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Randomized study evaluating the efficacy and safety of switching from an an abacavir/lamivudine-based regimen to an elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide single-tablet regimen

Rizzardini, Giulianoa,b; Gori, Andreac; Miralles, Celiad; Olalla, Juliáne; Molina, Jean-Michelf; Raffi, Françoisg; Kumar, Princyh; Antinori, Andreai; Ramgopal, Motij; Stellbrink, Hans-Jürgenk; Das, Moupalil; Chu, Hoal; Ram, Reneel; Garner, Willl; Shao, Yongwul; Chuck, Susan K.l; Piontkowsky, Davidl; Haubrich, Richard H.l

Author Information
doi: 10.1097/QAD.0000000000002244

Abstract

Introduction

As current antiretroviral therapy (ART) requires lifelong treatment, long-term antiretroviral-related toxicity should be considered in the selection of initial and subsequent regimens. In the nucleoside analog reverse transcriptase inhibitor (NRTI) class, bone, renal, hypersensitivity reaction, and cardiovascular disease (CVD) events are potential drug-associated toxicities [1]. Renal and bone toxicities observed with tenofovir disoproxil fumarate (TDF)-based regimens have been significantly reduced with the new tenofovir prodrug tenofovir alafenamide (TAF) [2–4] and with abacavir (ABC) [5]. CVD events are thought to have a multifactorial cause in HIV-infected patients; excess traditional risk factors, direct effects of HIV infection, and the effect of antiretroviral drugs are potential interacting factors that contribute to increased CVD risk [6–8]. Numerous studies have shown an association between ABC and myocardial infarction (MI) [6,7,9–20]. Most recently, an analysis of over 8200 participants in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) found an almost two-fold increased risk of combined MI outcome with ABC use in the prior 6 months, including both MI types 1 and 2 [18]. Additionally, the Swiss HIV Cohort Study, which analyzed 11 856 participants exposed to ABC, found that continued treatment with ABC for 4 years led to a two-fold increased risk of a CVD event [20]. Similarly, analyses of the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study, which includes nearly 50 000 participants, initially and again in 2015, reported a continuing association between ABC use and MI risk [7,10]. In the D:A:D study, risk of MI was partially mitigated 6 months after ABC cessation [21], indicating that the association between ABC and MI can be reversible. Further studies have suggested that this ABC-induced platelet dysfunction is mechanistically driven by enhanced platelet granule release, platelet aggregation, and thrombus formation [22,23]. Three analyses found no association between ABC use and MI [24–26]. However, these analyses, one of which constituted pooled data from GlaxoSmithKline/ViiV Healthcare-sponsored clinical trials, were limited by a small number of MI cases (36, 46, and 37, respectively) and person-years of follow-up (17 404, 42–1257 and 3670–3999, respectively) [24,25]. Two additional analyses were conducted without these limitations (289 and 278 MI events; 298 156 and 76 376 person-years of follow-up, respectively) [26–28]. One of these reported an increased risk of MI with short-term/recent exposure to ABC in the overall sample (but not in a subset of patients who did not use either cocaine or intravenous drugs) [27]. The second analysis reported a marginal, but nonsignificant association between cumulative ABC use and acute MI [28]. Current HIV treatment guidelines recommend using ABC with caution or avoiding it in individuals at high risk of CVD [29–31]. Simplification to a well tolerated, effective, once-daily emtricitabine (FTC)/TAF-containing single-tablet regimen (STR) may be a preferred option in individuals receiving an ABC/lamivudine (3TC)-based regimen, potentially reducing CVD risk, decreasing pill burden, and improving treatment satisfaction and adherence [32,33].

