; HAART; Triglicerídeos; Ômega 3 e óleo de peixe

Introduction

Highly activity antiretroviral therapy (HAART) is reducing the morbidity and mortality of HIV-infected patients. With improved prognosis, the disease’s chronic aspect started to be handled with¹1. Brazil. Ministry of Health (MoH). Health Vigilance Secretariat. Program of STD/AIDS. Recommendations on Antiretroviral Therapy in HIV Infected Adults. Brasília: MoH; 2008.,²2. Oh J, Hegele RA. HIV-associated dyslipidaemia: pathogenesis and treatment. Lancet Infect Dis 2007; 7(12):787-796.. However, treatment is associated to adverse reactions and HIV associated lipodystrophy syndrome characterized by dyslipidemia, glycemic alterations and morphologic alterations as lipoatrophy and lipohypertrophy³3. Valente AM, Reis AF, Machado DM, Succi RC, Chacra AR. Metabolic alterations in HIV-associated lipodystrophy syndrome. Arq Bras Endocrinol Metabol 2005; 49(6):871-881..

In case of dyslipidemia, when associated to HIV-infection, it occurs low HDL levels, total cholesterol and LDL increase (TC) and rise of triglycerides, conditions that favor the risk of cardiovascular disease⁴4. Montessori V, Press N, Harris M, Akagi L, Montaner JS. Adverse effects of antiretroviral therapy for HIV infection. CMAJ 2004; 170(2):229-238.,⁵5. Friis-Moller N, Sabin CA, Weber R, d’Arminio Monforte A, El-Sadr WM, Reiss P, Thiebaut R, Morfeldt L, De Wit S, Pradier C, Calvo G, Law MG, Kirk O, Phillips AN, Lundgren JD. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003; 349(21):1993-2003.. A few observational studies revealed that the incidence of cardiovascular event in HIV-infected patients on ART is higher than in the overall population⁶6. Sabin CA, d’Arminio Monforte A, Friis-Moller N, Weber R, El-Sadr WM, Reiss P, Kirk O, Mercie P, Law MG, De Wit S, Pradier C, Phillips AN, Lundgren JD. Changes over time in risk factors for cardiovascular disease and use of lipid-lowering drugs in HIV-infected individuals and impact on myocardial infarction. Clin Infect Dis 2008; 46(7):1101-1110.,⁷7. Saves M, Chene G, Ducimetiere P, Leport C, Le Moal G, Amouyel P, Arveiler D, Ruidavets JB, Reynes J, Bingham A, Raffi F. Risk factors for coronary heart disease in patients treated for human immunodeficiency virus infection compared with the general population. Clin Infect Dis 2003; 37(2):292-298..

Hypertriglyceridemia is one of the most frequent metabolic alterations in ART patients⁸8. Campanela RC FB, Lagos SL, Gavriolovics BA, Vasquez TP. Hypertriglyceridemia and antiretroviral therapy in HIV patients - clinical cases. Bol Hosp San Juan de Dios 2003; 50(1):47-51.. In a transversal study with 788 patients’ cohort, the authors identified the prevalence of 56% of hypertriglyceridemia⁹9. Samaras K, Wand H, Law M, Emery S, Cooper D, Carr A. Prevalence of metabolic syndrome in HIV-infected patients receiving highly active antiretroviral therapy using International Diabetes Foundation and Adult Treatment Panel III criteria: associations with insulin resistance, disturbed body fat compartmentalization, elevated C-reactive protein, and [corrected] hypoadiponectinemia. Diabetes Care 2007; 30(1):113-119..

It has been discussed the effect of Omega 3 fatty acids in metabolic complications in ART patients. Almeida et al., in a review, concluded that Omega 3 supplementation resulted in substantial reduction of serum triglycerides levels¹⁰10. Almeida LB, Giudici KV, Jaime PC. Dietary intake and dyslipidemia arising from combination antiretroviral therapy for HIV infection: a systematic review. Arq Bras Endocrinol Metabol 2009; 53(5):519-527.. In 2012, a new review showed that the reduction of triglycerides with Omega 3 fatty acids supplementation was the nutritional intervention that most gathered substantial scientific evidences¹¹11. Falco M, Castro Ade C, Silveira EA. Nutritional therapy in metabolic changes in individuals with HIV/AIDS. Rev Saude Publica 2012; 46(4):737-746..

In a meta-analysis published by Oliveira et al.¹²12. Oliveira JM, Rondo PH. Omega-3 fatty acids and hypertriglyceridemia in HIV-infected subjects on antiretroviral therapy: systematic review and meta-analysis. HIV Clin Trials 2011; 12(5):268-274.in 2011 with four controlled trials evaluating the use of Omega 3 fatty acids in the reduction of serum triglycerides in ART HIV-patients, it was observed a reduction of -80.34 with interval confidence of (IC of -129.08 to -31.60) in Omega-3 treated groups. In another meta-analysis where the effects of dietetic intervention in HIV dyslipidemia were analyzed it was observed a reduction of 99.11 (IC of -138.93 to -59.29) in triglycerides of the Omega 3-treated group¹³13. Stradling C, Chen YF, Russell T, Connock M, Thomas GN, Taheri S. The effects of dietary intervention on HIV dyslipidaemia: a systematic review and meta-analysis. PLoS One 2012; 7(6):e38121..

In another study of Jacobson¹⁴14. Jacobson TA. Role of n-3 fatty acids in the treatment of hypertriglyceridemia and cardiovascular disease. Am J Clin Nutr 2008; 87(6):1981S-1990S., the author discuss that the degree of TG reduction would be associated on the initial levels of triglycerides and the dose of EPA/DHA used.

