Even though life expectancy in people living with HIV (PLWH) treated with antiretroviral therapy (ART) has increased significantly, non-AIDS-related complications still have a major impact on morbidity and mortality in this population [1,2]. Among these comorbidities, cardiovascular disease (CVD) is of particular importance, accounting for up to 15% of total deaths in PLWH, especially in high-income countries [3,4]. The risk of myocardial infarction (MI) is nearly doubled in PLWH, with traditional risk factors, which are over-represented in PLWH, and factors, which are peculiar of HIV-infection, such as the influence of co-infections [i.e. hepatitis C virus and cytomegalovirus (CMV)], systemic immune activation, viral-specific factors and antiretroviral therapy (ART) [5–11] all implicated. Dyslipidaemia is common among PLWH, even in middle-income and low-income countries, with up to one third of PLWH on ART affected by hypercholesterolemia, representing one of the greatest contributors to increased CVD risk in HIV [12,13].
Although the impact on lipids of individual ART drugs and drug classes, particularly first generation, ritonavir-boosted protease inhibitors, has been well described, the different NRTIs have a heterogeneous effect on lipids, with tenofovir disoproxil fumarate (TDF) exhibiting a favorable impact on lipids by reducing levels of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides [14,15]. Even though the use of TDF has been associated with reduced bone mineral density (BMD) and kidney dysfunction, switching from another nucleoside reverse transcriptase inhibitor (NRTI) to a TDF-containing regimen in hypercholesterolaemia, virologically suppressed PLWH has been linked to improvements in lipid parameters [16–18]. Similar effects have also been demonstrated in studies where TDF was added to the ART regimen in treatment-experienced PLWH and in studies in healthy volunteers, where TDF exerted a ‘statin-like’ effect, without any impact on insulin sensitivity [19,20]. The mechanism underlying this beneficial effect on lipids by TDF has not been determined.
Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir (TFV) that achieves higher intracellular levels of the active metabolite tenofovir diphosphate (TFV-DP), permitting lower overall dosing and significant reductions in plasma TFV concentrations. This assures potent antiviral activity of TAF at oral doses 10 times lower than TDF , with lower plasma levels of TFV resulting in better kidney and bone safety profiles of TAF compared with TDF [22,23]. However, TAF also seems to lack the lipid-lowering properties of TDF. In a randomized double-blind trial in treatment-naive PLWH comparing TAF to TDF, each co-formulated with emtricitabine/elvitegravir/cobicistat (FTC/EVG/COBI), individuals in the TAF arm had significantly higher levels of TC, HDL, LDL and triglycerides compared with those receiving TDF . Similar findings were obtained in studies in which TDF and TAF were combined with emtricitabine/darunavir/cobicistat (FTC/DRV/COBI), both in treatment-naive and in treatment-experienced individuals switching from a TDF-containing to a TAF-containing combination [25,26]. However, the absolute mean changes observed were considered to be relatively small and the clinical relevance of the observed changes was unclear, particularly as studies did not report the proportion of individuals experiencing clinically relevant changes in lipids. In addition, real-life data outside of the context of randomized-controlled trials on the impact of TAF on lipids are lacking. Thus, the aim of our study was to assess changes in lipid parameters after switching from any ART regimen to a TAF-based treatment in a cohort of PLWH attending two tertiary care centres in Ireland.
Population and study design
Established in 2011, the University College Dublin Infectious Disease Cohort (UCD ID Cohort) is an on-going prospective, observational cohort that enrols consecutive adult individuals (>18 years old) attending the Mater Misericordiae University Hospital (MMUH) and the St Vincent's University Hospital (SVUH) infectious diseases outpatients services for routine HIV clinical care, sexual health services and care for other infectious diseases, including tuberculosis (TB) and viral hepatitis. The study protocol was approved by MMUH and SVUH Institutional Review Boards and each study individual provided written informed consent.
Specific to PLWH, individuals attend four to six monthly routine HIV clinical care visits. The cohort collects information on demographics (e.g. age, sex, ethnicity), HIV acquisition risk, date or year of HIV diagnosis, stage of HIV disease, previous and current medications (ART regimens, dose, frequency, start and stop dates, concomitant treatment related to co-infections and comorbidities), clinical events including relevant active and previous diagnosis (e.g. AIDS, non-AIDS events and comorbidities). In addition, routine virologic (including genotyping) and immunological data and relevant clinical routine laboratory data on HIV treatment tolerability and safety, including renal, liver, lipids and glucose are collected. Data are assimilated from periodic retrospective medical records abstraction and other hospital electronic information systems. Wherever available, all data are back dated to the time of the individuals initial HIV diagnosis or first clinic visit. All data are reviewed, entered onto a secure database and cleaned before being analysed.
