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] [2–4] [5] [6–8] [6,7,9–20] [18] [20] [7,10] [21] [22,23] [24–26] [24,25] [26–28] [27] [28] [29–31] [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] [31] [30,31] [2,34]
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
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] + 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
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] [37]
Treatment satisfaction, via a validated patient-reported outcomes tool [HIV Treatment Satisfaction Questionnaire [HIVTSQ] – Status Version and Change Version [38]
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 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.
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.
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.
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. 2 a). 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. 2 a). There were no cases of Fanconi syndrome or proximal renal tubulopathy in either group.
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). a Vitamin 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. 2 b and c). Supplementary Digital Content 5, https://links.lww.com/QAD/B480 [6,8] Fig. 2 d; 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. 2 e). 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. 2 f).
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.
Fig. 3: Findings from the HIV Treatment Satisfaction Questionnaire at Week 24a .Values shown are mean ± standard deviation. a The 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] [29–31] [3,4,39–45] N = 242), efficacy, renal function, and bone mineral density were maintained in those who switched from ABC to E/C/F/TAF [43] 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]
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] https://links.lww.com/QAD/B480 [47] [48–50] [51,52]
As the HIV population ages, management of comorbidities, such as CVD, and prevention of long-term toxicities become important [53] [37] [37] [37] [54,55]
Chronic kidney disease is a well known risk factor for CVD [56–60]
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.
References
1. Orkin C, Llibre JM, Gallien S, Antinori A, Behrens G, Carr A.
Nucleoside reverse transcriptase inhibitor-reducing strategies in HIV treatment: assessing the evidence .
HIV Med 2018; 19:18–32.
2. Arribas JR, Thompson M, Sax PE, Haas B, McDonald C, Wohl DA, et al.
Brief report: randomized, double-blind comparison of tenofovir alafenamide (TAF) vs tenofovir disoproxil fumarate (TDF), each coformulated with elvitegravir, cobicistat, and emtricitabine (E/C/F) for initial HIV-1 treatment: Week 144 results .
J Acquir Immune Defic Syndr 2017; 75:211–218.
3. Podzamczer D, Arribas JR, Clarke A, Cotte L, Mudrikova T, Negredo E, et al.
Adults with renal impairment switching from tenofovir disoproxil fumarate to tenofovir alafenamide have improved renal and bone safety through 144 weeks. 9th IAS Conference on HIV Science . 23–26 July 2017; Paris, France.
4. DeJesus E, Haas B, Segal-Maurer S, Ramgopal MN, Mills A, Margot N, et al.
Superior efficacy and improved renal and bone safety after switching from a tenofovir disoproxil fumarate- to a tenofovir alafenamide-based regimen through 96 weeks of treatment .
AIDS Res Hum Retroviruses 2018; 34:337–342.
5. Moyle GJ, Stellbrink HJ, Compston J, Orkin C, Arribas JR, Domingo P, et al.
96-Week results of abacavir/lamivudine versus tenofovir/emtricitabine, plus efavirenz, in antiretroviral-naive, HIV-1-infected adults: ASSERT study .
Antivir Ther 2013; 18:905–913.
6. Marcus JL, Neugebauer RS, Leyden WA, Chao CR, Xu L, Quesenberry CP Jr, et al.
Use of abacavir and risk of cardiovascular disease among HIV-infected individuals .
J Acquir Immune Defic Syndr 2016; 71:413–419.
7. Sabin CA, Reiss P, Ryom L, Phillips AN, Weber R, Law M, et al.
Is there continued evidence for an association between abacavir usage and myocardial infarction risk in individuals with HIV? A cohort collaboration .
BMC Med 2016; 14:61.
8. O’Halloran JA, Satchell CS, Mallon PW.
Dyslipidemia, atherosclerosis and cardiovascular disease: an increasingly important triad in an aging population living with HIV .
Future Virol 2013; 8:1021–1034.
9. Brouwer ES, Napravnik S, Eron JJ Jr, Stalzer B, Floris-Moore M, Simpson RJ Jr, Stürmer T.
Effects of combination antiretroviral therapies on the risk of myocardial infarction among HIV patients .
Epidemiology 2014; 25:406–417.
10. Worm SW, Sabin C, Weber R, Reiss P, El-Sadr W, Dabis F, et al.
Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study .
J Infect Dis 2010; 201:318–330.