There was no uniformity across clinical trials in the dosage of the supplement used, with a variation of 900 to 4000 mg/day of EPA/DHA. The same thing happens with the initial triglicerides dosage¹⁵15. Baril JG, Kovacs CM, Trottier S, Roederer G, Martel AY, Ackad N, Koulis T, Sampalis JS. Effectiveness and tolerability of oral administration of low-dose salmon oil to HIV patients with HAART-associated dyslipidemia. HIV Clin Trials 2007; 8(6):400-411.,¹⁶16. Oliveira JM, Rondo PH, Yudkin JS, Souza JM, Pereira TN, Catalani AW, Picone CM, Segurado AA. Effects of fish oil on lipid profile and other metabolic outcomes in HIV-infected patients on antiretroviral therapy: a randomized placebo-controlled trial. Int J STD AIDS 2014; 25(2):96-104..

New clinical trials were published¹⁶16. Oliveira JM, Rondo PH, Yudkin JS, Souza JM, Pereira TN, Catalani AW, Picone CM, Segurado AA. Effects of fish oil on lipid profile and other metabolic outcomes in HIV-infected patients on antiretroviral therapy: a randomized placebo-controlled trial. Int J STD AIDS 2014; 25(2):96-104.

17. Capili B, Anastasi JK. Exploratory study: evaluating the effects of fish oil and controlled diet to reduce triglyceride levels in HIV. J Assoc Nurses AIDS Care 2013; 24(3):276-282.-¹⁸18. Paranandi A, Asztalos BF, Mangili A, Kuvin J, Gerrior J, Sheehan H, Skinner SC, Tang AM, Wanke CA. Short communication: effects of omega-3 fatty acids on triglycerides and high-density lipoprotein subprofiles in HIV-infected persons with hypertriglyceridemia. AIDS Res Hum Retroviruses 2014; 30(8):800-805., and better answers are necessary to the questions mentioned above.

The aim of this study is to evaluate the effectiveness of the use of omega 3 fatty acids in the treatment of hypertriglyceridemia in HIV/AIDS patients on HAART.

Method

This study consists in a systematic review with meta-analysis of randomized clinical trials to assess the use of Omega 3 fatty acids for the treatment of hypertriglyceridemia in HIV/AIDS patients.

Studies with HIV/AIDS male and female, any ethnicity adult individuals on stable use of ARV’s with Omega 3 fatty acids-based interventions, at any dosage, compared with control group placebo and serum triglycerides as outcome were included. Studies comparing equivalence or superiority of n-3 supplement the drugs were excluded.

The research was made in electronic databases – PubMed, Cochrane Central of Clinical Trials, and Lilacs, using the terms: HIV, HAART, triglycerides, hypertriglyceridemia, Omega3 and fish oil. The searches were made between May 2013 and August 2014, and the terms were used in the follow combination, aiming to find the greatest number of studies: HIV, Hypertriglyceridemia, omega 3; HIV, Hypertriglyceridemia, fish oil; HIV, triglycerides, omega 3; HIV, triglycerides, fish oil; HAART, Hypertriglyceridemia, omega 3; HAART, Hypertriglyceridemia,fish oil; HAART, triglycerides, omega 3; HAART, triglycerides, fish oil. Articles were obtained from specific bibliographic references in manual search too. The quotes identified by the researchers were selected by two independent reviewers.

Jadad Scale¹⁹19. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17(1):1-12. was adopted to evaluate the quality of the articles comprehending the randomization (1 point to randomized plus 1 for adequate randomization), blinding (1 point to blinding plus 1 for adequate blinding) and losses (only 1 point). So the total sum of points is five and five is the better classification. However, such classification was applied only to discuss different results of each study and not to discard them.

Portions of the data were extracted independently by two reviewers.

Differences of weighted averages by the inversion of the variance of the study²⁰20. Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In: Egger M, Davey Smith G, Altman DG, editors. Systematic Reviews in Health Care : meta-analysis in context. 2nd ed. London: BMJ Books; 2001. p. 285-312. to evaluate the magnitude of the effect of the intervention and their respective intervals of confidence (IC) of 95% were used. The variable of the outcome was the final value of the triglycerides of each group. Initially, combined averages method were estimated using the fixed effects method²⁰20. Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In: Egger M, Davey Smith G, Altman DG, editors. Systematic Reviews in Health Care : meta-analysis in context. 2nd ed. London: BMJ Books; 2001. p. 285-312.. In case of heterogeneity, Dersimonian & Laird²¹21. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7(3):177-188. random effects model was used. The presence of heterogeneity was evaluated per the methods suggested by Deeks et al.²⁰20. Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In: Egger M, Davey Smith G, Altman DG, editors. Systematic Reviews in Health Care : meta-analysis in context. 2nd ed. London: BMJ Books; 2001. p. 285-312..

Initially, a graphic exploratory analysis was performed based in the visual inspection of the charts (forest-plot). Later, the chi-square test (χ²2. Oh J, Hegele RA. HIV-associated dyslipidaemia: pathogenesis and treatment. Lancet Infect Dis 2007; 7(12):787-796.) of homogeneity was calculated.

Because of the limitation of the test χ²2. Oh J, Hegele RA. HIV-associated dyslipidaemia: pathogenesis and treatment. Lancet Infect Dis 2007; 7(12):787-796., the heterogeneity was investigated as well through statistic I²2. Oh J, Hegele RA. HIV-associated dyslipidaemia: pathogenesis and treatment. Lancet Infect Dis 2007; 7(12):787-796. proposed by Higgins & Thompson²²22. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21(11):1539-1558.. Values below 30% mean mild heterogeneity, intermediate values of 30% to 50%, moderate and above 50%, an elevated level of heterogeneity.