Currently, the ‘Generally Recommended Initial Regimens’ by the International Antiviral Society-USA (IAS-USA) Panel include bictegravir/FTC/TAF (B/F/TAF), dolutegravir (DTG)/ABC/3TC, and DTG + FTC/TAF [30]. These recommendations are generally aligned within the Department of Health and Human Services (DHHS) guidelines, which also recommend DTG or raltegravir combined with FTC and either TDF or TAF [31]. Elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF) is a recommended initial regimen for individuals in certain situations [30,31]. Over 144 weeks, TAF has shown superior efficacy and significantly improved renal and bone safety compared with TDF in treatment-naïve participants taking elvitegravir/cobicistat [2,34]. The objective of the current study was to evaluate the efficacy (maintaining HIV-1 RNA <50 copies/ml at Week 24) and safety of switching to E/C/F/TAF versus continuing ABC/3TC plus a third antiretroviral agent in virologically suppressed, HIV-1-infected adults.

Methods

Study design

This phase 3b randomized, multicenter, open-label study was conducted across 49 centers in Europe and North America between November 2015 and June 2017 (NCT02605954). Participants who were receiving ABC/3TC plus a third antiretroviral agent were randomized 2 : 1 to receive either E/C/F/TAF STR (150 mg/150 mg/200 mg/10 mg, respectively) for 48 weeks (immediate-switch group) or continue ABC/3TC (600 mg/300 mg) plus the third agent for 24 weeks, followed by E/C/F/TAF for 24 weeks (delayed-switch group). E/C/F/TAF was administered orally, once daily with food at approximately the same time each day. Randomization was via an Interactive Web System and was stratified by age (<60 or ≥60 years). In the current analysis, we report the preplanned, primary endpoint findings at Week 24.

The institutional review board or independent ethics committee at each participating site approved the study, which was conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. All participants provided written informed consent.

Study population

Participants were virologically suppressed (HIV-1 RNA <50 copies/ml for ≥6 months), HIV-infected adults (aged ≥18 years) who were receiving ABC/3TC plus a third agent [nonnucleoside reverse transcriptase inhibitor (NNRTI), integrase inhibitor (INSTI), or protease inhibitor (PI)] for at least six consecutive months prior to screening. Participants had no history of TDF or FTC resistance, had normal or clinically insignificant abnormal electrocardiograms (investigator determined), estimated glomerular filtration rate (eGFR) ≥30 ml/min, and hepatic transaminases five times or less above the upper limit of normality. Participants were excluded if prior regimens included an INSTI and the current regimen contained a boosted PI; or, they had evidence of previous virologic failure on a boosted PI or INSTI-based regimen. Full inclusion criteria (with details of allowed antiretroviral regimens) and exclusion criteria are in Supplementary Digital Content 1 and 2, https://links.lww.com/QAD/B480, respectively.

Endpoints and assessments

The primary endpoint was maintenance of virologic response (HIV-1 RNA <50 copies/ml) at Week 24 according to the US Food and Drug Administration (FDA)-defined Snapshot algorithm [35]. Secondary endpoints included the proportion of participants maintaining virologic response (HIV-1 RNA <50 copies/ml) at Weeks 12 and 48, evaluation of changes from baseline in CD4+ cell counts at Weeks 24 and 48, and assessment of the safety and tolerability of each regimen over 24 and 48 weeks. Only the 24-week outcomes are presented in this report.

Full details of assessments can be found in Supplementary Digital Content 3, https://links.lww.com/QAD/B480. After screening, study visits occurred at Day 1 and Weeks 4, 8, 12, 24, 36, and 48. Participants in the delayed-switch group also had visits at Weeks 28 and 32 (4 and 8 weeks, respectively, after switching to E/C/F/TAF). HIV-1 RNA was measured at each visit using the COBAS TaqMan HIV RNA Test, v2.0 (Roche Molecular Diagnostics, Pleasanton, California, USA). Participants were considered to have virologic failure if they had HIV-1 RNA at least 50 copies/ml at any visit and confirmed at the next scheduled or unscheduled visit, or if they had HIV-1 RNA at least 50 copies/ml at the last visit within 72 h of study drug discontinuation. Plasma samples from virologic failure confirmation or the last visit were used for HIV-1 genotype/phenotype resistance testing.