11. Desai M, Joyce V, Bendavid E, Olshen RA, Hlatky M, Chow A, et al.
Risk of cardiovascular events associated with current exposure to HIV antiretroviral therapies in a US veteran population .
Clin Infect Dis 2015; 61:445–452.
12. Martin A, Bloch M, Amin J, Baker D, Cooper DA, Emery S, et al.
Simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavir-Lamivudine: a randomized, 96-week trial .
Clin Infect Dis 2009; 49:1591–1601.
13. The SMART/INSIGHT and the D:A:D study groups.
Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients .
AIDS 2008; 22:F17–F24.
14. Obel N, Farkas DK, Kronborg G, Larsen CS, Pedersen G, Riis A, et al.
Abacavir and risk of myocardial infarction in HIV-infected patients on highly active antiretroviral therapy: a population-based nationwide cohort study .
HIV Med 2010; 11:130–136.
15. Durand M, Sheehy O, Baril JG, Lelorier J, Tremblay CL.
Association between HIV infection, antiretroviral therapy, and risk of acute myocardial infarction: a cohort and nested case-control study using Quebec's public health insurance database .
J Acquir Immune Defic Syndr 2011; 57:245–253.
16. Choi AI, Vittinghoff E, Deeks SG, Weekley CC, Li Y, Shlipak MG.
Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons .
AIDS 2011; 25:1289–1298.
17. Rotger M, Glass TR, Junier T, Lundgren J, Neaton JD, Poloni ES, et al. MAGNIFICENT Consortium; INSIGHT; Swiss HIV Cohort Study.
Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons .
Clin Infect Dis 2013; 57:112–121.
18. Elion RA, Althoff KN, Zhang J, Moore RD, Gange SJ, Kitahata MM, et al. North American AIDS Cohort Collaboration on Research and Design of IeDEA.
Recent abacavir use increases risk for types 1 and 2 myocardial infarctions among adults with HIV .
J Acquir Immune Defic Syndr 2018; 78:62–72.
19. Dorjee K, Baxi SM, Reingold AL, Hubbard A.
Risk of cardiovascular events from current, recent, and cumulative exposure to abacavir among persons living with HIV who were receiving antiretroviral therapy in the United States: a cohort study .
BMC Infect Dis 2017; 17:708.
20. Young J, Xiao Y, Moodie EE, Abrahamowicz M, Klein MB, Bernasconi E, et al. Swiss HIV Cohort Study.
Effect of cumulating exposure to abacavir on the risk of cardiovascular disease events in patients from the Swiss HIV Cohort Study .
J Acquir Immune Defic Syndr 2015; 69:413–421.
21. Sabin CA, Worm SW, Weber R, Reiss P, El-Sadr W, Dabis F, et al.
Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multicohort collaboration .
Lancet 2008; 371:1417–1426.
22. Taylor KA, Rauzi F, Smyth E, Nelson M, Gazzard B, Emerson M.
Pharmacological impact of tenofovir alafenamide (TAF) compared with other antiretrovirals on platelet aggregation in vitro and in vivo. 16th European AIDS Conference . 25–27 October 2017, Milan, Italy.
23. Collado-Diaz V, Andujar I, Sanchez-Lopez A, Orden S, Blanch-Ruiz MA, Martinez-Cuesta MA, et al.
Abacavir induces arterial thrombosis in a murine model .
J Infect Dis 2018; 218:228–233.
24. Ribaudo HJ, Benson CA, Zheng Y, Koletar SL, Collier AC, Lok JJ, et al. ACTG A5001/ALLRT Protocol Team.
No risk of myocardial infarction associated with initial antiretroviral treatment containing abacavir: short and long-term results from ACTG A5001/ALLRT .
Clin Infect Dis 2011; 52:929–940.
25. Ding X, Andraca-Carrera E, Cooper C, Miele P, Kornegay C, Soukup M, et al.
No association of abacavir use with myocardial infarction: findings of an FDA meta-analysis .
J Acquir Immune Defic Syndr 2012; 61:441–447.
26. Nan C, Shaefer M, Urbaityte R, Oyee J, Hopking J, Ragone L, et al.
Abacavir use and risk for myocardial infarction and cardiovascular events: pooled analysis of data from clinical trials .
Open Forum Infect Dis 2018; 5:ofy086.
27. Lang S, Mary-Krause M, Cotte L, Gilquin J, Partisani M, Simon A, et al. Clinical Epidemiology Group of the French Hospital Database on HIV.