Multivariate models of meta-regression²³23. Stern JEM. Investigating and dealing with publication and other bases. In: Smith GD. Systematic reviews in Health care. London: Book B; 2001. p. 189-208. were adjusted to investigate possible sources of heterogeneity across the studies’ results.

It was adopted the sensibility analysis to explore the robustness of the results. This analysis consists in the repetition of the procedures, excluding, for example, non-published studies and of low methodological quality.

Stata 10.0 SE²⁴24. STATACORP. Stata Statistical Software/SE. release 10. College Station: Stata-Corp LP; 2007. software was used for statistical analysis.

Results

A total of 51 articles were encountered. At Pubmed 33, Cochrane 15, Lilacs 2 and 1 article as reference of references. Of a total of 51 articles, only 9 met the eligibility criteria previously defined and were included in the meta-analysis (Figure 1).

Of the nine (9) clinical trials included in this meta-analysis with total of 448 patients, five (5)consider diet together with intervention¹⁷17. Capili B, Anastasi JK. Exploratory study: evaluating the effects of fish oil and controlled diet to reduce triglyceride levels in HIV. J Assoc Nurses AIDS Care 2013; 24(3):276-282.,²⁵25. Carter VM, Woolley I, Jolley D, Nyulasi I, Mijch A, Dart A. A randomised controlled trial of omega-3 fatty acid supplementation for the treatment of hypertriglyceridemia in HIV-infected males on highly active antiretroviral therapy. Sex Health 2006; 3(4):287-290.

26. Peters BS, Wierzbicki AS, Moyle G, Nair D, Brockmeyer N. The effect of a 12-week course of omega-3 polyunsaturated fatty acids on lipid parameters in hypertriglyceridemic adult HIV-infected patients undergoing HAART: a randomized, placebo-controlled pilot trial. Clin Ther 2012; 34(1):67-76.

27. De Truchis P, Kirstetter M, Perier A, Meunier C, Zucman D, Force G, Doll J, Katlama C, Rozenbaum W, Masson H, Gardette J, Melchior JC. Reduction in triglyceride level with N-3 polyunsaturated fatty acids in HIV-infected patients taking potent antiretroviral therapy: a randomized prospective study. J Acquir Immune Defic Syndr 2007; 44(3):278-285.-²⁸28. Wohl DA, Tien HC, Busby M, Cunningham C, Macintosh B, Napravnik S, Danan E, Donovan K, Hossenipour M, Simpson Junior RJ. Randomized study of the safety and efficacy of fish oil (omega-3 fatty acid) supplementation with dietary and exercise counseling for the treatment of antiretroviral therapy-associated hypertriglyceridemia. Clin Infect Dis 2005; 41(10):1498-1504. and one of them adopted diet and physical work out²⁸28. Wohl DA, Tien HC, Busby M, Cunningham C, Macintosh B, Napravnik S, Danan E, Donovan K, Hossenipour M, Simpson Junior RJ. Randomized study of the safety and efficacy of fish oil (omega-3 fatty acid) supplementation with dietary and exercise counseling for the treatment of antiretroviral therapy-associated hypertriglyceridemia. Clin Infect Dis 2005; 41(10):1498-1504.. The other four (4) did not address co-interventions. The result of the quality analysis according to Jadad Scale was three trials (3) with five points, three trials (3) with four points and three trials (3) with Three points.