In this analysis, we studied adult PLWH enrolled in the UCD ID Cohort since inception who switched their ART to TAF-containing ART regimes between January 2016 and July 2017. We collated demographics, medication history [including ART and concomitant medications such as lipid-lowering therapy (LLT)] and laboratory data, including lipid profiles [total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides].
The main outcome measure was change in lipid parameters postswitch to a TAF-containing regimen. A secondary outcome was the change in the proportion with dyslipidaemia postswitch to TAF, with classification of dyslipidaemia based on the National Cholesterol Education Program-Adult Panel III (NCEP-ATP III) (Table 1) .
Categorical variables were summarized using frequencies and percentage. Continuous variables were summarized using the median and interquartile range (IQR). Change in lipid parameters and change in the proportion of dyslipidaemia NCEP-ATP III classification postswitch to TAF-containing ART was assessed using the paired t-test or Wilcoxon sign rank test and the Stuart--Maxwell test, respectively. In addition to performing these analyses on the study cohort, we conducted a sensitivity analysis restricted to PLWH without any change in ART other than switch from TDF to TAF. For each lipid parameter, we constructed a binary outcome, clinically significant worsening dyslipidaemia, defined as an increase in lipid values (TC, LDL, HDL and triglycerides) from preswitch to postswitch to TAF, which resulted in a change from normal/borderline category to abnormal/very abnormal category or change from an abnormal category to very abnormal category, as defined by the NCEP-ATP III classification. Using logistic regression models, we assessed for factors associated with worsening dyslipidaemia. All analyses were conducted using Stata 13.1 (StataCorp, College Station, Texas, USA).
Of 775 PLWH enrolled in the UCD ID Cohort, 238 switched to TAF-containing ART regimes between January 2016 and July 2017, of whom 194 (81.5%) had both pre-TAF and post-TAF switch lipid profile measurements. Preswitch lipids were measured a median (IQR) 16 (0–54) weeks prior to switch and postswitch lipids a median (IQR) 24 (14–41) weeks after switching to TAF-containing ART. There were no significant differences in demographic characteristics, clinical and treatment variables between the 238 who switched to TAF-containing ART and the 194 analysed (Table 2).
Of the 194 PLWH included in the study analysis, the median age at switch was 46 (39–53) years. The study cohort was predominantly men (70.6%), Caucasian (69.1%), with heterosexual contact (37.1%) the most represented HIV transmission risk group. The majority of the individuals (90.2%) were virologically suppressed with robust CD4+ T-cell response [621 (400, 813) cell/μl). The median time since HIV diagnosis and cumulative preswitch ART exposure was 10 (4–15) years and 7.5 (2.7–12.5) years, respectively. Preswitch, 82 (42.3%) of the individuals were on integrase strand transfer inhibitors (INSTI) [35 on elvitegravir/cobicistat), 40 (20.6%) boosted protease inhibitor (PI/r) (8 on darunavir/cobicistat)], 66 (34.0%) nonnucleoside reverse transcriptase inhibitors (NNRTI) and 6 (3.1%) on INSTI/PI-based ART regimens. Among these ART regimens, TDF was the most common backbone (84.5% of individuals). Forty-six individuals (23.7%) were on LLT at switch and four (2.1%) commenced LLT postswitch to TAF-containing ART. Postswitch regimens were INSTI+FTC/TAF in 155 (79.9%), PI+FTC/TAF in 25 (12.9%) and NNRTI+FTC/TAF in 14 (7.2%). Of 164 of 194 with preswitch TDF exposure, 72 with switch to TAF had no change in other ART components. Characteristics of the analyzed cohort are presented in Table 2.
At switch to TAF containing ART, median (IQR) (mmol/l) lipid concentrations were: TC 4.60 (3.80–5.30), LDL 2.80 (2.10–3.30), HDL 1.16 (0.97–1.39), triglycerides 1.25 (0.90–1.80) and TC : HDL-C ratio 3.88 (3.20–4.56) (Fig. 1a). On the basis of NCEP-ATP III, the proportion of PLWH with abnormal to very high grade abnormal lipids parameters for TC (>6.2 mmol/l) was 10 (5.2%), LDL (>3.3 mmol/l) 46 (23.7%), HDL (<1.03 mmol/l) 60 (30.9%) and triglycerides (>2.23 mmol/l) 29 (14.9%).