Impact of individual antiretroviral drugs on the risk of myocardial infarction in human immunodeficiency virus-infected patients: a case-control study nested within the French Hospital Database on HIV ANRS cohort CO4 .
Arch Intern Med 2010; 170:1228–1238.
28. Bedimo RJ, Westfall AO, Drechsler H, Vidiella G, Tebas P.
Abacavir use and risk of acute myocardial infarction and cerebrovascular events in the highly active antiretroviral therapy era .
Clin Infect Dis 2011; 53:84–91.
29. European AIDS Clinical Society. EACS Guidelines version 9.1. 2018. Available at:
http://www.eacsociety.org/files/2018_guidelines-9.1-english.pdf . [Accessed 22 November 2018]
30. Saag MS, Benson CA, Gandhi RT, Hoy JF, Landovitz RJ, Mugavero MJ, et al.
Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2018 recommendations of the International Antiviral Society-USA Panel .
JAMA 2018; 320:379–396.
31. DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC). Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. 2018. Available at:
https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf . [Accessed 31 July 2018]
32. Hodder SL, Mounzer K, Dejesus E, Ebrahimi R, Grimm K, Esker S, et al. AI266073 Study Group.
Patient-reported outcomes in virologically suppressed, HIV-1-Infected subjects after switching to a simplified, single-tablet regimen of efavirenz, emtricitabine, and tenofovir DF .
AIDS Patient Care STDS 2010; 24:87–96.
33. Nachega JB, Parienti JJ, Uthman OA, Gross R, Dowdy DW, Sax PE, et al.
Lower pill burden and once-daily antiretroviral treatment regimens for HIV infection: a meta-analysis of randomized controlled trials .
Clin Infect Dis 2014; 58:1297–1307.
34. Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, et al.
Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, noninferiority trials .
Lancet 2015; 385:2606–2615.
35. Food and Drug Administration. Human immunodeficiency virus-1 infection: developing antiretroviral drugs for treatment guidance for industry. 2015. Available at:
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm355128.pdf . [Accessed 29 August 2018]
36. Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, D’Agostino RB, Gibbons R, et al.
2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines .
Circulation 2014; 129 (25 Suppl 2):S49–S73.
37. Friis-Moller N, Ryom L, Smith C, Weber R, Reiss P, Dabis F, et al. D:A:D study group.
An updated prediction model of the global risk of cardiovascular disease in HIV-positive persons: the data-collection on Adverse Effects of Anti-HIV Drugs (D:A:D) study .
Eur J Prev Cardiol 2016; 23:214–223.
38. Woodcock A, Bradley C.
Validation of the revised 10-item HIV Treatment Satisfaction Questionnaire status version and new change version .
Value Health 2006; 9:320–333.
39. Mills A, Arribas JR, Andrade-Villanueva J, DiPerri G, Van Lunzen J, Koenig E, et al.
Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, noninferiority study .
Lancet Infect Dis 2016; 16:43–52.
40. Gallant JE, Daar ES, Raffi F, Brinson C, Ruane P, DeJesus E, et al.
Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial .
Lancet HIV 2016; 3:e158–e165.
41. Raffi F, Orkin C, Clarke A, Slama L, Gallant J, Daar E, et al.
Brief report: long-term (96-week) efficacy and safety after switching from tenofovir disoproxil fumarate to tenofovir alafenamide in HIV-infected, virologically suppressed adults .
J Acquir Immune Defic Syndr 2017; 75:226–231.
42. Post FA, Tebas P, Clarke A, Cotte L, Short WR, Abram ME, et al.
Brief report: switching to tenofovir alafenamide, coformulated with elvitegravir, cobicistat, and emtricitabine, in HIV-infected adults with renal impairment: 96-week results from a single-arm, multicenter, open-label phase 3 study .
J Acquir Immune Defic Syndr 2017; 74:180–184.
43. Pozniak A, Arribas JR, Gathe J, Gupta SK, Post FA, Bloch M, et al. GS-US-292-0112 Study Team.
Switching to tenofovir alafenamide, coformulated with elvitegravir, cobicistat, and emtricitabine, in HIV-infected patients with renal impairment: 48-week results from a single-arm, multicenter, open-label phase 3 study .
J Acquir Immune Defic Syndr 2016; 71:530–537.