Six studies accepted the stable use of hypolipemiants for a minimum period (prior to the beginning of the study) of 8 weeks¹⁸18. Paranandi A, Asztalos BF, Mangili A, Kuvin J, Gerrior J, Sheehan H, Skinner SC, Tang AM, Wanke CA. Short communication: effects of omega-3 fatty acids on triglycerides and high-density lipoprotein subprofiles in HIV-infected persons with hypertriglyceridemia. AIDS Res Hum Retroviruses 2014; 30(8):800-805.; 3 months¹⁵15. Baril JG, Kovacs CM, Trottier S, Roederer G, Martel AY, Ackad N, Koulis T, Sampalis JS. Effectiveness and tolerability of oral administration of low-dose salmon oil to HIV patients with HAART-associated dyslipidemia. HIV Clin Trials 2007; 8(6):400-411.,²⁹29. Thusgaard M, Christensen JH, Morn B, Andersen TS, Vige R, Arildsen H, Schmidt EB, Nielsen H. Effect of fish oil (n-3 polyunsaturated fatty acids) on plasma lipids, lipoproteins and inflammatory markers in HIV-infected patients treated with antiretroviral therapy: a randomized, double-blind, placebo-controlled study. Scand J Infect Dis 2009; 41(10):760-766.; 6 months²⁵25. Carter VM, Woolley I, Jolley D, Nyulasi I, Mijch A, Dart A. A randomised controlled trial of omega-3 fatty acid supplementation for the treatment of hypertriglyceridemia in HIV-infected males on highly active antiretroviral therapy. Sex Health 2006; 3(4):287-290.; one of them accepted the use of statin, but excluded who were on fibrates for 6 weeks before the beginning of the study²⁸28. Wohl DA, Tien HC, Busby M, Cunningham C, Macintosh B, Napravnik S, Danan E, Donovan K, Hossenipour M, Simpson Junior RJ. Randomized study of the safety and efficacy of fish oil (omega-3 fatty acid) supplementation with dietary and exercise counseling for the treatment of antiretroviral therapy-associated hypertriglyceridemia. Clin Infect Dis 2005; 41(10):1498-1504.; and on another, the use of fibrate or niacin was allowed, but the use of niacin for less or equal to 3 months prior to the beginning of the study was exclusion criteria²⁶26. Peters BS, Wierzbicki AS, Moyle G, Nair D, Brockmeyer N. The effect of a 12-week course of omega-3 polyunsaturated fatty acids on lipid parameters in hypertriglyceridemic adult HIV-infected patients undergoing HAART: a randomized, placebo-controlled pilot trial. Clin Ther 2012; 34(1):67-76.. Various TARV regimens were described, using protease inhibitors (PIs), NRTI (nucleoside analog reverse-transcriptase inhibitors) and NNRTI (non-nucleoside analog reverse-transcriptase inhibitors) in various combinations; and the stable use for a period of ≥ 2 months²⁷27. De Truchis P, Kirstetter M, Perier A, Meunier C, Zucman D, Force G, Doll J, Katlama C, Rozenbaum W, Masson H, Gardette J, Melchior JC. Reduction in triglyceride level with N-3 polyunsaturated fatty acids in HIV-infected patients taking potent antiretroviral therapy: a randomized prospective study. J Acquir Immune Defic Syndr 2007; 44(3):278-285.; ≥ 3 months¹⁶16. Oliveira JM, Rondo PH, Yudkin JS, Souza JM, Pereira TN, Catalani AW, Picone CM, Segurado AA. Effects of fish oil on lipid profile and other metabolic outcomes in HIV-infected patients on antiretroviral therapy: a randomized placebo-controlled trial. Int J STD AIDS 2014; 25(2):96-104.,¹⁸18. Paranandi A, Asztalos BF, Mangili A, Kuvin J, Gerrior J, Sheehan H, Skinner SC, Tang AM, Wanke CA. Short communication: effects of omega-3 fatty acids on triglycerides and high-density lipoprotein subprofiles in HIV-infected persons with hypertriglyceridemia. AIDS Res Hum Retroviruses 2014; 30(8):800-805.,²⁶26. Peters BS, Wierzbicki AS, Moyle G, Nair D, Brockmeyer N. The effect of a 12-week course of omega-3 polyunsaturated fatty acids on lipid parameters in hypertriglyceridemic adult HIV-infected patients undergoing HAART: a randomized, placebo-controlled pilot trial. Clin Ther 2012; 34(1):67-76.,²⁸28. Wohl DA, Tien HC, Busby M, Cunningham C, Macintosh B, Napravnik S, Danan E, Donovan K, Hossenipour M, Simpson Junior RJ. Randomized study of the safety and efficacy of fish oil (omega-3 fatty acid) supplementation with dietary and exercise counseling for the treatment of antiretroviral therapy-associated hypertriglyceridemia. Clin Infect Dis 2005; 41(10):1498-1504.,²⁹29. Thusgaard M, Christensen JH, Morn B, Andersen TS, Vige R, Arildsen H, Schmidt EB, Nielsen H. Effect of fish oil (n-3 polyunsaturated fatty acids) on plasma lipids, lipoproteins and inflammatory markers in HIV-infected patients treated with antiretroviral therapy: a randomized, double-blind, placebo-controlled study. Scand J Infect Dis 2009; 41(10):760-766.; ≥ 6 months¹⁵15. Baril JG, Kovacs CM, Trottier S, Roederer G, Martel AY, Ackad N, Koulis T, Sampalis JS. Effectiveness and tolerability of oral administration of low-dose salmon oil to HIV patients with HAART-associated dyslipidemia. HIV Clin Trials 2007; 8(6):400-411.,¹⁷17. Capili B, Anastasi JK. Exploratory study: evaluating the effects of fish oil and controlled diet to reduce triglyceride levels in HIV. J Assoc Nurses AIDS Care 2013; 24(3):276-282.,²⁵25. Carter VM, Woolley I, Jolley D, Nyulasi I, Mijch A, Dart A. A randomised controlled trial of omega-3 fatty acid supplementation for the treatment of hypertriglyceridemia in HIV-infected males on highly active antiretroviral therapy. Sex Health 2006; 3(4):287-290. was inclusion criteria.

Supplements used and dosages of EPA/DHA (eicosapentaenoic acid and docosahexaenoic acid) per day were:

Omacor® – 3360 mg²⁶26. Peters BS, Wierzbicki AS, Moyle G, Nair D, Brockmeyer N. The effect of a 12-week course of omega-3 polyunsaturated fatty acids on lipid parameters in hypertriglyceridemic adult HIV-infected patients undergoing HAART: a randomized, placebo-controlled pilot trial. Clin Ther 2012; 34(1):67-76.,²⁹29. Thusgaard M, Christensen JH, Morn B, Andersen TS, Vige R, Arildsen H, Schmidt EB, Nielsen H. Effect of fish oil (n-3 polyunsaturated fatty acids) on plasma lipids, lipoproteins and inflammatory markers in HIV-infected patients treated with antiretroviral therapy: a randomized, double-blind, placebo-controlled study. Scand J Infect Dis 2009; 41(10):760-766.;