Laboratory analyses (hematology, chemistry, creatinine clearance, glucose, and urinalysis), CD4+ cell count, and assessment of adverse events were performed at all visits. The fasting lipid panel [total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein, and triglycerides) was collected at Day 1 and Weeks 12, 24, 36 (delayed-switch group only), and Week 48. Blood and urine for selected evaluations of bone and renal safety were collected at Day 1 and Weeks 4, 12, 24, and 48 (all participants) and also at Weeks 28 and 36 for the delayed-switch group only. Participants’ CVD risk was assessed at baseline and Week 24 using two different equations. The American College of Cardiology/American Heart Association (ACC/AHA) 2013 Pooled Cohort Risk equation was used to estimate the 10-year risk for a first atherosclerotic cardiovascular event (ASCVD) [36]. The 2015 D:A:D study equation was used to estimate the 5-year risk and accounted for current ABC use and cumulative exposure to other NRTIs and PIs [37].

Treatment satisfaction, via a validated patient-reported outcomes tool [HIV Treatment Satisfaction Questionnaire [HIVTSQ] – Status Version and Change Version [38]], was also evaluated throughout the study.

Statistical analysis

All efficacy and safety analyses were conducted in all randomized participants who received at least one dose of study drug.

For the primary study endpoint, a noninferiority analysis was conducted to evaluate the difference in treatment groups for virologic response at Week 24. The difference between the groups (E/C/F/TAF and ABC/3TC regimens) was assessed by constructing a two-sided exact 95% confidence interval (CI). Noninferiority of switching to E/C/F/TAF would be confirmed if the lower bound of the 95% CI was greater than −12%. Secondary endpoints were summarized using descriptive statistics, including changes in CD4+ cell count and safety. The differences in changes from baseline between the two treatment groups in CD4+ cell counts and the associated 95% CIs were constructed using the analysis of variance model, including the treatment group as fixed effect.

A sample size of 300 participants (200 immediate switch, 100 delayed switch) was determined to have greater than 90% power to evaluate the primary noninferiority endpoint, provided the proportion of virologic responders in each group was at least 90% at Week 24. The sample size was revised to be 274 participants using the score test statistics instead of normal approximations.

Results

Participants

Overall, 346 individuals were assessed for eligibility, and 183 participants were randomized to the immediate-switch group and 92 to the delayed-switch group (Supplementary Digital Figure 1, https://links.lww.com/QAD/B480). One participant in the delayed-switch group did not receive treatment. Fifteen participants in the immediate-switch group and three participants in the delayed-switch group discontinued prior to completion of 24 weeks of study treatment (Supplementary Digital Figure 1, https://links.lww.com/QAD/B480).

Baseline demographics were similar between the two groups (Table 1). Overall, the mean age of participants was 49 years (range: 25–82 years), most were men (84%), and 82% were white. Baseline HIV disease characteristics were generally similar between the treatment groups. Overall, median (range) baseline CD4+ cell count was 669 (121–1818) cells/μl. Hepatitis C virus antibody status was positive in 7% of participants and the median (range) baseline eGFR was 98 (28–328) ml/min. Baseline antiretroviral regimens consisted of an NNRTI, INSTI, or PI in 51, 27, and 22% of participants, respectively. Baseline calculated CVD risk scores were balanced between groups for both equations.

T1-5
Table 1:
Baseline demographics and HIV disease characteristics of study participants.

Efficacy

At Week 24, virologic response (HIV-1 RNA <50 copies/ml; FDA-defined Snapshot algorithm) was maintained by 171 (93.4%) participants switching to E/C/F/TAF and 89 (97.8%) participants continuing ABC/3TC plus a third agent (P = 0.15; Fig. 1). The treatment difference for virologic response at Week 24 was −4.4 (95% CI −9.4 to 1.9%) (Fig. 1). The lower limit of the two-sided 95% CI was greater than the protocol-specified noninferiority margin of −12%; therefore, switching to E/C/F/TAF from ABC/3TC plus a third agent was noninferior to continuing ABC/3TC plus a third agent.

