In the past 30 years, lipid abnormalities paralleled the clinical manifestation of HIV disease from wasting syndrome in the pre-ART era, to lipodystrophy in the early ART era, and more recently to weight gain in the contemporary ART scenario. This historical perspective can be also recognized at an individual level: acute and untreated HIV infections are associated with reduced total cholesterol (TC) and high-density lipoprotein-cholesterol (HDL-C) levels and increased triglyceride levels [1–3]. Although effective treatment of HIV may reduce or increase lipid levels depending on the antiretroviral (ARV) regimen employed [4], it must nevertheless be recognized that the impact of HIV and ART on lipids are also related to genetic, environmental and lifestyle factors. Dyslipidemia per se cannot be considered a disease condition but rather, jointly with glucose abnormalities and insulin resistance, should be included under the broad umbrella definition of ‘metabolic abnormalities’.
These complex and interrelated biochemical pathways produce tissue damage depicted by ectopic fat accumulation (visceral adipose tissue and liver fat), lean mass reduction (sarcopenia), osteopenia and endothelial dysfunction leading to specific ‘metabolic diseases’ including obesity, nonalcoholic steatohepatitis, diabetes, osteoporosis, cardiovascular disease, chronic kidney disease, neurocognitive impairment, and frailty. In addition to HIV infection, metabolic abnormalities are also a major driver of systemic inflammation, the so-called meta-inflammation, potentially affecting the natural history of HIV disease.
Different ARV regimens have different metabolic consequences, and due to expected better bone and renal tolerability, tenofovir alafenamide (TAF) has largely replaced tenofovir disoproxil fumarate (TDF) as preferred nucleotide reverse transcriptase inhibitor in initial treatment of ART [5]. Although increases in TC and low-density lipoprotein (LDL) are observed with TAF compared to TDF, the relatively recent findings that TAF was also associated with significant weight gain has been concerning [6].
Do increases in lipid levels and weight gain (and possible metabolic consequences) outweigh the better renal and bone tolerability of TAF compared to TDF? Are these reversible with a switch back to TDF? The current manuscript by Kauppinen et al.[7] is an important attempt at answering the second question.
Kauppinen et al.[7], in a retrospective, case–control study of 292 subjects, attempted to describe the ‘metabolic’ impact of the switch back from TAF to TDF assessing the implication of lipids changes on cardiovascular risk assessed with atherosclerotic cardiovascular disease (ASCVD) and on weight gain. The authors compared a group of 147 individuals who switched from TAF to TDF with a control group with the same number of individuals maintaining TAF based regimen. Groups were well matched for baseline sex, ethnicity, type and duration of ART, cigarette use, non-ARV use, HIV-1 transmission mode and estimated duration of HIV-1 infection. Of note, age and use of cobicistat were increased in the control group [7].
During 1 year of follow up, no significant changes in lipid levels occurred in the control (nonswitch) group while TC, LDL-C, and HDL-C significantly decreased in those switching to TDF [7]. For unclear reasons, LDL-C significantly increased between 1 and 2 years follow up for both groups. Toxicities (estimated glomerular filtration rate, creatinine and plasma phosphate levels) were not different between groups; however, small but significant increases in urine protein and plasma alanine amino transferase and alkaline phosphatase were observed in those who switched to TDF. Similarly, small but significant increases in body weight were observed in the control TAF group during one and two years of follow up (0.9 and 1.5 kg respectively). To identify any potential clinical relevance of these findings, the ASCVD risk was calculated at the two years follow up timepoint using the American College of Cardiology method. Predicted ASCVD risk decreased by 0.4% in the switch group while it increased 0.9% in the control group (P = 0.056 for the latter measurement). The key message of the study is that TAF appears to be ‘metabolic neutral’ while TDF may display some ‘metabolic benefit’. The strength of the study by Kauppinen et al.[7] is the attempt to explore the relationship between lipid abnormalities and metabolic diseases including weight gain and cardiovascular disease. Limitations noted and addressed by the authors include the baseline age and use of cobicistat difference between individuals who switched from TAF to TDF, both variables that are associated with increased rates of cardiovascular events. The finding that those receiving TDF had decreased ASCVD score reduces this concern somewhat; however, in the context of lower HDL-C, further studies are needed to determine if either switch (TDF to TAF or TAF to TDF) influences the development of cardiovascular events.
Should we alter prescribing practices based on these data?
The increased use of TAF in people living with HIV has been driven by the goal of reducing tenofovir-related renal and bone metabolic toxicities. Every 1 year of exposure to TDF has been associated with 33% increased risk of chronic kidney disease [8]; however, a recent meta-analysis examining TAF and TDF toxicities found no significant differences between TAF and TDF for the key safety endpoints studied including bone markers and renal tubular effects with the exception of subgroups receiving cobicistat or ritonavir [9]. Nevertheless, there are many reports demonstrating bone metabolic toxicities and incident fractures have been associated with 48% greater risk of all-cause mortality associated with TDF [10]. On the contrary, weight gain noted in individuals treated with TAF has not been associated with cardiovascular disease.
Current practice guidelines recommend both TAF or TDF as effective antiretroviral therapies, and suggest that selection of one over the other should be driven by the risk of metabolic toxicities, cost and access for each individual living with HIV. The current study provides additional support for the premise that TDF use is associated with more favorable lipid profiles, and potentially reduced future cardiovascular risk in people receiving TDF-based antiretroviral therapy.
These data support a patient centered approach in ART prescription which considers the comprehensive metabolic health of people living with HIV, rather than the lipid metabolic toxicity of individual drugs.
Acknowledgements
This work was funded in part by the Department of Veterans Affairs and the National Institutes of Health (Merit Review Grant BX000207 and R61 AI 169659, J.T.S. [Li Wu, PhD is principal investigator), and Department of Veterans Affairs Merit Review Grant CX000418 to R.J.B.
Conflicts of interest
There are no conflicts of interest.
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