Maxepa® – 2700 mg²⁵25. Carter VM, Woolley I, Jolley D, Nyulasi I, Mijch A, Dart A. A randomised controlled trial of omega-3 fatty acid supplementation for the treatment of hypertriglyceridemia in HIV-infected males on highly active antiretroviral therapy. Sex Health 2006; 3(4):287-290.,1800 mg²⁷27. De Truchis P, Kirstetter M, Perier A, Meunier C, Zucman D, Force G, Doll J, Katlama C, Rozenbaum W, Masson H, Gardette J, Melchior JC. Reduction in triglyceride level with N-3 polyunsaturated fatty acids in HIV-infected patients taking potent antiretroviral therapy: a randomized prospective study. J Acquir Immune Defic Syndr 2007; 44(3):278-285.;

Lovaza® – 3360 mg¹⁸18. Paranandi A, Asztalos BF, Mangili A, Kuvin J, Gerrior J, Sheehan H, Skinner SC, Tang AM, Wanke CA. Short communication: effects of omega-3 fatty acids on triglycerides and high-density lipoprotein subprofiles in HIV-infected persons with hypertriglyceridemia. AIDS Res Hum Retroviruses 2014; 30(8):800-805.;

Coromega® – 2900 mg²⁸28. Wohl DA, Tien HC, Busby M, Cunningham C, Macintosh B, Napravnik S, Danan E, Donovan K, Hossenipour M, Simpson Junior RJ. Randomized study of the safety and efficacy of fish oil (omega-3 fatty acid) supplementation with dietary and exercise counseling for the treatment of antiretroviral therapy-associated hypertriglyceridemia. Clin Infect Dis 2005; 41(10):1498-1504.;

Salmon oil – 900 mg¹⁵15. Baril JG, Kovacs CM, Trottier S, Roederer G, Martel AY, Ackad N, Koulis T, Sampalis JS. Effectiveness and tolerability of oral administration of low-dose salmon oil to HIV patients with HAART-associated dyslipidemia. HIV Clin Trials 2007; 8(6):400-411.;

Fish oil – 4000 mg¹⁷17. Capili B, Anastasi JK. Exploratory study: evaluating the effects of fish oil and controlled diet to reduce triglyceride levels in HIV. J Assoc Nurses AIDS Care 2013; 24(3):276-282., 900 mg¹⁶16. Oliveira JM, Rondo PH, Yudkin JS, Souza JM, Pereira TN, Catalani AW, Picone CM, Segurado AA. Effects of fish oil on lipid profile and other metabolic outcomes in HIV-infected patients on antiretroviral therapy: a randomized placebo-controlled trial. Int J STD AIDS 2014; 25(2):96-104.

The studies included in this revision are shown in Chart 1.

Effect of the Omega 3 fatty acids on triglycerides in individuals with HIV/AIDS associated hypertriglyceridemia

Of the studies encountered and considering those with sufficient data for calculation purposes, nine clinical trials evaluated the outcome of interest. Heterogeneity measured by I² of Higgins & Thompson²²22. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21(11):1539-1558. was 43.7%. The results of each study, their respective intervals of confidence (IC) of 95% and the summary measure are shown in Graphic 1. The reduction of combined averages through random effects was -77.55 mg/dL (IC of -121.85 to -33.25; p = 0.001), that can be interpreted as presence of significant reduction of triglycerides of the Omega 3group.

Year variables, classification of Jadad et al.¹⁹19. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17(1):1-12., EPA and DHA dosage and initial triglycerides were analyzed to evaluate heterogeneity. However, none of the variables used explained the heterogeneity.

As the AHA cardioprotective recommended dosage is approximately 1g/d and the recommended dosage to reduce triglycerides levels is 2 to 4g/d³⁰30. Kris-Etherton PM, Harris WS, Appel LJ. Omega-3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arterioscler Thromb Vasc Biol 2003; 23(2):151-152. it was performed the analysis of subgroups considering studies with more than 1000 mg of EPA/DHA. Of the nine studies included, seven used more than 1000 mg of EPA/DHA and, when these seven were analyzed, the heterogeneity measured by I² of Higgins & Thompson²²22. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21(11):1539-1558. dropped to 0%. The results of each study, their respective intervals of confidence (IC) of 95% and the summary measure are shown in Graphic 2. The reduction of combined averages through the random effects was

-101.56 mg/dL (IC of -145.76 to -57.37; p= 0.00), which can be interpreted as presence of significant reduction of triglycerides of the group that used more than 1000 mg of EPA/DHA.

Was performed the analysis of subgroups in studies with patients that had more than 200 mg/dL serum triglycerides in the beginning of the study, a value defined as elevated level of triglyceride³¹31. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285(19):2486-2497.. Of the nine studies used in this meta-analysis, seven included patients with initial average triglycerides over 200 mg/dL and when these seven were analyzed, the heterogeneity measured by I² of Higgins & Thompson²²22. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21(11):1539-1558. dropped to 0%. The results of each study, their respective intervals of confidence (IC) of 95% and the summary measure are shown in Graphic 3. The reduction of combined averages through random effects was -114.15 mg/dL

(IC from -162.34 to -65.97; p = 0.00), which can be interpreted as presence of significant reduction of triglycerides of the group with initial serum triglyceride above 200 mg/dL.

Discussion

This meta-analysis with nine studies indicated a statistically significant reduction of serum triglycerides in the Omega 3 (EPA/DHA) group when compared to control group. Similar results to the encountered in the meta-analysis of Oliveira e Stradling¹²12. Oliveira JM, Rondo PH. Omega-3 fatty acids and hypertriglyceridemia in HIV-infected subjects on antiretroviral therapy: systematic review and meta-analysis. HIV Clin Trials 2011; 12(5):268-274.,¹³13. Stradling C, Chen YF, Russell T, Connock M, Thomas GN, Taheri S. The effects of dietary intervention on HIV dyslipidaemia: a systematic review and meta-analysis. PLoS One 2012; 7(6):e38121.. The poor result of the triglycerides reduction in the present study can be explained by the inclusion of new clinical trials¹⁶16. Oliveira JM, Rondo PH, Yudkin JS, Souza JM, Pereira TN, Catalani AW, Picone CM, Segurado AA. Effects of fish oil on lipid profile and other metabolic outcomes in HIV-infected patients on antiretroviral therapy: a randomized placebo-controlled trial. Int J STD AIDS 2014; 25(2):96-104.

