Efficacy and safety of co-formulated elvitegravir/cobicistat/emtricitabine/ tenofovir alafenamide in HIV-positive patients: real-world data
Fehmi Tabak, Esra Zerdali, Ozlem Altuntas, Alper Gunduz, Sibel Bolukcu, Bilgul Mete, Inci Y Nakir, Hayat Kumbasar Karaosmanoglu, Dilek S Yildiz, Meliha Meric Koc, ˙Ilyas Dokmetas and [ACTHIV-IST (Action Against HIV in Istanbul) Study Group]
1 Department of Infectious Diseases and Clinical Microbiology, Cerrahpasa School of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
2 Department of Infectious Diseases and Clinical Microbiology, Haseki Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
3 Department of Infectious Diseases and Clinical Microbiology, Bakirkoy Dr.Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
4 Department of Infectious Diseases and Clinical Microbiology, Sisli Hamidiye Etfal Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
5 Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Bezmialem Vakıf University, Istanbul, Turkey
Abstract
Objectives:
Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) is a recommended and widely used regimen for HIV infection. In this study, we aimed to determine the efficacy and safety of E/C/F/TAF in people living with HIV (PLWH), who are either treatment-na¨ıve or switched from any tenofovir disoproxil fumarate-containing regimen. For switched patients, we aimed to determine the impact of switching from tenofovir disoproxil fumarate (TDF) to TAF on lipid profile and kidney functions.
Methods:
ACTHIV-IST Study Group produced a database, and five dedicated HIV centres in Istanbul entered data of PLWH who switched from any TDF-containing regimen to E/C/F/TAF and treatment-na¨ıve patients who were initiated with the E/C/F/TAF regimen between January 2017 and December 2019. Clinical findings, viral pa- rameters, lipid studies, renal function tests, adverse events and adherence to the treatment were recorded in this prospective observational study.
Results:
The study included a total of 614 switched and treatment-na¨ıve patients. Of 430 treatment- experienced patients, 89% (382) were men, and the mean age was 42 ± 12 years. Among them, 47% (181/382) self-identified as men who have sex with men (MSM). The median duration of HIV diagnosis was 54 ± 29 months. The median duration of E/C/F/TAF use was 20 ± 36 months and that of previous treatment was 23 ± 18 months. HIV-RNA was undetectable at baseline and month 12 in 84.1% (360/428) and 86.1% (328/381) of patients, respectively (p > 0.05). Mean CD4 counts were 708 ± 287 cells/µL and 802 ± 305 cells/µL at baseline and month 12, respectively (p < 0.001). Serum creatinine levels remained stable during the treatment period. Mean total cholesterol levels at baseline and month 12 were 172 and 211 mg/dL (p < 0.01), LDL- cholesterol 104 and 138 mg/dL (p < 0.01), HDL-cholesterol 39 and 49 mg/dL (p < 0.01) and triglycerides 134 and 174 mg/dL (p < 0.01), respectively. The treatment was generally well tolerated. Eight patients discontinued the therapy (drug interaction: 3; lost to follow-up: 1; pregnancy: 1; pulmonary tuberculosis: 1; side effect: 1; patient’s decision: 1). Of 184 treatment-na¨ıve patients, 88% (162) were men, and the mean age was 36.5± 12 years. Among them, 50% (81/162) self-identified as MSM. The mean duration of HIV infection was 21.6 ± 17.1 months. The mean duration of E/C/F/TAF use was 16 ± 4 months. HIV-RNA was undetectable at baseline and month 12 in 1% and 89.1% of patients, respectively. Mean CD4 counts at baseline and month 12 were 469 ± 223 cells/µL and 740 ± 298 cells/µL, respectively. During the treatment period, creatinine levels remained stable. Total cholesterol, LDL-cholesterol, triglyceride and also HDL-cholesterol levels increased. Mean total cholesterol levels at baseline and month 12 were 167 and 211 mg/dL (p < 0.01), LDL-cholesterol 108 and 143 mg/dL (p < 0.01), HDL- cholesterol 41 and 47 mg/dL (p < 0.01) and triglycerides 136 and 172 mg/dL, respectively (p < 0.01). The treatment was generally well tolerated. Three patients discontinued the therapy (drug interaction: 1; non-responder: 1; patient’s decision: 1).
