A pilot study of the safety and efficacy of cholestin in treating HIV-related dyslipidemia

NURSES COLUMN

Editor: Leocadia Varella, RN, MSN, CNSN, ANP

A Pilot Study of the Safety and Efficacy of Cholestin in Treating HIV-Related Dyslipidemia Joyce K. Keithley, DNSc, RN, Barbara Swanson, DNSc, RN, Beverly E. Sha, MD, Janice M. Zeller, PhD, RN, Harold A. Kessler, MD, and Kimberly Y. Smith, MD From the Rush University College of Nursing, the Clinic for Infectious Diseases, RushPresbyterian-St. Luke’s Medical Center, and the Department of Immunology/ Microbiology, Rush University College of Medicine, Chicago, Illinois, USA OBJECTIVE: We collected preliminary safety and efficacy data on the effects of Cholestin, a statincontaining dietary supplement, in individuals with dsylipidemia related to human immunodeficiency virus. METHODS: Fourteen adults with dsylipidemia related to human immunodeficiency virus characterized by hypercholesterolemia, hypertriacylglycerolemia, or both participated in a randomized, double-blind, placebo-controlled pilot study in an infectious disease clinic based in an academic medical center. Participants were randomly assigned to receive 1.2 g of Cholestin twice daily (n ⫽ 7) or placebo (n ⫽ 7) for 8 wk. The main outcome measures were safety (hepatic function tests, plasma human immunodeficiency virus-1 RNA levels, CD4⫹ cell counts, adverse effects) and efficacy (fasting serum cholesterol: total, high- and low-density lipoproteins, and fasting serum triacylglycerols). Safety and efficacy outcomes were evaluated at 2- and 8-wk intervals. RESULTS: Twelve participants (n ⫽ 6 per group) completed the 8-wk treatment protocol. After 8 wk of treatment with Cholestin, there were significant declines from baseline in mean (⫾ standard error of the mean) fasting total cholesterol (⫺30.8 ⫾ 8.8 versus 7.7 ⫾ 5.6; P ⫽ 0.01) and low-density lipoprotein cholesterol (⫺32.2 ⫾ 7.2 versus 26.3 ⫾ 14.2; P ⫽ 0.01) versus placebo. Moreover, the decline in fasting total cholesterol was significant (⫺40.2 ⫾ 4.8 versus 2.8 ⫾ 11.9; P ⫽ 0.006) after 2 wk of therapy, at which time the low-density lipoprotein cholesterol approached significance (⫺30.2 ⫾ 7.4 versus 4.4 ⫾ 15.2; P ⫽ 0.068). High-density lipoprotein cholesterol and triacylglycerol levels did not change at either time point. No adverse effects were seen with Cholestin. CONCLUSIONS: Cholestin may safely lower total and low-density lipoprotein cholesterol in patients with dsylipidemia related to human immunodeficiency virus. Larger and longer-term trials of this approach are warranted. Nutrition 2002;18:201–204. ©Elsevier Science Inc. 2002 KEY WORDS: dyslipidemia, Cholestin, dietary supplement, safety, efficacy

INTRODUCTION Human immunodeficiency virus (HIV) infection and its treatment are associated with a number of adverse effects. One adverse effect of considerable concern is HIVrelated dyslipidemia. HIV-related dyslipidemia is characterized by elevations in serum triacylglycerols and total and low-density lipoprotein (LDL) cholesterol and/or a reduction in high-density lipoprotein (HDL) cholesterol.1– 6 The exact prevalence of dyslipidemia in individuals with HIV infection is unknown, but estimates range from 5% to 58%.2,7–9 Greater elevations in triacylglycerols and cholesterols are reported in pro-

This study was supported by the Rush University College of Nursing Research Fund.

tease inhibitor recipients than in nonprotease inhibitor recipients.10 –12 Several recent reports have suggested that cardiovascular abnormalities and events are increased in patients with HIV-related dyslipidemia.8,13–16 A few preliminary studies have indicated that lipid-lowering drugs, such as statins and fibrates, may be partly efficacious in normalizing serum lipid levels,17–21 but they are expensive and can have serious adverse effects.22–25 Therefore, we conducted an 8-wk, randomized, doubleblind, placebo-controlled pilot study to assess the safety and efficacy of Cholestin, a statin-containing dietary supplement, in patients with HIV-related dyslipidemia.