17. Capili B, Anastasi JK. Exploratory study: evaluating the effects of fish oil and controlled diet to reduce triglyceride levels in HIV. J Assoc Nurses AIDS Care 2013; 24(3):276-282.-¹⁸18. Paranandi A, Asztalos BF, Mangili A, Kuvin J, Gerrior J, Sheehan H, Skinner SC, Tang AM, Wanke CA. Short communication: effects of omega-3 fatty acids on triglycerides and high-density lipoprotein subprofiles in HIV-infected persons with hypertriglyceridemia. AIDS Res Hum Retroviruses 2014; 30(8):800-805. with specific characteristics discussed next. The heterogeneity encountered was considered moderate according to Higgins &Thompson²²22. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21(11):1539-1558.. Two analysis of the subgroup were conducted, the first excluding the studies that used under 1000 mg EPA/DHA day¹⁵15. Baril JG, Kovacs CM, Trottier S, Roederer G, Martel AY, Ackad N, Koulis T, Sampalis JS. Effectiveness and tolerability of oral administration of low-dose salmon oil to HIV patients with HAART-associated dyslipidemia. HIV Clin Trials 2007; 8(6):400-411.,¹⁶16. Oliveira JM, Rondo PH, Yudkin JS, Souza JM, Pereira TN, Catalani AW, Picone CM, Segurado AA. Effects of fish oil on lipid profile and other metabolic outcomes in HIV-infected patients on antiretroviral therapy: a randomized placebo-controlled trial. Int J STD AIDS 2014; 25(2):96-104. dosages and the second, excluding the studies with initial triglycerides under 200 mg/dL¹⁶16. Oliveira JM, Rondo PH, Yudkin JS, Souza JM, Pereira TN, Catalani AW, Picone CM, Segurado AA. Effects of fish oil on lipid profile and other metabolic outcomes in HIV-infected patients on antiretroviral therapy: a randomized placebo-controlled trial. Int J STD AIDS 2014; 25(2):96-104.,²⁹29. Thusgaard M, Christensen JH, Morn B, Andersen TS, Vige R, Arildsen H, Schmidt EB, Nielsen H. Effect of fish oil (n-3 polyunsaturated fatty acids) on plasma lipids, lipoproteins and inflammatory markers in HIV-infected patients treated with antiretroviral therapy: a randomized, double-blind, placebo-controlled study. Scand J Infect Dis 2009; 41(10):760-766.; in both studies, the heterogeneity was 0%.

Studies of the overall population show that there is a relation between levels of triglycerides and the percentage of reduction. Individuals with higher triglycerides have major percent of reduction of the EPA/DHA dosage used³²32. Skulas-Ray AC, Kris-Etherton PM, Harris WS, Vanden Heuvel JP, Wagner PR, West SG. Dose-response effects of omega-3 fatty acids on triglycerides, inflammation, and endothelial function in healthy persons with moderate hypertriglyceridemia. Am J Clin Nutr 2011; 93(2):243-252.. Balk et al.³³33. Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis 2006; 189(1):19-30. in a systematic review with meta-analysis verified that each raise of 1 g/d of fish oil was associated to the reduction of triglycerides levels of approximately 8 mg/dL. Additionally, each raise of 10 mg/dL in the initial levels of triglycerides is associated to a decline of 1,6 mg/dL of triglycerides after consumption of fish oil. The degree of TG reduction would be contingent, therefore, on the initial levels of triglycerides and the dose of EPA/DHA used¹⁴14. Jacobson TA. Role of n-3 fatty acids in the treatment of hypertriglyceridemia and cardiovascular disease. Am J Clin Nutr 2008; 87(6):1981S-1990S..

There was no uniformity across clinical trials in the dosage of the supplement used, with a variation of 900 to 4000 mg/day of EPA/DHA. Only two clinical trials used values below 1000mg of EPA/DHA¹⁵15. Baril JG, Kovacs CM, Trottier S, Roederer G, Martel AY, Ackad N, Koulis T, Sampalis JS. Effectiveness and tolerability of oral administration of low-dose salmon oil to HIV patients with HAART-associated dyslipidemia. HIV Clin Trials 2007; 8(6):400-411.,¹⁶16. Oliveira JM, Rondo PH, Yudkin JS, Souza JM, Pereira TN, Catalani AW, Picone CM, Segurado AA. Effects of fish oil on lipid profile and other metabolic outcomes in HIV-infected patients on antiretroviral therapy: a randomized placebo-controlled trial. Int J STD AIDS 2014; 25(2):96-104. and presented different results. Oliveira et al.¹⁶16. Oliveira JM, Rondo PH, Yudkin JS, Souza JM, Pereira TN, Catalani AW, Picone CM, Segurado AA. Effects of fish oil on lipid profile and other metabolic outcomes in HIV-infected patients on antiretroviral therapy: a randomized placebo-controlled trial. Int J STD AIDS 2014; 25(2):96-104. did not find significant reduction when compared to the control group while in the study of Baril et al.¹⁵15. Baril JG, Kovacs CM, Trottier S, Roederer G, Martel AY, Ackad N, Koulis T, Sampalis JS. Effectiveness and tolerability of oral administration of low-dose salmon oil to HIV patients with HAART-associated dyslipidemia. HIV Clin Trials 2007; 8(6):400-411. the reduction was substantial. The difference among these studies is most likely in the initial levels of triglycerides: Oliveira, under 200m/dL, and Baril, above 400mg/dL, which is the justification of Baril’s study best results.