Conclusion:
Starting with or switching to E/C/F/TAF in PLWH effectively suppresses HIV infection, is associated with an increase in CD4 cell count and is well tolerated in a real-life setting. Renal functions remained stable during the treatment. E/C/F/TAF use was associated with an increase in LDL-cholesterol and triglyceride levels along with an increase in HDL- cholesterol levels.
Introduction
Elvitegravir/cobicistat/emtricitabine/tenofovir alafena- mide (E/C/F/TAF) combination is a recommended regi- men in the current human immunodeficiency virus (HIV) treatment guidelines and is widely used in clinicalpractice. 1–3
Elvitegravir is an integrase strand transfer inhibitor(INSTI). INSTIs are anchor drugs for treatment-na¨ıve pa- tients with their high efficacy and favourable safety profiles, compared to non-nucleoside reverse transcriptase inhibitors (NNRTIs)4–6 and protease inhibitors (PIs).7–9 INSTIs show a high genetic barrier to resistance and high potency.
INSTIs are generally safe and well tolerated. In rando- mised clinical trials, 1–4% of the patients discontinued the therapy due to adverse effects.10 Observational studies showed that discontinuations due to any reason tended to be less common with elvitegravir, but discontinuations dueto toxicity did not differ among integrase inhibitors. Yet, neuropsychiatric toxicity leading to drug discontinuation was more frequent with dolutegravir, especially amongst women and older patients.11–16
Co-formulated E/C/F/TAF contains tenofovir alafena-mide (TAF), a tenofovir prodrug with a 90% reduction in plasma tenofovir concentrations compared to the use of tenofovir disoproxil fumarate (TDF). Relatively higher rates of renal and bone toxicity are associated with high plasma tenofovir concentrations. TAF-containing regi- mens were shown to have advantages in renal function, bone parameters and lipid profile for treatment-na¨ıve people living with HIV (PLWH).17 Nevertheless, owing to the TAF component, a reduction in estimated glomerular filtration rate (eGFR) during the first 4 weeks of treatment, both in na¨ıve and experienced patients, has beenreported.8,17–21
Real-life studies are observational studies providing dataabout the treatment in a wider population. They determinewhether the expected outcomes are obtained in routine clinical practice. They have more relaxed inclusion criteria, and exclusion criteria are not strict.22 It is possible to see almost all scenarios in clinical practice with exposure to a large number of patients. On the other hand, real-life observational studies are often biased if they are used as an alternative to randomised trials since the balance between the groups is not ensured.23
In this observational study, we aimed to determine the efficacy and safety of E/C/F/TAF on PLWH, who are either treatment-na¨ıve or switched from any tenofovir disoproxil fumarate-containing regimen. For switched patients, we also aimed to determine the impact of switching from te- nofovir disoproxil fumarate (TDF) to TAF on lipid profile and kidney functions.
We evaluated the clinical (patient history, physical ex- amination, complete blood count and biochemistry), im- munological (CD4 count) and virological (HIV-RNA levels) parameters of the patients.
Methods
Between January 2017 and December 2019, 614 PLWH older than 18 years of age were enrolled in this observa- tional, prospective, multi-centre study by ACTHIV-IST (Action Against HIV in Istanbul) Study Group, which in- cludes five centres following up PLWH in Istanbul. The first 6 months were the recruitment period.
The centres entered the data of PLHW who switched from any TDF-containing regimen to E/C/F/TAF and treatment-na¨ıve patients who were initiated with the E/C/F/ TAF regimen (Figure 1). All the patients in every centre received standard of care.