METHODS Study Population

Correspondence to: Joyce K. Keithley, DNSc, RN, Professor, Adult Health Nursing, Rush University College of Nursing, 600 South Paulina, Suite 1080 AAC, Chicago, IL 60612, USA. E-mail: [email protected]

Participants were recruited from the Infectious Disease Clinic at Rush-PresbyterianSt. Luke’s Medical Center in Chicago between February and July 2000. They were

Nutrition 18:201–204, 2002 ©Elsevier Science Inc., 2002. Printed in the United States. All rights reserved.

eligible for the study if they met the following inclusion criteria: documented HIV-1 infection; between 18 and 60 y of age; plasma HIV RNA less than 10 000 copies/mL and CD4⫹ cell counts greater than 200 cells/mm3 within the prior 2 mo; stable antiretroviral regimen for the past 2 mo; and fasting total cholesterol level greater than 200 mg/dL, fasting LDL cholesterol level greater than 130 mg/dL, and/or fasting triacylglycerol level greater than 135 mg/dL. Persons were excluded if they had histories of renal impairment (serum creatinine ⬎ l.3 mg/dL) or liver impairment (aspartate aminotransferase and/or alanine aminotransferase ⬎ three times upper limit of normal); histories of cardiovascular disease or metabolic or endocrine conditions that influence lipid levels (e.g., diabetes mellitus, Cushing’s syndrome); use of antilipid medications, appetite stimulants, anabolic steroids, glucocorticoids, growth hormone, cyclosporine, or erythromycin within the past 2 mo; substance abuse within past 6 mo; histories of sensitivity to statins; opportunistic infection, malignancy, 0899-9007/02/$22.00 PII S0899-9007(01)00688-8

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Nutrition Volume 18, Number 2, 2002 TABLE I. BASELINE CLINICAL CHARACTERISTICS AND MEAN CHANGES AT 8 WK* Baseline

Age (y) Male/female CD4 count (cells/mm3) Viral load (copies/mL) Albumin (g/dL) Total bilirubin (mg/mL) Direct bilirubin (mg/mL) Alkaline phosphatase (␮L) Aspartate aminotransferase (␮L) Alanine aminotransferase (␮L) Weight (lb) Body mass index Activity score

Mean change from baseline at 8 wk

Placebo (n ⫽ 6)

Cholestin (n ⫽ 6)

Placebo (n ⫽ 6)

44.2 (2.8) 5/1 559 (63) 994.5 (487.2) 3.8 (0.2) 0.62 (3.1) 0.32 (6.0) 102.5 (11.6) 29.8 (2.3) 37.3 (7.2) 175.3 (16.5) 25.2 (1.6) 1.5 (0.2)

40.8 (3.6) 4/2 547 (84) 50.3 (36.2) 4.0 (0.2) 0.63 (0.1) 0.37 (8.8) 78 (7.1) 27.8 (2.9) 25.5 (6.9) 184.2 (14.0) 27.4 (2.1) 1.7 (0.2)

NA NA ⫺75.5 (30.3) 2023.0 (1665.8) 0.3 (0.1) ⫺0.007 (4.5) ⫺0.015 (5.9) ⫺3.5 (7.4) ⫺4.3 (3.1) ⫺10.0 (7.4) 1.5 (3.8) 25.5 (1.6) 1.5 (0.2)

Cholestin (n ⫽ 6) NA NA 104.0 (99.0) 412.2 (252.6) ⫺0.2 (0.2) ⫺0.017 (0.1) ⫺0.033 (3.3) 0.83 (3.0) 3.5 (4.0) 7.4 (10.3) ⫺0.5 (1.1) 27.3 (2.1) 1.7 (0.2)

P

0.08 0.62 0.08 0.94 1.0 0.34 0.15 0.39 0.69 0.52 0.58

* Data are unadjusted mean (standard error of the mean). NA, not applicable.

or surgery within past 2 mo; body mass index higher than 36; or pregnancy. Procedures The study was approved by the Institutional Review Board at Rush-Presbyterian-St. Luke’s Medical Center, and all participants gave written informed consent before enrollment into the study. Participants were randomly assigned to receive Cholestin (1.2 g orally twice per day) or placebo for 8 wk. All investigators and participants were blinded to treatment assignment. Participants were followed prospectively for 8 wk, with study visits scheduled at baseline, 2 wk, and 8 wk. Fasting serum lipids (total cholesterol, LDL cholesterol, HDL cholesterol, triacylglycerols), liver function tests (albumin, total bilirubin, direct bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase), HIV-1 RNA, and CD4⫹ cell counts were measured at baseline and at 2-wk and 8-wk follow-up visits. All laboratory analyses were performed by the Clinical Hematology and Immunology Laboratories at Rush-Presbyterian-St. Luke’s Medical Center using established procedures. Fasting specimens were obtained after an 8-h overnight fast. Height was measured at baseline, and weight was measured at each study visit using standardized procedures. Physical activity level was determined from the Lipid Research Clinics Physical Activity Questionnaire26 at baseline and study completion. Physical activity was scored as active (reporting any strenuous activity ⫽ 1) or inactive (reporting no strenuous activity ⫽ 2).