In the present study the results were clearly better when the EPA/DHA was more than 1000mg and triglycerides was over than 200 mg/dL. This becomes clear when look at the summary measured: -77,55 (-121,85 to -33,25) all group; -101,56 (-145,76 to -57,37) >1000 mg EPA/DHA; -144,15 (-162,34 to -65,97) >200 mg/dL of triglycerides.

Other studies that also adopted the same dosage of EPA/DHA¹⁸18. Paranandi A, Asztalos BF, Mangili A, Kuvin J, Gerrior J, Sheehan H, Skinner SC, Tang AM, Wanke CA. Short communication: effects of omega-3 fatty acids on triglycerides and high-density lipoprotein subprofiles in HIV-infected persons with hypertriglyceridemia. AIDS Res Hum Retroviruses 2014; 30(8):800-805.,²⁶26. Peters BS, Wierzbicki AS, Moyle G, Nair D, Brockmeyer N. The effect of a 12-week course of omega-3 polyunsaturated fatty acids on lipid parameters in hypertriglyceridemic adult HIV-infected patients undergoing HAART: a randomized, placebo-controlled pilot trial. Clin Ther 2012; 34(1):67-76.,²⁹29. Thusgaard M, Christensen JH, Morn B, Andersen TS, Vige R, Arildsen H, Schmidt EB, Nielsen H. Effect of fish oil (n-3 polyunsaturated fatty acids) on plasma lipids, lipoproteins and inflammatory markers in HIV-infected patients treated with antiretroviral therapy: a randomized, double-blind, placebo-controlled study. Scand J Infect Dis 2009; 41(10):760-766. and that had different initial levels of TG, also presented different results. The reduction was commensurate to the initial levels of triglycerides. The higher TG, major reduction is encountered (Peters et al.²⁶26. Peters BS, Wierzbicki AS, Moyle G, Nair D, Brockmeyer N. The effect of a 12-week course of omega-3 polyunsaturated fatty acids on lipid parameters in hypertriglyceridemic adult HIV-infected patients undergoing HAART: a randomized, placebo-controlled pilot trial. Clin Ther 2012; 34(1):67-76. > 400 mg/dL, Paranandi et al.¹⁸18. Paranandi A, Asztalos BF, Mangili A, Kuvin J, Gerrior J, Sheehan H, Skinner SC, Tang AM, Wanke CA. Short communication: effects of omega-3 fatty acids on triglycerides and high-density lipoprotein subprofiles in HIV-infected persons with hypertriglyceridemia. AIDS Res Hum Retroviruses 2014; 30(8):800-805. >200 mg/dL and Thusgaard et al.²⁹29. Thusgaard M, Christensen JH, Morn B, Andersen TS, Vige R, Arildsen H, Schmidt EB, Nielsen H. Effect of fish oil (n-3 polyunsaturated fatty acids) on plasma lipids, lipoproteins and inflammatory markers in HIV-infected patients treated with antiretroviral therapy: a randomized, double-blind, placebo-controlled study. Scand J Infect Dis 2009; 41(10):760-766. < 200 mg/dL)

Our study has limitations, due to the reduced number of studies included, different dosages of Omega 3, difference of interventions associated with concomitant use of diets, use of hypolimiants, further to initial TG levels and differences of TARV regimen. Among them, it is possible to single out the absence of non-published studies, the impossibility of evaluating the existence of bias of publication due to the small number of studies included and heterogeneity.

The recommendations for the treatment of dyslipidemia, including HIV-patients hypertriglyceridemia, are the same for the overall population. The guidelines of IDSA (Infectious Disease Society of America)³⁴34. Dube MP, Stein JH, Aberg JA, Fichtenbaum CJ, Gerber JG, Tashima KT, Henry WK, Currier JS, Sprecher D, Glesby MJ. Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis 2003; 37(5):613-627. and ACTG (Adult AIDS Clinical Trial Group)³⁵35. Aberg JA, Gallant JE, Ghanem KG, Emmanuel P, Zingman BS, Horberg MA, Infectious Diseases Society of A. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the Infectious Diseases Society of America. Clin Infect Dis 2013; 58(1):e1-34. follow the recommendations of NCEP ATPIII³¹31. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285(19):2486-2497.. EACS (European AIDS Clinical Society)³⁶36. Lundgren JD, Battegay M, Behrens G, De Wit S, Guaraldi G, Katlama C, Martinez E, Nair D, Powderly WG, Reiss P, Sutinen J, Vigano A. European AIDS Clinical Society (EACS) guidelines on the prevention and management of metabolic diseases in HIV. HIV Med 2008; 9(2):72-81. guidelines recommend healthy diet, work out and weight control to reduce dyslipidemia and among the drugs recommended for dyslipidemia management, it appears Omega 3 with dosage indication, Maxepa® 5g 2x/d(3000 mg EPA/DHA) and Omacor® 1g to 2g 2x/d (1680 mg to 3360 mg EPA/DHA) to reduce TG.