F1-5
Fig. 1:
Virologic outcomes at Week 24 by US FDA-defined Snapshot algorithm.ABC/3TC, abacavir/lamivudine; CI, confidence interval; E/C/F/TAF, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide; FDA, Food and Drug Administration.

Two participants (1%) switching to E/C/F/TAF were classified as virologic failures (HIV-1 RNA ≥50 copies/ml) at Week 24. The first participant withdrew consent after a single dose of E/C/F/TAF on Day 1, and was categorized as a virologic failure because of a detectable predose HIV-1 RNA of 58 copies/ml at baseline, despite an HIV-1 RNA less than 50 copies/ml at screening. The second participant was discontinued at the investigator's discretion at Week 15 because of poor adherence (overall adherence of 85%; 62% adherence from Weeks 4 to 8); this participant developed treatment-emergent mutations (M184V in HIV-1 reverse transcriptase plus N155H in HIV-1 integrase) with phenotypic resistance to 3TC, FTC, elvitegravir, and raltegravir, but susceptibility to TAF, TDF, ABC, DTG, and bictegravir. At Week 24, no virologic data were available for eleven (6%) and two (2%) participants receiving E/C/F/TAF and ABC/3TC plus a third agent, respectively (reasons provided in Supplementary Digital Content 4, https://links.lww.com/QAD/B480).

Overall, participants had a median baseline CD4+ count of 669 cells/μl, and there were small mean (standard deviation) changes from baseline to Week 24 in CD4+ cell counts: −28 (161) cells/μl in the immediate-switch group and +8 (193) cells/μl in the delayed-switch group.

Safety

Safety data up to Week 24 (including an overview of adverse events and laboratory abnormalities) are summarized in Table 2. With E/C/F/TAF, there was a low proportion of grade 2–4 adverse events (26%). Drug-related adverse events of any grade occurred in 18 and 0% of participants receiving E/C/F/TAF and ABC/3TC plus a third agent, respectively. No grade 3 or 4 adverse events were reported in the delayed-switch group. In the immediate-switch group, no participants had grade 4 adverse events and 10 (5%) participants had grade 3 adverse events. Of these 10 participants, 2 (1%) experienced grade 3 adverse events deemed study drug-related [hepatocellular injury and hypercholesterolemia); grade 3 adverse events in the other 8 participants were considered unrelated to the study drug (pericarditis; pneumonia; neutropenia; urinary tract infection; nephrolithiasis; osteoarthritis, and spinal osteoarthritis; acute kidney injury; hypertriglyceridemia; and hypercholesterolemia (n = 2)]. No deaths or drug-related serious adverse events were reported in either treatment arm. In this open-label study, nine participants experienced an adverse event leading to study drug discontinuation prior to Week 24; seven of eight E/C/F/TAF participants discontinued because of adverse events considered to be drug-related by the investigators. All adverse events were single occurrence, except for diarrhea (n = 2). Six of the eight E/C/F/TAF discontinuations were because of grade 1 or 2 adverse events. One participant discontinued because of grade 3 worsening hypercholesterolemia on Day 111; the other participant discontinued because of grade 3 hepatic cytolysis on Day 35, which resolved in 2 months.

T2-5
Table 2:
Adverse event summary, most common adverse events (≥5%), and grade 2–4 laboratory abnormalities (>2%) up to Week 24.

In terms of renal safety, switching from ABC/3TC plus a third agent to E/C/F/TAF resulted in significant improvements in urine albumin to creatinine ratio (UACR; median percentage change: −14.1 versus +19.0% with E/C/F/TAF and ABC/3TC plus a third agent, respectively; P = 0.002) and beta-2-microglobulin to creatinine ratio (β2 M:Cr; median percentage change: −9.9 versus +3.7%; P = 0.016) at Week 24 (Fig. 2a). A trend for improvement in retinol-binding protein to creatinine ratio (RBP:Cr) was also observed (median percentage change: −2.4 versus +12.3%; P = 0.068) at Week 24 (Fig. 2a). There were no cases of Fanconi syndrome or proximal renal tubulopathy in either group.