Participants were instructed to return unused study medications, and percentage of adherence was calculated. At the 2- and 8-wk follow-up visits, participants were asked about the occurrence of any adverse effects since the previous visit. The primary efficacy outcome was normalization of fasting serum lipid levels. The safety outcomes were significant changes in plasma HIV RNA, CD4⫹ cell counts, and liver function tests from baseline and the occurrence of adverse effects. Statistical Analysis Statistical analyses were performed using SPSS for Windows (version 10), and statistical significance was defined as P ⬍ 0.05. The groups’ baseline clinical characteristics were compared by t tests and chi-square tests. Group differences at 2- and 8-wk were analyzed using independent-sample Wilcoxon tests.

RESULTS Of the 44 persons screened, 14 met eligibility criteria and were enrolled in the study (Cholestin, n ⫽ 7; placebo, n ⫽ 7). One participant (Cholestin group) was withdrawn from the study upon request, and one participant (placebo group) was lost to follow-up. Data are reported for the 12 participants who completed the study. At baseline and at 8-wk, the two groups did not differ significantly with respect to clinical characteristics (Table I). Participants were on stable antiretroviral regimens throughout the 8-wk study period. All participants except one

were taking at least one nucleoside reverse transcriptase inhibitor; 6 of 12 participants were receiving a regimen containing a protease inhibitor; and 4 of 12 participants were receiving a regimen containing a non– nucleoside reverse transcriptase inhibitor. Two participants were on antihypertensive therapy. All participants took at least 95% of the recommended number of placebo or Cholestin capsules (data not shown) during the 8-wk period. The two groups had similar fasting lipid levels at baseline, with the Cholestin group having slightly higher values in all categories (Table II). As compared with placebo, Cholestin therapy was associated with significant mean (⫾ standard error of the mean) reductions in fasting total cholesterol (⫺30.8 ⫾ 8.8 versus 7.7 ⫾ 5.6; P ⫽ 0.01) and LDL cholesterol (⫺32.2 ⫾ 7.2 versus 26.3 ⫾ 14.2; P ⫽ 0.01) after 8 wk of treatment. These reductions in fasting total cholesterol and LDL cholesterol represent a decrease from baseline of 12% and 23%, respectively. In addition, a significant decline in fasting total cholesterol was found after 2 wk of Cholestin therapy (⫺40.2 ⫾ 4.8 versus 2.8 ⫾ 11.9; P ⫽ 0.006) and, at this time, LDL cholesterol approached significance (⫺30.2 ⫾ 7.4 versus 4.4 ⫾ 15.2; P ⫽ 0.068). There was no significant effect of Cholestin on fasting triacylglycerols or HDL cholesterol. Further, Cholestin did not adversely affect CD4⫹ cell counts, HIV viral load, or liver function tests (albumin, total bilirubin, direct bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase; Table I). Cholestin therapy was well tolerated, and no patients discontinued the study because of adverse effects.

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TABLE II. BASELINE FASTING LIPID LEVELS AND MEAN CHANGES AT 2 AND 8 WK* Baseline

Cholesterol (mg/dL) LDL-C (mg/dL)† HDL-C (mg/dL) Triacylglycerols (mg/dL)

Mean change from baseline at 2 wk

Mean change from baseline at 8 wk

Placebo (n ⫽ 6)

Cholestin (n ⫽ 6)

Placebo (n ⫽ 6)

Cholestin (n ⫽ 6)

P

Placebo (n ⫽ 6)

Cholestin (n ⫽ 6)

P

189.8 (20.7) 104.7 (16.7) 42.2 (12.0) 272.3 (55.1)

229.5 (18.1) 139.2 (12.0) 54.0 (8.6) 324.2 (218.8)

2.8 (11.9) 4.4 (15.2) 1.4 (1.9) ⫺45.8 (60.9)

⫺40.2 (4.8) ⫺30.2 (7.4) ⫺2.0 (3.6) ⫺182.7 (175.3)

0.006 0.068 0.520 0.873

7.7 (5.6) 26.3 (14.2) ⫺7.3 (8.6) 9.2 (21.2)

⫺30.8 (8.8) ⫺32.2 (7.2) 0.17 (3.7) ⫺139.0 (167.4)

0.010 0.014 0.747 0.873

* Data are unadjusted mean (standard error of the mean). † LDL-C data not available for triacylglycerol levels above 400 mg/dL (n ⫽ 2 for placebo; n ⫽ 1 for Cholestin). HDL-C ⫽ high-density lipoprotein cholesterol; LDL-C ⫽ low-density lipoprotein cholesterol.