Postswitch, lipids levels significantly increased; mean change (SE) mmol/l, TC +0.37 (0.06), LDL +0.25 (0.06) (both P < 0.001); HDL +0.05 (0.02), P = 0.003; triglycerides +0.13 (0.07), P = 0.02 and TC :HDL ratio +0.16 (0.08), P = 0.013. This corresponded to a postswitch significant increase of 8% for TC, LDL 9%, HDL 4.3%, triglycerides 8.7% and TC : HDL ratio 4%.
Overall, there was a significant change in NCEP-ATP III classification postswitch for TC and LDL (Fig. 2 a). In particular, compared with preswitch, there was a significant increase in the proportions of PLWH with postswitch abnormal to very high grade abnormal dyslipidemia for TC (5.2 vs. 15.5%, P < 0.001) and LDL (23.7 vs. 36.6%, P < 0.001). There were no significant differences in the proportion with abnormal to very high-grade abnormal dyslipidemia postswitch for triglycerides (14.9 vs. 18%, P = 0.41) and HDL (30.9 vs. 25.8%, P = 0.14).
In a sensitivity analysis including 72 PLWH with TDF to TAF and no change in other ART components, postswitch lipid levels were significantly increased compared with preswitch, median (IQR) mmol/l, TC [4.45 (3.75–5.15) vs. 4.80 (3.95–5.45), P = 0.002], LDL [2.60 (2.00–3.20) vs. 3.00 (2.00–3.45), P = 0.002], triglycerides [1.25 (0.86–1.69) vs. 1.23 (0.99–2.03), P = 0.03], TC : HDL ratio [3.90 (3.17–4.51) vs. 3.89 (3.14–5.00), P = 0.083] and not for HDL [1.14 (0.95–1.36) vs. 1.21 (0.97–1.40), P = 0.08] (Fig. 1b). Similarly, compared with preswitch, we observed an overall significant change in NCEP-ATP III classification postswitch for TC and LDL and not HDL and triglycerides (Fig. 2 b).
Factors associated with worsening dyslipidaemia
At least 26 (13.4%) and 47 (24.2%) individuals experienced worsening TC and LDL dyslipidemia, respectively. In unadjusted logistic regression models, higher preswitch TC and LDL levels were significantly associated with increased odds of worsening TC dyslipidemia postswitch [odds ratio (OR) = 2.25, 95% confidence interval (CI) 1.46–3.46; OR = 3.24, 95% CI 1.84–5.70) respectively], while use of LLT preswitch was associated with a trend towards reduced risk of worsening TC dyslipidemia postswitch (OR = 0.23, 95% CI 0.05–1.04). Similar direction of association was observed between the above factors and LDL dyslipidemia (Table 3). In multivariable models controlled separately for preswitch TC and LDL levels, use of LLT preswitch remained independently associated with reduced risk of worsening TC and LDL dyslipidemia postswitch [adjusted OR (AOR) = 0.14, 95% CI 0.02–0.77 and AOR = 0.17, 95% CI 0.05–0.55, Table 3].
In this study, among the first to describe the effect of switch to TAF on lipid profiles in a ‘real life’ setting, we have observed a clinically relevant, significant worsening of lipid profiles over a period of 24 weeks after switch (range 14–41 weeks) in PLWH on stable ART who switch to regimens containing TAF. The number of individuals switching to TAF who experience increases in LDL levels to grades considered abnormal or very high rose to over a third (36.6%) of the population under study, raising concerns as to the potential atherogenic consequences of these changes. That individuals prescribed statins were relatively protected from the increases in lipids observed with switch to TAF highlights the need for appropriate monitoring and intervention for dyslipidaemia in this vulnerable population.
Cardiovascular disease is among the most frequent non-AIDS-related complications reported in PLWH in the modern ART era, responsible for up to 15% of the total deaths in this population, with a significant impact also on morbidity and quality of life [1–4]. Dyslipidaemia, a major risk factor for CVD, is particularly common in PLWH on ART. Compared with INSTI and some NNRTI, use of pharmacologically boosted protease inhibitors have long been associated with more dyslipidaemia and in some cases also to an increased risk of MI and severe cardiovascular events [11,28–30].
