A pilot study to determine the impact on dyslipidemia of adding tenofovir to stable background antiretroviral therapy: ACTG 5206

Several studies have reported improvement in lipids after antiretroviral therapy switches to tenofovir disoproxil fumarate (TDF)-containing regimens. We assessed lipid-lowering effects of TDF by adding it to a stable antiretroviral therapy regimen in this double-blind, placebo-controlled crossover study. We demonstrated that nonhigh-density lipoprotein cholesterol, low-density lipoprotein cholestrol, and total cholestrol improved significantly over TDF vs. placebo treatment in HIV-infected individuals with dyslipidemia. Adding TDF to stable, virologically suppressive antiretroviral therapy regimens improved lipid parameters, supporting a lipid-lowering effect of TDF.

Coronary heart disease (CHD) and dyslipidemia have been associated with antiretroviral therapy (ART) and HIV itself in addition to traditional risk factors ^[1–4]. Current guidelines advocate managing dyslipidemia in HIV-infected individuals similar to the general population ^[5,6]. However, these recommendations often do not achieve lipid-lowering goals in HIV-infected individuals ^[7]. Antiretroviral guidelines advocate selecting regimens with less adverse lipid effects as one approach to modifying CHD risk ^[8].

Prior studies ^[9–13] demonstrated that switching from other antiretroviral agents to tenofovir (TDF) improved most lipid parameters. However, these improvements may be owing to withdrawal of the offending agent or from TDF itself. Therefore, we designed a prospective study to evaluate the specific effect of TDF on lipids by adding TDF to a fully virologically suppressive antiretroviral regimen.

AIDS Clinical Trials Group (ACTG) A5206 was a double-blind, randomized, placebo-controlled, crossover pilot study. The Institutional Review Boards of all participating institutions approved the protocol. All individuals provided informed consent.

Inclusion criteria: HIV-infected individuals who are at least 18 years old, dyslipidemia (fasting triglycerides ≥150 and <1000 mg/dl or nonhigh-density lipoprotein cholesterol (HDL-C) ≥100 and <250 mg/dl), virologically suppressed (HIV-1 RNA <400 copies/ml) on stable ART for 90 days prior to study entry. Didanosine and ‘unboosted’ atazanavir were not allowed owing to concerns of drug–drug interactions. Exclusion criteria: CHD history, active hepatitis B, uncontrolled diabetes, untreated hypothyroidism, or hormonal anabolic therapy. Lipid-lowering agents could not be changed or added.

Twelve-week treatment periods randomized to order of treatment (TDF and placebo, respectively) were separated by a 4-week washout period. Individuals were evaluated with fasting lipids [total cholesterol (TC), HDL-C, low-density lipoprotein cholestrol (LDL-C), and triglycerides] prior to the start of each treatment period and every 4 weeks. Lipid measurements were performed at the ACTG Central Metabolic Laboratory (Nicholls Institute, Quest Diagnostics, San Juan Capistrano, California, USA) by standard techniques as described elsewhere ^[14].

The primary endpoint was the change in non-HDL-C over 12 weeks of active TDF minus the change over 12 weeks of placebo. Because it was assumed there would be no period effect the primary analysis used the Wilcoxon signed-rank test. As this was a pilot study, we used a one-sided significance test with a liberal type I error of 10.

Seventeen individuals enrolled: four (24%) women; six (35%) black; three (18%) Hispanic. Six individuals received protease inhibitors, thirteen received nonnucleoside reverse transcriptase inhibitors, and fifteen received nucleoside reverse transcriptase inhibitors (three abacavir, 10 zidovudine, two both). One individual from each study arm did not complete the protocol, a third individual started a lipid-lowering agent in violation of the protocol, and a fourth did not have week 28 lipid results. As the primary analysis was a per protocol analysis, it and all other analyses were performed on the 13 individuals with complete data (six in arm TDF→P and seven in arm P→TDF).

At baseline, the median [interquartile range (IQR)] fasting lipids (mg/dl) were 180 (142–199) for non-HDL-C, 220 (185–236) for TC, 109 (98–151) for LDL-C, and 274 (178–437) for triglycerides. Table 1 details the outcomes. Non-HDL-C, LDL-C, and TC decreased significantly over the TDF period for all individuals in comparison to over the placebo period. HDL-C and triglycerides did not improve significantly. However, the data did suggest a period effect (P = 0.07) for triglycerides, which appears to be driven by the fact that the median changes while on placebo were −1 (−83 to 22) mg/dl in P→TDF and −149 (−221 to 24) mg/dl in TDF→P.

Table 1

Over the 4-week washout period after TDF was discontinued, in arm TDF→P, triglycerides (mg/dl) increased a median (IQR) 145.5 (35–176) and 34% (28–51) to 630 (365–762) at week 16, suggesting a rebound after the discontinuation of TDF. For the individuals in arm P→TDF, the median increase over the washout period (weeks 28–32) was 63 (29–115) and 32% (9–66). For all individuals, triglycerides increased significantly (P = 0.01) over the 16 weeks of their TDF period and washout by a median of 80 (43–158) mg/dl. In contrast, over the 16 weeks of their placebo period and washout, triglycerides increased by a median of 6.5 (−71 to 73) (P = 0.97).