All newly diagnosed HIV/AIDS patients were confirmed by the Western Blot verification test (HIV BLOT 2.2, MPBiomedicals Asia Pacific, Singapore). The CD4+ cell counts were studied by flow cytometry (FACSCalibur, Becton Dickinson, New Jersey, USA), and HIV viral load was measured by PCR (COBAS AmpliPrep/COBAS TaqMan HIV-1 Test, Roche Molecular Systems, USA). Data on age, sex, CD4+ counts and HIV-RNA, complete blood count, renal function tests (creatinine levels and estimated glomerular filtration rate (eGFR)), lipid parameters (total cholesterol, LDL-cholesterol, HDL-cholesterol and tri- glycerides), adverse events and treatment adherence were collected from medical records and were transferred to an HIV database system. For those switching to the E/C/F/ TAF regimen, the following parameters were recordedbefore the switch, and tests were repeated every 3– 6 months.
Patients with high creatinine and low eGFR were also compared. For this comparison, the US National Kidney Foundation Classification for chronic kidney disease was used24: high creatinine was defined as >1.1 mg/dL in women and >1.3 mg/dL in men; low eGFR was defined as 90 mL/min/1.73 m2 for both genders. Rates of patients with low HDL and high triglyceride were compared using the National Cholesterol Education Program criteria25: low HDL (<55 mg/dL in women and <45 mg/dL in men) and high triglyceride (>200 mg/dL) were compared. Hepatitis B and C co-infections were screened by anti-HCV and HBsAg. The results at baseline and 3, 6 and 12 months were used for the analysis.
Adherence was assessed by the self-reporting of the patients. Reported side effects included those that were patient-reported (symptoms and complaints), based on laboratory data and clinically reported (signs and physical examination findings).
Statistical Analysis
For descriptive statistics, continuous variables were given as mean ± standard deviation, and categorical variables were given as rate and percent. Continuous variables at baseline, month 3, month 6 and month 12 were compared byrepeated-samples ANOVA, and categorical variables were compared by Cochran’s Q test. p < 0.05 was accepted as statistically significant.
Ethics
The study was approved by the Ethics Committee of Is- tanbul University, Cerrahpasa Medical School.
Results
The study included 430 treatment-experienced and 184 treatment-na¨ıve patients.
Treatment-experienced patients
Demographic characteristics and clinical features before switching to E/C/F/TAF are given in Table 1. Before switching to E/C/F/TAF, 96% of the patients were treated with TDF-containing regimens. After switching to E/C/F/ TAF, HIV-RNA levels and the rate of virologically sup- pressed patients did not change significantly, while CD4 count increased during the observation period (Table 2).
E/C/F/TAF treatment was generally well tolerated. Eight patients discontinued the treatment (drug interaction: 3; pregnancy: 1; pulmonary tuberculosis: 1; adverse event: 1; patient’s decision: 1; lost to follow-up: 1).
Renal functions remained stable during the observation period: Creatinine level, the rate of patients with high creatinine, eGFR and those with low eGFR did not change significantly (Table 3). Total cholesterol levels, those with high total cholesterol, LDL level, triglyceride level and those with high triglyceride increased. HDL level increased while those with low HDL decreased.
Treatment-na¨ıve patients
Demographic characteristics and clinical features of treat- ment-na¨ıve patients treated with E/C/F/TAF are given in Table 1. Following the E/C/F/TAF regimen, HIV-RNA levels decreased, the rate of virologically suppressed pa- tients decreased, and CD4 count increased significantly (Table 2).
E/C/F/TAF treatment was generally well tolerated. Three patients discontinued the therapy (drug interaction: 1; non- responder: 1; patient’s decision: 1).
Creatinine levels and those with stage 2 kidney diseaseincreased within the first 3 months of therapy and then remained stable (Table 3). eGFR and those with high creatinine did not change. Total cholesterol levels, those with high total cholesterol, LDL level, triglyceride level and those with high triglyceride increased. HDL level increased while those with low HDL decreased.
The rate of adherence was 98.1% and 98.4% for 1 year in treatment-experienced and treatment-naive patients, respectively.
Discussion
A total of 614 patients were analysed in this retrospective study of treatment-experienced or treatment-na¨ıve PLWH who were prescribed the co-formulated E/C/F/TAF regimen. The study showed that the INSTI-based co-formulated regimen is effective in providing a viral suppression rate of 86% and 90% after 12 months of therapy in treatment- experienced and treatment-na¨ıve patients, respectively. These results are comparable with other real-life clinical studiesyielding 67%–88%26–29 and 75%–96%28–30 in treatment- experienced and treatment-na¨ıve patients, respectively.