Likewise, specific NRTI have also been linked to altered CVD risk, although through mechanisms not always related to dyslipidaemia. Abacavir (ABC) has been associated in some studies with higher rates of MI [31,32], with altered coagulation and platelet function proposed as underlying mechanisms , while use of TDF has been associated with lipid-lowering effects [14,15,17–20], considered as a possible explanation for an observed reduced risk of heart failure observed in ART-treated patients in a large cohort study .
Links between TDF use and renal impairment and osteopaenia encouraged switches to TAF, which achieves high intracellular but lower systemic exposure of active tenofovir, and therefore, less renal and bone effects [16,21–23]. However, these benefits were tempered by the loss of ‘lipid-friendly’ profile of TDF in some trials. The relatively small increase in TC, LDL, HDL and triglycerides observed at a population level with switch away from TDF to TAF, in the absence of changes in the TC : HDL ratio, were thought not to be of clinical relevance [21,22,24–26,35,36]. However, our study not only confirmed statistically significant increases in the levels of TC, LDL, HDL, triglycerides but also increases in the TC : HDL ratio and, importantly, changes in the severity of dyslipidaemia, based on NCEP-ATP III classification, that highlight the clinical relevance of these changes for a sizable proportion of our population following switch to a TAF-containing ART.
Use of LLT before switch was associated with reduced odds of worsening dyslipidemia after switch to TAF in multivariate analyses adjusting for age, ethnicity, sex and preswitch lipid levels. Of the 194 individuals enrolled in the study, only four (2.1%) were started on LLT following switch to a TAF-containing regimen. However, we were unable to determine whether this represents appropriate use of LLT or if there existed missed opportunities for statin use within this cohort as a result of the switch to TAF.
The impact of the observed lipid increases, even if they resulted in relatively small increases in estimated CVD risk, could be noteworthy in PLWH, particularly considering that subclinical atherosclerosis is frequently detected in PLWH, even in ART-treated, virologically suppressed PLWH with low estimated CVD risk . Moreover, abnormally high lipid levels (especially LDL and non-HDL cholesterol), have been linked to an increase in the relative risk of CVD mortality in the general population, even in individuals with a low 10-year risk of atherosclerotic CVD (ASCVD) .
Our data are consistent with a previous analysis of retrospectively collated data, comparing both treatment-naive and treatment-experienced PLWH initiating either TDF/FTC or TAF/FTC, both co-formulated with EVG/c . Although treatment-naive individuals starting TAF had significant increases only in TC, LDL, HDL and triglycerides after 48 weeks of treatment, treatment-experienced individuals had also significant increases in TC/HDL ratio and higher rates of initiation of LLT.
TAF-containing regimens have been explored extensively in clinical trials including when not compared with TDF. When TAF/FTC was compared with ABC/3TC in virologically suppressed adults with HIV-1 infection, a small but significant decrease in HDL (median value −2 mg/dl, P = 0.0003) was observed after switch to TAF, but no significant changes in the other lipid parameters were described . Similarly, in another trial of virologically suppressed individuals switching from ABC/3TC co-formulated with dolutegravir (DTG) to TAF/FTC co-formulated with bictegravir (BIC), only triglycerides differed between groups over 48 weeks (−5 mg/dl in the TAF group vs. 3 mg/dl in the other arm, P = 0.028), without any difference in other lipid measures . These findings suggest that the lipid changes after initiation of a TAF-based regimen might not be unfavourable and that greater changes are seen when switching from a TDF-containing combination to TAF. In fact, 84.5% of the individuals enrolled in our study were on TDF prior to switching to TAF, and this might have had a major impact on the observed changes in lipid parameters, considering the well known lipid-lowering effect of TDF compared with other NRTIs [17–20]. Therefore, further data on a greater number of patients switching from a non-TDF regimen to TAF are needed to understand to what extent the observed changes are as a result of loss of TDF as compared with a direct impact of TAF on cholesterol metabolism. Of note, as already pointed out in the retrospective analysis by Cid-Silva et al., patients enrolled in clinical trials are generally younger (31–35 years) compared with our cohort (39–53 years) and this might account for the differences in lipid changes between clinical trials and ‘real life’ data, representing a potential strength of our study in being more representative of the population of PLWH.