Virologic suppression (<400 copies/ml) was maintained in all individuals throughout the study. The median difference between the change in CD4⁺ cell count over 12 weeks of TDF vs. placebo was 49 (−74 to 146) cells/μl and not statistically significant. Four grade 3 events were observed during the study. Of these, two were observed while the individual was receiving study drug: an elevation in bilirubin, which was felt to be not study related and an elevation in phosphorus level. No grade 4 events or graded creatinine elevations were reported during the study. For all individuals, the change in creatinine while on TDF was not significantly different than the change while on placebo.

We aimed to specifically assess whether TDF has direct lipid-lowering effects. Prior studies had suggested TDF may have a lipid-lowering effect but it was not clear whether this was owing to the addition of TDF or because of removal of an offending agent during the switch of nucleosides.

In this pilot study, adding TDF to existing virologically suppressive ART regimens improved lipid parameters at 12 weeks of TDF study treatment, supporting an independent lipid-lowering effect of TDF. Also, the observation that triglycerides increased over the washout period suggests a possible ‘rebound’ effect after discontinuation of TDF. Although the potential mechanism is unclear, it is unlikely to be associated with viremia as virologic suppression was maintained throughout the study. This is the first prospective study to our knowledge to evaluate the specific effect of TDF on lipids by adding TDF to a stable ART regimen. Our findings support that TDF independently lowers lipids.

Acknowledgements

This multicenter trial was conducted by the AIDS Clinical Trials Group (ACTG) funded by the National Institute of Allergy and Infectious Diseases (AI38558 and AI068636). Pharmaceutical support provided by Gilead Sciences, Inc.

M.T.: AI-070078 and AI-069501 to Case Western Reserve University. D.W.K.: AI-068634 to SDAC/ Harvard School of Public Health. M.J.G.: AI078884 and AI069419 to Weill Cornell Medical College. S.K.G.: AI-25859 to Indiana University. J.W.M.: AI-069494 to University of Pittsburgh. J.A.A.: AI-27665, AI069532, and M01RR00096 to New York University. S.K.G.: Gilead Sciences: Speaker's fees, consultant fees, and grant support. J.W.M.: Gilead Sciences: Consultant. Merck: Consultant and grant support. Chimerix: Consultant. RFS Pharmaceuticals: Owns stock options. J.F.R.: employee of Gilead Sciences. J.A.A.: Gilead Sciences: Advisory Board, Clinical Trial support, CME sponsored events Honorarium.

We acknowledge the work of other members of the ACTG 5206 team: Carl J. Fichtenbaum, MD (University of Cincinnati), Robert Parker, ScD (SDAC/ Harvard School of Public Health), Paul Tran, R Ph (DAIDS Protocol Pharmacist), John Stoneman, RN (Field Representative), Lori Mong-Kryspin, BS, MT (Laboratory Technologist), Mark Reed (CCG Representative), Andrew Cheng, MD (Gilead Sciences, Inc), Jeffry Enejosa, MD (Gilead Sciences, Inc), and Courtney Ashton (Laboratory Data Coordinator). The authors also wish to thank Gilead for providing study medication and especially the patients who enrolled in our study.

The following persons and institutions participated in the conduct of this trial:

Barbara Philpotts RN and Dr Benigno Rodriguez-Case CRS (Site 2501) CTU Grant #AI69501. Carl J. Fichtenbaum, MD and Franette Hyc RN BSN SOC-University of Cincinnati CRS (Site 2401) CTU Grant #AI-069513. Karen Cavanagh, RN and Margie Vasquez, RN-NYU/NYC HHC at Bellevue (A0401) GCRC Grant # M01RR00096, CTU Grant #AI27665 and AI069532. Frances Canchola, RN & Luis M. Mendez-University of Southern California CRS (Site 1201) CTU Grant # AI069428. Michael Dube, MD and Martha Greenwald, RN, MSN-Indiana University School of Medicine, Infectious Disease Research Clinic (Site 2601) CTU Grant #AI25859. Sharon Riddler, MD, MPH and Carol Oriss, BSN, RN-University of Pittsburgh CRS (Site 1001) CTU Grant # 1 U01 AI 069494. Judy Frain, RN, BSN and Teresa Spitz, RN, CCRC-Washington University at St Louis CRS (Site 2101) CTU Grant # U01AI069495.

Conflicts of interest notification: S.K.G.: Gilead Sciences: Speaker's fees, consultant fees, and grant support; J.W.M.: Gilead Sciences: Consultant. Merck: Consultant and grant support. Chimerix: Consultant. RFS Pharmaceuticals: Owns stock options; J.F.R.: employee of Gilead Sciences; J.A.A.: Gilead Sciences: Advisory Board, Clinical Trial support, CME sponsored events honorarium; M.T., D.W.K, M.J.G., L.M., L.J., B.A.S: no conflicts to declare.