DISCUSSION The results of this study indicate that Cholestin, a dietary supplement that is available over the counter, has the potential to reduce selected lipid parameters in HIV-related dyslipidemia. Compared with placebo, treatment with Cholestin resulted in significant decreases in fasting total and LDL cholesterol levels. Cholestin also was well tolerated and not associated with changes in CD4⫹ cell counts, viral load, or hepatic function. To our knowledge, the current study is the first randomized, placebo-controlled trial to examine the safety and efficacy of Cholestin in treating HIV-related dyslipidemia. Cholestin (Pharmanex, LLC, Provo, UT) is a proprietary form of Monascus purpureus Went yeast fermented on rice, a traditional Chinese health food. Cholestin is manufactured by growing a single strand of Monascus purpureus on rice under carefully controlled conditions that increase the statin content.27 The statin composition of Cholestin is 0.4% by weight. Approximately 75% of these statins are lovastatin, either in the prodrug lactone form or the active hydroxyacid form.28 The Cholestin dosage used in this study (2.4 g/d) delivered approximately 5 mg of lovastatin per day.27 In previous studies of non–HIV-infected persons,28 –30 an 8-wk course of this dosage was shown to lower lipids to levels that were comparable to levels acheived with dosages of lovastatin ranging from 20 to 80 mg/d.31 This suggests that the other statin, and possibly non-statin (unsaturated fatty acids, natural compounds), components of Cholestin contribute to its lipid-lowering effects.28 Data pertaining to the efficacy of Cholestin in individuals with HIV infection are not available. Three recent clinical trials, however, have documented the beneficial effects of Cholestin in non–HIV-infected individuals. In a placebo-controlled, randomized trial, Heber et al.28 found that 12 wk of Cholestin supplementation (2.4 g/d) lowered total cholesterol (P ⬍ 0.001) in 83

men and women with elevated LDL cholesterol concentrations. Cholestin also reduced LDL cholesterol and triacylglycerols but did not significantly change HDL cholesterol. Qin et al.,29 in a placebo-controlled, randomized trial of 70 elderly patients with primary hyperlipidemia, found that an 8-wk course of Cholestin (1.2 g/d) significantly reduced serum total cholesterol by 25.9% and LDL cholesterol by 32.8% (both P ⬍ 0.001) and lowered triacylglycerols by 19.9% (P ⫽ 0.02). Rippe et al.30 evaluated an 8-wk course of Cholestin (2.4 g/d) in 187 subjects with mildly to moderately elevated levels of cholesterol (mean ⫽ 242 mg/dL). Levels of total cholesterol were reduced by 16.4%, LDL cholesterol by 21.0%, and triacylglycerols by 24.5%; and levels of HDL cholesterol were increased by 14.6% when compared with the placebo group. Consistent with these studies, we found that Cholestin significantly or substantially reduced total and LDL cholesterol after an 8-wk course of therapy. In contrast, we did not find an improvement in HDL cholesterol as reported by Rippe et al.,30 nor did we find significant or substantial reductions in triacylglycerol levels, as reported in each of these studies. Safety data are not available for Cholestin in HIV disease. In the study by Rippe et al.,30 the incidence of Cholestin-associated adverse reactions was 18%. These reactions included headache, abdominal bloating, and gas. No or few adverse effects were reported in the studies by Heber et al.28 and Qin et al.29 In addition, in clinical trials involving thousands of participants, Cholestin was not associated with clinically significant changes in tests of kidney and liver function, whereas only a few case reports of mild gastrointestinal discomfort were reported.32 Because many of the antilipid agents compete with HIV medications for metabolism via cytochrome P450 enzyme 3A4,24 there is concern about increased risk for adverse reactions, such as myopathy or rhabdomyolysis. Our data suggest that Cho-

lestin is safe and well tolerated in patients with HIV-related dyslipidemia. CD4⫹ cell counts, viral load, and liver function tests remained stable throughout the 8-wk treatment period. The results of this pilot study must be interpreted with caution due to several study limitations such as small sample size, strict eligibility criteria that excluded participants with known liver or renal disease, and short treatment interval. Despite these limitations, Cholestin shows promise as a more natural, less toxic strategy to manage HIV-related dyslipidemia. Long-term studies are necessary to definitively determine the safety and efficacy of Cholestin. Although cholestin is no longer available in the US, it is available in Canada, Europe, and Asia.

ACKNOWLEDGMENTS The authors are grateful to Pharmanex, LLC, (Provo, Utah, USA) for donating the Cholestin and placebo capsules used in the study.

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