Given the renal and bone safety profile, current clinical practice guidelines on the management of individuals with HIV-1 infection recommend TAF-based regimen as first-line option, especially in patients at higher risk of renal impairment and BMD loss [42,43]. However, the increased risk of worsening lipids observed in our study would suggest that consideration should be given to the relative impact of use of TAF versus TDF in patients at increased CVD risk, especially in those who already have abnormal lipid values.
Even though the majority of the individuals in our cohort were switched to an INSTI-based regimen (79.9%), the use of protease inhibitors (14.9%) and NNRTIs (7.25%) as third agents might have had different effects on lipid changes after switch. Of note, 51 of 66 individuals who were on NNRTI-based regimens preswitch were started on EVG/c following switch to TAF, and therefore, there is potential for lipid changes to be influenced both by the discontinuation of NNRTIs and the initiation of boosted INSTI. However, we still observed significant lipid changes in individuals who only switched TDF to TAF while maintaining the other components of their antiretroviral regimens, which would indicate an effect predominantly driven by the switch to TAF rather than change in third agent.
Our study has several limitations. Firstly, a significant proportion of individuals in our cohort (23.7%) were already on LLT prior to the switch to TAF, which may have masked the real effect on lipids of a switch to TAF. Some of the study individuals had a long history of ART exposure (median cumulative preswitch exposure to ART 7.5 years, with a maximum of 12.5 years), and the metabolic effects of previous antiretroviral regimens (which were not assessed) might have influenced lipid levels. In addition, considering also that a high proportion (84.5%) of the patients was previously on a TDF-based regimen, losing the protective effect of TDF might have favoured dyslipidaemia in an already susceptible population. Additionally, bictegravir was not available at the time the study was conducted and the majority of the individuals switched to INSTI-based regimens were started on EVG/c rather than DTG, limiting the applicability of our findings to second generation INSTI. Finally, data on comorbidities that could have a significant impact on lipid metabolism, such as diabetes, cardiovascular disease and metabolic syndrome, were not available and could not be included in the logistic regression model. Lastly, the inclusion of a small proportion of viraemic individuals, even though the majority (90.2%) of the cohort were virologically suppressed introduces a potential bias. Despite these limitations, our cohort is diverse in its makeup, with male and female well represented and inclusion of individuals from common ethnic and risk acquisition groups included in a real-world setting.
In conclusion, we have demonstrated significant worsening of lipid profiles after switch to a TAF-containing regimen in a real life setting, particularly evident in those with higher preswitch TC and LDL. Even though these data should be confirmed in larger cohorts, they raise concerns regarding the potential negative impact on CVD risk in PLWH arising from this dyslipidaemia. Development of dyslipidaemia should be taken into consideration alongside renal and bone safety when choosing between TDF and TAF.
The authors and the UCD ID Cohort Study Team would like to thank all individuals, both with and without HIV, who participated in the UCD ID Cohort Study.
Author contributions: P.W.M., A.L. and W.T. conceived the study and contributed to the writing of the article. E.A.B., S.S. and E.F. contributed to the interpretation of the results and to the writing of the article. A.L. and W.T. performed the statistical analyses and interpretations, and contributed to the writing of the article. P.W.M., A.G.C., E.M., A.M., G.S., J.S.L. and S.S. collected clinical data contributed to the interpretation of the results and reviewed the article.
Other members of the UCD ID Cohort Study Team: Tara McGinty, Padraig McGettrick (Department of Infectious Diseases, Mater Misericordiae University Hospital & Centre for Experimental Pathogen Host Research, School of Medicine, University College Dublin), Aoife McDermott, Bindu Krishnanivas, Alejandro Abner Garcia Leon, Christine Kelly (Centre for Experimental Pathogen Host Research, School of Medicine, University College Dublin).
Conflicts of interest
P.W.M. has received support from the following: Molecular Medicine Ireland, Scientific Foundation Ireland, ViiV Healthcare, Gilead Sciences Ltd., Glaxo-SmithKline Ltd. (Ireland), Abbott, M.S.D. and Janssen-Cilag. A.G.C. has received support, in the form of sponsorship to attend meetings, from Gilead Sciences Ltd., Glaxo-SmithKline Ltd. (Ireland), Bristol-Myers Squibb Pharmaceuticals and M.S.D. and Janssen-Cilag. W.T has received support from the European Union's Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie (grant agreement No. 666010). The remaining authors declare no conflict of interest.
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