F2-5
Fig. 2:
Safety analyses at Week 24.(a) Median percentage changes (Q1, Q3) in quantitative proteinuria (renal safety). (b) Median changes (Q1, Q3) in serum creatinine with IQR. (c) Median changes (Q1, Q3) in eGFRCG. (d) Median percentage changes (Q1, Q3) in PTH and vitamin Da (bone safety). (e) Median changes (Q1, Q3) in fasting lipids. (f) Change in CVD risk (ASCVD, 10 years; D:A:D, 5 years). aVitamin D measured as 25-hydroxyvitamin D. ABC/3TC, abacavir/lamivudine; (AS)CVD, (atherosclerotic) cardiovascular disease; β2 M:Cr, beta-2-microglobulin to creatinine ratio; D:A:D, Data Collection on Adverse events of Anti-HIV Drugs; E/C/F/TAF, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide; eGFR(CG), estimated glomerular filtration rate (by Cockcroft–Gault equation); HDL, high-density lipoprotein; IQR, interquartile range; LDL, low-density lipoprotein; PTH, parathyroid hormone; Q, quartile; RBP:Cr, retinol-binding protein to creatinine ratio; TC, total cholesterol; TG, triglyceride; UACR, urinary albumin to creatinine ratio.

Small median changes in serum creatinine (SCr) (+0.04 mg/dl) and eGFR (−4.8 ml/min) were observed in participants switching to E/C/F/TAF (Fig. 2b and c). Supplementary Digital Content 5, https://links.lww.com/QAD/B480 shows the relationship between SCr/eGFR changes and the presence or absence of creatinine secretion inhibitors (CSIs) (cobicistat, rilpivirine, ritonavir, and DTG [6,8]) in the antiretroviral regimen being used at screening. Bone safety analyses are summarized in Fig. 2d; median percentage changes in parathyroid hormone and vitamin D did not differ significantly between treatment groups. There were no cases of nontraumatic fracture in either group. Switching to E/C/F/TAF as opposed to continuing ABC/3TC plus a third agent resulted in similar, small changes in median TC:HDL ratio and individual lipid parameters (Fig. 2e). Of the median lipid changes, only the difference in TC was significant (P = 0.019).

Calculated CVD risk analysis at Week 24 showed small median increases in ASCVD score that were not different between E/C/F/TAF and ABC/3TC plus a third agent (+0.1 versus +0.2%; P = 0.46). The D:A:D calculated score, which considers CVD impact of ABC, showed significantly lower median CVD risk in participants switching to E/C/F/TAF (−0.8 versus +0.2%, P < 0.001; Fig. 2f).

Patient-reported outcomes

Findings from the HIVTSQ at Week 24 are summarized in Figure 3. Overall, switching to E/C/F/TAF was associated with a significant improvement in treatment satisfaction in both the general satisfaction/clinical and lifestyle/ease subscales compared with continuing ABC/3TC plus a third agent.

F3-5
Fig. 3:
Findings from the HIV Treatment Satisfaction Questionnaire at Week 24a.Values shown are mean ± standard deviation. aThe ranges of the HIV Treatment Satisfaction Questionnaire are as follows: overall 0–60 (baseline) and −30 to 30 (postbaseline); subscale 0–30 (baseline) and −15 to 15 (postbaseline). ABC/3TC, abacavir/lamivudine; E/C/F/TAF, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide.

Discussion

This study demonstrates that the once-daily E/C/F/TAF STR is an efficacious option for individuals switching from ABC/3TC-based regimens. Switching to E/C/F/TAF was noninferior to continuing ABC/3TC plus a third agent (primary endpoint) and high rates of virologic suppression were maintained. In the current study, only two participants switching to E/C/F/TAF were classified as virologic failures. The first participant had a detectable HIV RNA prior to the first dose of E/C/F/TAF (despite a screening HIV RNA <50 copies/ml), with no follow-up HIV RNA value. The second participant was discontinued because of poor adherence, which led to the only case of treatment-emergent mutations in reverse transcriptase (M184 V) and in integrase (N155H). However, emergence of resistance was rare, occurring in just one of the 183 participants (0.5%) in the E/C/F/TAF group and none in the group continuing ABC/3TC plus a third agent. The virologic response at Week 24 is consistent with the previous phase 3 E/C/F/TAF switch study [39].

