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Switch from Tenofovir Disoproxil Fumarate to Tenofovir Alafenamide in People Living with HIV: Lipid Changes and Statin Underutilization
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published Sept 21 2021 -
authors
Epividian, Inc., 4819 Emperor Blvd., Suite 400, Durham, NC, 27703, USA. Laurence Brunet, Jennifer S. Fusco & Gregory P. Fusco
Centre for Experimental Pathogen Host Research, University College Dublin, Dublin, Ireland. Patrick Mallon
AIDS Healthcare Foundation, Miami, FL, USA. Michael B. Wohlfeiler
Merck & Co., Inc., Kenilworth, NJ, USA. Girish Prajapati & Andrew Beyer
This work was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Abstract
Background and Objective
Many people living with HIV (PLWH) on stable tenofovir disoproxil fumarate (TDF)-containing regimens have switched to tenofovir alafenamide (TAF), despite the potential lipid-lowering effect of TDF. We aimed to assess the impact of switching from TDF to TAF on lipids in real-world clinical practice.
Methods
PLWH prescribed TDF for ≥ 4 weeks who switched to TAF were identified in the OPERA cohort. Patterns of dyslipidemia were compared before and after switch based on NCEP ATPIII guidelines. Elevated 10-year risk of atherosclerotic cardiovascular disease (ASCVD ≥ 7.5%) and statin use were assessed.
Results
Among 6423 PLWH switched from TDF to TAF, the proportion with dyslipidemia/severe dyslipidemia observed after switch from TDF to TAF increased statistically significantly (p < 0.0001) with total cholesterol (5-10%), low-density lipoprotein cholesterol (16-23%), and triglycerides (21-27%), but decreased statistically significantly with high-density lipoprotein cholesterol (35-30%, p < 0.0001). These patterns of dyslipidemia persisted in sensitivity analyses restricted to PLWH who maintained all other antiretrovirals (N = 4328) or stratified by pharmaco-enhancer use before and after switch. An elevated ASCVD risk was detected in 29% before and 31% after switch. As many as 59% of PLWH with an elevated ASCVD risk were not prescribed a statin after switch from TDF to TAF.
Conclusions
In this large, diverse population of PLWH in the USA, the switch from TDF to TAF was associated with development of less favorable lipid profiles, regardless of pharmaco-enhancers or third-agent use. Statins remained underutilized after a switch from TDF to TAF.
Discussion
In this large, diverse cohort of PLWH in care in the USA, switching from TDF to TAF was associated with worsening CHOL, LDL and TG. The observed development of less favorable lipid profiles was not driven by changes in other ARVs as part of the switch, as almost identical changes in lipids were observed in an analysis restricted to PLWH who maintained all other ARVs, nor was it driven by use of pharmacological boosting agents, as demonstrated in stratified analysis. In addition, while switching from TDF to TAF was associated with a 10% increase in statin use among PLWH with high ASCVD risk, 59% of PLWH with an elevated risk of ASCVD were still not prescribed statins after switch.
The magnitude of lipid increases observed in this study (CHOL: + 7.9%, LDL: + 11.1%, HDL: + 7.1%, TG: + 23.8%) was consistent with the results of a smaller observational study of 238 PLWH switching from TDF to TAF, which reported statistically significant relative increases in CHOL, LDL and HDL of a similar magnitude to those reported here [19,20,21,22]. However, other observational studies reported larger statistically significantly increases in lipids for up to 6 months after switch [18]. Nevertheless, the statistically significant increases in lipid levels reported in this OPERA study are consistent with the literature comparing lipid changes with TAF compared to TDF [15,16,17, 28,29,30,31]. This OPERA study did not focus on other surrogates of dyslipidemia, including the CHOL/HDL ratio, as this measure does not form part of the ATPIII guideline grading for severity of dyslipidemia, nor does it form a target for treatment initiation or treatment response for dyslipidemia within the ATPIII guidelines. Of note, studies that estimated changes in CHOL/HDL ratio found only negligible differences after a switch from TDF to TAF [20,21,22]. However, despite the CHOL/HDL ratio being a predictor of cardiovascular disease risk, statistically significant increases in the ASCVD risk were observed in one cohort [21], although there was no change in the D:A:D coronary heart disease score or the Framingham risk score in another [22]. In addition, the ATPIII guidelines focus on thresholds for treatment that are based on total, LDL and HDL cholesterol and treatment targets focused on LDL cholesterol, as these are most relevant to overall risk of CVD events.
Clinically meaningful changes in lipids were also observed in this OPERA study. Indeed, the proportion of PLWH with dyslipidemia or severe dyslipidemia increased significantly after switching from TDF to TAF, when measured with CHOL (5.1-9.5%), LDL (15.5-22.5%) and TG (21.2-27.0%), although it decreased when measured with HDL (34.8-30.2%). Overall, these patterns of dyslipidemia are concerning for increased potential to adversely affect the risk of cardiovascular disease. These data are consistent with a smaller observational study of 194 PLWH switching from any non-TAF-containing regimen to a TAF-containing regimen: the proportion with dyslipidemia increased statistically significantly after switch, with a worsening of CHOL (pre switch: 4.5%, post-switch: 15.5%, p = 0.012) and LDL (pre-switch: 26.4%, post-switch: 42.3%, p = 0.003) [32]. In this study, increases in lipids after switch from TDF to TAF did not appear to be driven by boosting agent use. However, despite the fact that switching from ritonavir to cobicistat has been associated with a decrease in TG at 24 weeks [33], the stratified analyses did not distinguish between boosting with ritonavir versus cobicistat; as ritonavir represented only 10% of boosted regimens, it was insufficient for a stratified analysis by individual boosting agent.