44. Winston A, Post FA, DeJesus E, Podzamczer D, Di Perri G, Estrada V, et al.
Tenofovir alafenamide plus emtricitabine versus abacavir plus lamivudine for treatment of virologically suppressed HIV-1-infected adults: a randomised, double-blind, active-controlled, noninferiority phase 3 trial .
Lancet HIV 2018; 5:e162–e171.
45. Wang H, Lu X, Yang X, Xu N.
The efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate in antiretroviral regimens for HIV-1 therapy: meta-analysis .
Medicine (Baltimore) 2016; 95:e5146.
46. German P, Liu HC, Szwarcberg J, Hepner M, Andrews J, Kearney BP, et al.
Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function .
J Acquir Immune Defic Syndr 2012; 61:32–40.
47. Huhn G, Shamblaw D, Baril JG, Baker D, Ward D, Guo S, et al.
Atheroslerotic CVD risk profile of tenofovir alafenamide versus tenofovir disoproxil fumarate .
Antivir Ther 2016; 21 (Suppl 1):A45.
48. Barber T, Hill A, Singh GJ, Boffito M, Nelson M, Moyle G.
Impact of NRTI backbone on renal, bone and cardiovascular markers in HIV-infected individuals receiving a boosted protease inhibitor .
J Int AIDS Soc 2014; 17 (4 Suppl 3):19562.
49. Rasmussen TA, Jensen D, Tolstrup M, Nielsen US, Erlandsen EJ, Birn H, et al.
Comparison of bone and renal effects in HIV-infected adults switching to abacavir or tenofovir based therapy in a randomized trial .
PLoS One 2012; 7:e32445.
50. Wohl DA, Bhatti L, Small CB, Edelstein H, Zhao HH, Margolis DA, et al.
Simplification to abacavir/lamivudine + atazanavir maintains viral suppression and improves bone and renal biomarkers in ASSURE, a randomized, open label, noninferiority trial .
PLoS One 2014; 9:e96187.
51. Molina JM, Ward D, Brar I, Mills A, Stellbrink HJ, Lopez-Cortes L, et al.
Switching to fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide from dolutegravir plus abacavir and lamivudine in virologically suppressed adults with HIV-1: 48 week results of a randomised, double-blind, multicentre, active-controlled, phase 3, noninferiority trial .
Lancet HIV 2018; 5:e357–e365.
52. Gallant J, Lazzarin A, Mills A, Orkin C, Podzamczer D, Tebas P, et al.
Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled noninferiority trial .
Lancet 2017; 390:2063–2072.
53. Palella FJ Jr, Phair JP.
Cardiovascular disease in HIV infection .
Curr Opin HIV AIDS 2011; 6:266–271.
54. Thompson-Paul AM, Lichtenstein KA, Armon C, Palella FJ Jr, Skarbinski J, Chmiel JS, et al.
Cardiovascular disease risk prediction in the HIV outpatient study .
Clin Infect Dis 2016; 63:1508–1516.
55. Triant VA, Perez J, Regan S, Massaro JM, Meigs JB, Grinspoon SK, et al.
Cardiovascular risk prediction functions underestimate risk in HIV infection .
Circulation 2018; 137:2203–2214.
56. Liu M, Li XC, Lu L, Cao Y, Sun RR, Chen S, et al.
Cardiovascular disease and its relationship with chronic kidney disease .
Eur Rev Med Pharmacol Sci 2014; 18:2918–2926.
57. Best PJ, Reddan DN, Berger PB, Szczech LA, McCullough PA, Califf RM.
Cardiovascular disease and chronic kidney disease: insights and an update .
Am Heart J 2004; 148:230–242.
58. McCullough PA, Steigerwalt S, Tolia K, Chen SC, Li S, Norris KC, et al. KEEP Investigators.
Cardiovascular disease in chronic kidney disease: data from the Kidney Early Evaluation Program (KEEP) .
Curr Diab Rep 2011; 11:47–55.
59. Weiner DE, Tighiouart H, Amin MG, Stark PC, MacLeod B, Griffith JL, et al.
Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies .
J Am Soc Nephrol 2004; 15:1307–1315.
60. Weiner DE, Tighiouart H, Stark PC, Amin MG, MacLeod B, Griffith JL, et al.
Kidney disease as a risk factor for recurrent cardiovascular disease and mortality .
Am J Kidney Dis 2004; 44:198–206.