As new ART options become available, switching treatment to reduce toxicity or to prevent antiretroviral-associated events (i.e. renal, bone, or cardiovascular) may be beneficial. The aims of ART regimen switch are to maintain viral suppression, preserve or improve the safety profile, and not jeopardize future treatment options [29–31]. Switching is indicated for several reasons, including documented toxicity, prevention of long-term toxicity, aging and/or comorbidity, and simplification [29–31]. The favorable safety profile of TAF has been demonstrated in a number of switch studies [3,4,39–45]. However, prior to this study, data on switching from ABC/3TC-based regimens to TAF-containing treatments were relatively limited. In a phase 3 study of switching from a TDF-containing or ABC-containing regimen to a TAF-based regimen in participants with renal impairment (N = 242), efficacy, renal function, and bone mineral density were maintained in those who switched from ABC to E/C/F/TAF [43]. In another phase 3 switch study (N = 556), FTC/TAF was noninferior to ABC/3TC in maintaining virologic suppression at Week 48 in combination with a variety of third agents [44]. There were no differences in lipid profile, renal, and bone biomarkers versus ABC/3TC.

Our study confirms that switching to E/C/F/TAF from ABC/3TC-based regimens was generally well tolerated with 18% of participants experiencing study drug-related adverse events, and 4% discontinuing the study drug because of adverse events. No study drug-related adverse events or discontinuations because of adverse events were reported in the ABC/3TC group. The stability of the ABC/3TC regimens at screening as well as the open-label and delayed-switch design may explain the lack of discontinuations among participants continuing with ABC/3TC plus a third agent. Adverse events were consistent with the known safety profile of E/C/F/TAF. We found that switching to E/C/F/TAF resulted in no parathyroid hormone and vitamin D changes, significant improvements in renal protein biomarkers (β2M:Cr and UACR), and no discontinuations because of renal adverse events. There were minimal changes in SCr and calculated eGFR; changes were driven by the baseline antiretroviral drugs’ ability to inhibit creatinine secretion (CSIs including cobicistat, rilpivirine, ritonavir, and DTG). CSIs tend to increase SCr by 0.1 mg/dl because of inhibition of tubular creatinine transporters, but do not affect actual renal function [46]. Thus, in participants who switched from a CSI-containing regimen to E/C/F/TAF, there was no change in SCr or eGFR; whereas there was a small and expected change in SCr and eGFR in participants who were not on a CSI at baseline (Supplementary Digital Content 5, https://links.lww.com/QAD/B480). Small changes in fasting lipid parameters and TC:HDL ratio were observed with E/C/F/TAF. However, these changes did not demonstrate clinical relevance based on the cardiovascular risk equation analyses [47]. As ABC/3TC has not been associated with either renal-related or bone-related safety events [48–50], our finding that renal and bone markers with E/C/F/TAF were comparable with or improved compared with ABC/3TC-based regimens demonstrates that E/C/F/TAF is an appropriate option to consider in individuals with or at risk of bone density disorders or renal disease. Indeed, differences in renal biomarkers were not observed in studies with the TAF-containing regimen B/F/TAF either as initial treatment versus DTG/ABC/3TC, or when patients were switched from DTG/ABC/3TC to B/F/TAF. In both studies, renal biomarkers were similar in the treatment groups after 48 weeks [51,52].