Taken together, these data support the hypothesis that switching to a TAF-containing regimen could have a clinically relevant impact on cardiovascular health. Risks and benefits of switching from TDF to TAF must be weighed prior to switch. Risks to the kidney and bones with TDF (e.g., renal tubular dysfunction, bone mineral density) [2, 3] must be balanced against cardiovascular risks with TAF (e.g., dyslipidemia, weight gain) [32, 34,35,36]. The patient’s history, comorbidities and other risk factors must therefore be considered in the decision-making process, and regular screening may be advised.
An elevated risk of ASCVD (10-year ASCDVD risk ≥ 7.5%) was identified in 29% of PLWH before switch and 31% after switch to TAF. These estimates are consistent with the prevalence of 10-year ASCVD risk ≥ 7.5% in other studies, ranging from 24 to 66% [37,38,39,40,41,42,43]. While this increase in the proportion of PLWH with an elevated ASCVD risk may not be clinically meaningful, it remains that close to one-third of the study population was considered at-risk, and one-fifth were at-risk and untreated. Although statin prescription increased after switch in this study, an estimated 59% of PLWH with an elevated 10-year ASCVD risk who could have benefited from treatment did not receive a statin prescription at any point while on TAF. This is particularly concerning given that the Pooled Cohort Equations calculator may underestimate risk among PLWH due to non-traditional risk factors driving their ASCVD risk [44]. Estimates of statin underutilization among PLWH meeting various guideline criteria for therapy vary greatly based on the population studied, ranging from 19 to 70% [37, 39, 40, 43]. The important variation in the proportion of PLWH who would benefit from lipid-lowering therapy and statin utilization derives from the use of different criteria in each study. Despite variations in the magnitude of lipid changes across regimens, statin use may be of benefit regardless of ART regimen used. In addition, lifestyle changes such as diet and exercise are also key elements to focus on to improve cardiovascular health that must be considered in addition to discussions about lipid-lowering agent use.
A large, diverse, and representative cohort of PLWH in care in the USA was used to identify 6451 PLWH who switched directly from TDF to TAF. In the OPERA cohort, clinical diagnoses, prescriptions, and laboratory results are captured prospectively from EMRs for all patients receiving healthcare at participating sites, providing complete and accurate clinical information reflecting real-world clinical practices. An important design element was the implementation of a self-controlled study. Lipid levels were compared within PLWH before and after switch, thus controlling for important risk factors for dyslipidemia such as family history or lifestyle, which are often unavailable in EMRs. Analyses restricted to PLWH who maintained all other ARVs as well as analyses stratified by boosted regimen use before and after switch confirmed that the lipid changes observed were not solely driven by boosting agents or other ARVs.
Despite these strengths, this analysis does have limitations. While changes in lipids after a switch from TDF to TAF were observed, this study could not control for a potential upward trend in lipids that may have occurred without switch due to the absence of a comparison group of PLWH remaining on TDF. Moreover, these analyses could not determine whether the changes observed were related to the removal of TDF or to the initiation of TAF. There is some evidence that switching to TAF may result in significantly increased CHOL and LDL values if switching from TDF, but may lead to decreased values if switching from a non-TDF-containing regimen [45], although an observational study reported statistically significantly higher CHOL, LDL and HDL levels with TAF compared to any other backbones [32]. Yet, the mechanism through which TAF would induce dyslipidaemia remains unknown.
This is a purely descriptive study without control for confounding (e.g., changes in antihypertensive use, change in smoking status, diet, and exercise) or the role of viral suppression, beyond the level of control achieved with the self-control design, study population restrictions, and stratifications. These findings were limited to the short-term impact of switching from TDF to TAF, using the first lipid panel performed at least 7 days after switch. In addition, the analysis was not restricted to fasting lipids as fasting status is variable in routine outpatient clinical care and either random or fasting lipid profiles are now recommended in guidelines [24, 46]. Integrase strand transfer inhibitors (INSTIs) have become the preferred third agent in the USA, which may have been better reflected with an extended inclusion period; at the time of the study (2015-2018), INSTIs were included in 47% of the TDF-containing regimens and 65% of the TAF-containing regimens. However, PIs and non-nucleoside reverse transcriptase inhibitors remain in use among ART-experienced PLWH such as those included in this study population.
While this study offers insight on missed opportunities for statin therapy in the context of a change in ART regimen, the analysis was limited to elevated 10-year ASCVD risk only and did not examine CVD outcomes; thus, not accounting for other high-risk groups defined in clinical guidelines [23]. Additionally, PLWH with pre-existing CVD events were not excluded in the evaluation of statin use by ASCVD risk. Moreover, the Pooled Cohort Equations calculator used to estimate the 10-year ASCVD risk was developed for a certain range of ages (40-79 years), systolic blood pressure (90-200 mmHg), HDL (20-100 mg/dL), and CHOL (130-320 mg/dL) [26]. Therefore, imputation of the score for individuals falling outside of these ranges may have led to some misclassification. Finally, validation studies in HIV cohorts have found that the Pooled Cohort Equation underestimated the ASCVD risk in PLWH [47]. Therefore, the number of PLWHs who would benefit from statin therapy is likely an underestimate.
Conclusion
In this large cohort of PLWHs who switched from TDF to TAF, switching was associated with an increase in the prevalence of clinically relevant dyslipidemia. Differences were not driven by boosted regimens or other ARVs. Risks associated with both TDF and TAF use must be weighed when deciding which agent is preferable for each person. Clinical interactions around the time of a regimen change represent an opportunity to intervene when PLWH present with an elevated risk of ASCVD. However, statin prescription remained suboptimal in this population.
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