Publications about dyslipidemia management for HIV mention fish oil (supplement of EPA/DHA) as a safe and alternative treatment to reduce serum TG because it is well tolerated and does not present drug interactions with antiretroviral therapy³⁷37. Aberg JA. Lipid management in patients who have HIV and are receiving HIV therapy. Endocrinol Metab Clin North Am 2009; 38(1):207-222.

38. Stein JH. Dyslipidemia in the era of HIV protease inhibitors. Prog Cardiovasc Dis 2003; 45(4):293-304.-³⁹39. Blanco F, San Roman J, Vispo E, Lopez M, Salto A, Abad V, Soriano V. Management of metabolic complications and cardiovascular risk in HIV-infected patients. AIDS Rev 2010; 12(4):231-241..Recommended dosage vary from 2 to 9g/d and the supplements are indicated some times as fish oil, others as Omega 3 fatty acids and others as EPA/DHA³⁷37. Aberg JA. Lipid management in patients who have HIV and are receiving HIV therapy. Endocrinol Metab Clin North Am 2009; 38(1):207-222.,³⁸38. Stein JH. Dyslipidemia in the era of HIV protease inhibitors. Prog Cardiovasc Dis 2003; 45(4):293-304.,⁴⁰40. Wohl DA, McComsey G, Tebas P, Brown TT, Glesby MJ, Reeds D, Shikuma C, Mulligan K, Dube M, Wininger D, Huang J, Revuelta M, Currier J, Swindells S, Fichtenbaum C, Basar M, Tungsiripat M, Meyer W, Weihe J, Wanke C. Current concepts in the diagnosis and management of metabolic complications of HIV infection and its therapy. Clin Infect Dis 2006; 43(5):645-653.

41. Silva EFR, Barbaro G. New options in the treatment of lipid disorders in HIV-infected patients. Open AIDS J. 2009; 3:31-37.-⁴²42. Feeney ER, Mallon PW. HIV and HAART-Associated Dyslipidemia. Open Cardiovasc Med J 2011; 5:49-63..

Fish oil is a source of Omega 3 fatty acid containing EPA/DHA. And 1g of fish oil (or Omega 3) is not necessarily equal to 1 g of EPA/DHA, it will depend on the prescribed formulation. For this reason, the selection of supplement with bigger concentration of EPA/DHA is essential to reduce the quantity of required pills to get an effective result, thus improving the adherence to the treatment.

To achieve the dosage recommended by the AHA cardioprotective approximately 1g/day of EPA/DHA need to ingest ≈ 71g of salmon, 71-340 g of tuna, 57g of herring, 354 of cod daily⁴³43. Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002; 106(21):2747-2757.. The recommendation for the reduction of TG is 2 to 4 g/of which prevents the use of fish consumption for this purpose.

In two studies⁴⁴44. Manfredi R. Management of hypertriglyceridaemia caused by combination antiretroviral therapy in HIV-infected patients: role of omega-3 polyunsaturated fatty acids at different dosages, compared with fibrates. Int J STD AIDS 2010; 21(1):73-74.,⁴⁵45. Manfredi R, Calza L, Chiodo F. Polyunsaturated ethyl esters of n-3 fatty acids in HIV-infected patients with moderate hypertriglyceridemia: comparison with dietary and lifestyle changes, and fibrate therapy. J Acquir Immune Defic Syndr 2004; 36(3):878-880. comparing the use of Omega 3 and fibrates to reduce TG in HIV patients, the authors conclude that the reduction with fibrates is bigger, but it occurs also with Omega3 (n-3 polynsaturated fatty acids-PUFA, polyunsaturated ethyl esters of n-3 fatty acids- PEE) showing improved tolerability, and this may potentially mean an effective and safe alternative to fibrates.

In another study⁴⁶46. Gerber JG, Kitch DW, Fichtenbaum CJ, Zackin RA, Charles S, Hogg E, Acosta EP, Connick E, Wohl D, Kojic EM, Benson CA, Aberg JA. Fish oil and fenofibrate for the treatment of hypertriglyceridemia in HIV-infected subjects on antiretroviral therapy: results of ACTG A5186. J Acquir Immune Defic Syndr 2008; 47(4):459-466. evaluating the associated use of fish oil supplement with fenofibrate, which initially separated the patients received treatment for 8 weeks and those who did not respond to treatment, received combination therapy for 10 weeks. In the group receiving fish oil only TG was reduced by 46%, as received fenofibrate was 58% and that received combination therapy reduction was 65.5%, concluding that the fish oil alone or combined the fenofibrate is safe and significantly reduces TG levels in HIV patients with hypertriglyceridemia and that the combination therapy is effective for those who do not respond to therapy alone.

EPA/DHA dosage to reduce TG needs more trials. As there exists a relation between the initial TG and EPA/DHA dosage in the effective reduction, the following questions need to be responded: Will initial high TG respond better to a lower EPA/DHA dosage? And even why not ask whether, depending on the case, would it be interesting to attempt initially only with EPA and DHA prior to prescribing fibrate in specific cases, as we are dealing with patients using multiple medicines daily?

Conclusions

The findings of this study led to the conclusion that supplementation with EPA/DHA in 900 to 4,000 mg/day dosages reduce the serum levels of triglycerides in HIV/AIDS associated hypertriglyceridemia patients in stable use of antiretroviral therapy.

Supplementation with EPA/DHA promotes better responses in individuals with higher triglyceride and when offered in higher doses than 1000 mg/day.

Other clinical trials to attempt to determine EP/DHA dosages in different scenarios to promote the reduction of TG are necessary, considering the relation of initial TG and EPA/DHA dosage.

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