Comparative effects of antiretroviral treatments on metabolomics, cytokine profiles and platelet activation in HIV-positive individuals

Abstract

As of 2020, approximately 37.7 million (30.2 million – 45.1 million) people were living with human immunodeficiency virus (HIV) worldwide, with 7.8 million of these infections being accounted for in the South African population. The introduction of combination antiretroviral therapy (cART) has considerably improved the morbidity and mortality rates of people living with HIV (PLWH); however, these individuals are still at a higher risk of developing diseases associated with microbial infections and metabolic syndromes such as hypertension, elevated blood sugar levels, and excess body fat accumulation, often culminating in type II diabetes mellitus (T2DM), insulin resistance as well as cardiovascular diseases (CVD).

To combat opportunistic microbial infections associated with HIV infection, the World Health Organisation (WHO) recommended the initiation of prophylactic co-trimoxazole (CTX) in conjunction with cART (which was implemented in 2000). The cART regimen recommended by the WHO before 2019 comprised a non-nucleoside reverse transcriptase inhibitor (efavirenz [EFV]), and two nucleotide/nucleoside reverse transcriptase inhibitors (tenofovir disoproxil fumarate [TDF] and emtricitabine). However, after 2019, the WHO recommended that PLWH receive a cART regimen that includes an integrase strand transfer inhibitor (dolutegravir [DTG]), TDF, and lamivudine. The rationale for the transition to the DTG-containing regimen, was based on the reported superiority of DTG-based regimens regarding increased viral suppression rates, low drug-drug interactions, reduced side effects, and high barrier to drug resistance compared to EFV-based treatments. The current study, therefore, aimed to build on the knowledge base of EFV- and DTG-based cART regimens by investigating the effect of the EFV-based cART in the absence and presence of prophylactic CTX, as well as the effect of DTG-based regimens on the metabolic profiles, inflammatory responses (interleukin [IL]-1beta [β], IL-4, IL-6, IL-8, IL-10, interferon-gamma [IFN-γ], tumour necrosis factor–alpha [TNF-α], granulocyte-macrophage colony-stimulating factor [GM-CSF]), and C-reactive protein [CRP]), as well as platelet activation (soluble cluster of differentiation 40 ligand [sCD40L] and regulated upon activation, normal T-cell expressed and secreted [RANTES]) to establish the risk of individuals receiving these treatments developing metabolic and inflammatory associated diseases, including cardiovascular disease.

A total of 28 PLWH of African descent were enrolled in the current study. The first group of participants (recruited between 2014 and 2016) comprised 16 EFV-experienced individuals that were either administered a placebo (10 participants) or CTX (six participants) for six months following recruitment. The second cohort of participants (recruited between 2020 and 2022) consisted of 12 individuals that transitioned from the EFV- to the DTG-based regimen at recruitment. Follow-up samples were collected six months after the initiation of treatment. In addition, 20 plasma samples were collected from healthy, HIV-uninfected volunteers. Subsequently, metabolic profiles and expression of inflammatory markers and platelet activation markers were performed using untargeted nuclear magnetic resonance, a bead-based suspension array, and an enzyme-linked immunosorbent assay, respectively.

The results from the study indicated that prophylactic CTX treatment had no significant effect on the metabolic profile or expression of inflammatory markers and platelet activation markers in PLWH. However, the samples used in these assays appeared to be altered by pre-analytical factors, including temperature during transportation and time before processing and storage, as well as the samples' storage length. Therefore, the results obtained on the effect of CTX on these markers may need to be verified in an additional, carefully controlled study. In those individuals transitioning from the EFV- to the DTG-based regimen, metabolic profiles and inflammatory and platelet activation marker levels appeared to return to those found in the healthy, HIV-uninfected cohort. This was especially true for D-glucose, L-tyrosine, IL-6, IL-8, GM-CSF, and CRP. On the other hand, the observed increase in creatinine levels within the DTG-treated cohort may indicate kidney dysfunction and, as such, should be monitored in individuals receiving DTG-based cART. The 'normalisation' in the energy-associated metabolic pathways and inflammatory response in the DTG-treated cohort may point towards a reduced risk of developing metabolic syndromes, which may, in turn, decrease the possibility of developing type II diabetes mellitus, insulin resistance as well as a cardiovascular disease within this population.