As the HIV population ages, management of comorbidities, such as CVD, and prevention of long-term toxicities become important [53]. The results of the current study suggest that E/C/F/TAF may be a feasible option for clinicians wishing to switch individuals from an ABC/3TC-containing regimen. Indeed, according to the validated 2015 D:A:D study equation, which is specific for people living with HIV and accounts for the ABC-associated CVD risk [37], switching from an ABC/3TC-containing regimen to E/C/F/TAF significantly decreased 5-year CVD risk at Week 24. In contrast, 10-year risk according to the ACC/AHA ASCVD risk equation was stable at Week 24 with E/C/F/TAF. Of note, the small but statistically significant differences in cholesterol fractions did not yield differences in calculated cardiovascular risk by the ACC/AHA equation. The differences in CVD risk between the two equations could be because of the discontinuation of ABC in the immediate-switch group as current ABC use is a covariable in the D:A:D equation [37]. It should also be recognized that these CVD risk equations are not without limitations and findings should be interpreted with caution. For example, while a comparison of D:A:D versus the Framingham Risk Score concluded that the D:A:D equation more accurately predicted 5-year CVD risk [37], other studies suggest that the ACC/AHA Pooled Cohort equations and D:A:D equation may underestimate CVD risk [54,55].

Chronic kidney disease is a well known risk factor for CVD [56–60]. Before TAF was available, clinicians had no recommended alternative options other than ABC-containing therapy for individuals with (or at risk of) renal disease, despite the potential for a further increase in cardiovascular risk. Switching such individuals from ABC/3TC-based regimens to E/C/F/TAF may reduce the potential lifetime risk of a cardiovascular event, without adversely affecting renal function. However, longer term data with TAF and cardiovascular events are still needed.

Strengths of the current study include the prospective, randomized design, whereas limitations include the potential bias associated with the nonblinding design, which may have affected adverse events reporting and attribution, as well as patient-reported outcomes. The administration of randomized therapy up to Week 24 only is another potential limitation. However, the 24-week delayed-switch design was intended to minimize dropout and to provide the opportunity for all participants to receive E/C/F/TAF.

To conclude, E/C/F/TAF was an efficacious and generally well tolerated option for participants switching from ABC/3TC-based regimens and resulted in a significant improvement in treatment satisfaction.

Acknowledgements

We thank all participants and investigators involved in the study. Medical writing support was provided by Joanna Chapman, PhD, at Aspire Scientific (Bollington, UK), and funded by Gilead Sciences, Inc., Foster City, California, USA.

Data sharing: The authors do not have any additional information to share.

Author contributions: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, have substantially contributed to the study's conception, design, and performance; take responsibility for the integrity of the work as a whole; and have given their approval for this version to be published.

Funding: This study was funded by Gilead Sciences, Inc.

Conflicts of interest

G.R. has received honoraria for speaking or attending advisory boards for AbbVie, Angelini, Gilead, Janssen, MSD, and ViiV. A.G. has received grants/research supports, honoraria/consultation fees and travel grant/support and participated in a company sponsored speaker's bureau for Abbvie, Astellas, BMS, Boeringher Ingelheim, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, ViiV, and GSK. C.M. has received consulting fees from Gilead and Merck and research grants from Gilead and ViiV. J.O. has received consulting fees from Gilead, Merck, and ViiV and research grants from Gilead. J.-M.M. has participated in advisory boards for Gilead, Merck, ViiV, and Teva and received a research grant from Gilead. F.R. has received research grants or honoraria from or consulted for Gilead, Janssen, Merck, MSD, and ViiV. P.K. has received honoraria for attending advisory boards for Gilead, Janssen, TheraTechnologies, and ViiV. A.A. has received honoraria for consultancy from Abbvie, BMS, Gilead, Janssen-Cilag, Merck, and ViiV, and institutional research grants from BMS, Gilead, Janssen-Cilag, and ViiV. M.R. has been a speaker for Gilead, Janssen, AbbVie, and Allergan and a consultant for Gilead, Merck, and ViiV. H.-J.S. has received honoraria and travel reimbursement from Gilead, Janssen-Cilag, and MSD. M.D., R.R., Y.S., S.K.C., D.P., and R.H.H. are all employees of Gilead Sciences, Inc. H.C. and W.G. were employees of Gilead Sciences, Inc. at the time of the study.

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Keywords:

abacavir/lamivudine; antiretroviral agents; drug switching; elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide; HIV

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