Comparative Effects of Efavirenz and Dolutegravir on Metabolomic and Inflammatory Profiles, and Platelet Activation of People Living with HIV: A Pilot Study

Abstract

Antiretroviral therapy (ART) has reduced the mortality and morbidity associated with HIV. However, irrespective of treatment, people living with HIV remain at a higher risk of developing non-AIDS-associated diseases. In 2019, the World Health Organization recommended the transition from efavirenz (EFV)- to dolutegravir (DTG)-based ART. Data on the impact of this transition are still limited. The current study therefore investigated the metabolic profiles, cytokine inflammatory responses, and platelet activation before and after the treatment transition. Plasma samples from nine virally suppressed adults living with HIV and sixteen healthy, HIV-uninfected individuals residing in Gauteng, South Africa were compared. Metabolite and cytokine profiles, and markers associated with platelet activation, were investigated with untargeted proton magnetic resonance metabolomics, multiplex suspension bead array immunoassays, and sandwich enzyme-linked immunosorbent assays, respectively. In those individuals with normal C-reactive protein levels, the transition to a DTG-based ART regimen resulted in decreased concentrations of acetoacetic acid, creatinine, adenosine monophosphate, 1,7-dimethylxanthine, glycolic acid, 3-hydroxybutyric acid, urea, and lysine. Moreover, increased levels of formic acid, glucose, lactic acid, myo-inositol, valine, glycolic acid, and 3-hydroxybutyric acid were observed. Notably, levels of interleukin-6, platelet-derived growth factor-BB, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, soluble cluster of differentiation 40 ligand, as well as regulated on activation, normal T-cell expressed and secreted (RANTES) reached levels close to those observed in the healthy control participants. The elevated concentration of macrophage inflammatory protein-1 alpha was the only marker indicative of elevated levels of inflammation associated with DTG-based treatment. The transition from EFV- to DTG-based regimens therefore appears to be of potential benefit with metabolic and inflammatory markers, as well as those associated with cardiovascular disease and other chronic non-AIDS-related diseases, reaching levels similar to those observed in individuals not living with HIV.

Keywords: cardiovascular disease; chronic inflammation; cytokines; dolutegravir; efavirenz; human immunodeficiency virus; metabolites; metainflammation; platelet activation.

Figure 1

Violin and box plots depicting metabolite peak intensities of interest of five people living with HIV, before and after transitioning from an efavirenz- to a dolutegravir-based regimen, compared to sixteen healthy, HIV-uninfected control individuals. The results presented exclude participants with CRP concentrations above 5 mg/L. Levels of significance (p-values) between the treatment groups and control cohort are unpaired; p-values indicated between the two treatment groups are paired analyses. Abbreviations: Con: control; DTG: dolutegravir; EFV: efavirenz; NS: not significant.

Figure 2

Violin and box plots depicting inflammatory markers of interest. Concentrations are depicted in pg/mL in five people living with HIV before and after transitioning from an efavirenz- to a dolutegravir-based regimen, compared to sixteen healthy, HIV-uninfected control individuals. Results exclude participants with concentrations of CRP above 5 mg/L. Levels of significance (p-values) between the treatment groups and control cohorts are unpaired; p-values between the two treatment groups are paired analyses. Abbreviations: α: alpha; Con: control; DTG: dolutegravir; EFV: efavirenz; IL: interleukin; MIP: macrophage inflammatory protein; NS: not significant; G-CSF: granulocyte colony-stimulating factor; GM-CSF: granulocyte–macrophage colony-stimulating factor; PDGF: platelet-derived growth factor.

Figure 3

Violin and box plots of the platelet activation markers in five people living with HIV receiving efavirenz- or dolutegravir-based regimens, as well as the concentrations of sixteen healthy, HIV-uninfected controls. Results exclude participants with CRP concentrations above 5 mg/L. Levels of significance (p-values) between the treatment groups and control cohort are unpaired; p-values between the two treatment groups are paired analyses. Abbreviations: Con: control, DTG: dolutegravir; EFV: efavirenz; NS: not significant; RANTES: regulated on activation, normal T-cell expressed and secreted; sCD40L: soluble cluster of differentiation 40 ligand.