Clinical studies, real-life data, meta-analyses and systematic reviews support the efficacy of INSTIs-based regimens.31,32 The tolerability was optimal in both treatment- experienced and treatment-na¨ıve patients. Among INSTI- based regimens, there have been unexpectedly high discontinuation rates, mainly due to the neuropsychiatricside effects of dolutegravir. Discontinuation rates were 4%– 6%.12–14 Elvitegravir use was not associated with this side effect in our cohort. The high rate of adherence in our cohortis probably multifactorial. The study includes five dedicated HIV centres which have much fewer barriers to HIV care. A multidisciplinary approach to complicated challenges ofHIV care increases the patients’ adherence to a given centre. Moreover, taking one co-formulated pill obviously de- creases the pill burden and increases adherence, thus sus-tains viral suppression and improves the quality of life.33–34 Renal function remain a concern in tenofovir-containing regimens. TAF contains much less tenofovir than TDF, andrenal adverse events are expected less and milder in severity. Although our study is an observational one, in the treatment-experienced patients’ cohort, the vast majority of the patients were switched from a TDF-containing regimento a TAF-containing one. This switch resulted in improved renal functions in some cohorts.35,36 During the switch and in the following 12 months, there were no significant changes in renal functions in our study. Baseline eGFR was suggested as a significant predictor of the change in eGFR; patients on TDF with poorer baseline renal function would benefit more from switching to TAF.37 Baseline renal functions were optimal in our treatment-experienced pa- tients, which may explain why any such positive impact ofTDF–TAF switch was not observed.
Lipid parameters showed significant changes in bothtreatment-experienced and treatment-na¨ıve patients. There were significant increases in the proportions of patients treated with TAF-containing regimens with more severe dyslipidemia in other cohorts.38–40 This change was sug- gested to be reversible after switching back to TDF.41 A posthoc study evaluated the impact of lipid changes on predicted atherosclerotic cardiovascular disease (ASCVD) risk and statin eligibility in treatment-na¨ıve 1774 adults living with HIV treated with TAF or TDF.42 In that study, lipid changes (increases in total cholesterol, LDL and HDL) with TAF as part of co-formulated regimens did not substantively affect CVD risk profiles compared to TDF. However, considering the increasing age and other cardiovascular risk factors of patients living with HIV, changes in lipid parameters should be followed up closely and for the long term.
Our study has some limitations inherent to its retro- spective design. Most patients in our study were young men with optimal renal functions and relatively high CD4 counts. Fewer comorbidities and favourable baseline patient characteristics decrease the significance of difference, which is expected from a real-life study. The second lim- itation is the relatively short duration of the cohort study. Both renal functions and lipid parameters may be further affected in the long term, and in order to reach conclusions from this treatment regimen, a longer time of follow-up is required.
Our observational real-life study showed that starting with or switching to E/C/F/TAF in PLWH effectively suppresses HIV infection, is associated with an increase in CD4 cell count and is well tolerated in a real-life setting. Renal functions remained stable during the treatment. E/C/F/TAF use was associated with increases in LDL-cholesterol, triglyceride and also HDL-cholesterollevels, which may require closer long-term follow-up for their probable clinical significance.
References
1. U.S. Department of Health and Human Services. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV, https://aidsinfo.nih.gov/guidelines/brief-html/1/ adult-and-adolescent-arv/0 (accessed 20 July 2020).
2. EACS European AIDS Clinical Society. Guidelines. version10.0 November 2019, https://www.eacsociety.org/files/ guidelines-10.0_final_2_2.pdf (accessed 20 July 2020).
3. Saag MS, Benson CA, Gandhi RT, 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(4): 379–396.
4. Sax PE, Pozniak A, Montes ML, et al. Coformulated bicte-gravir, emtricitabine, and tenofovir alafenamide versus do- lutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV- 1 infection (GS-US-380-1490): a randomised, double-blind, multicentre, phase 3, non- inferiority trial. Lancet (London, England) 2017; 390:2073–2082.
5. Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plusabacavir-lamivudine for the treatment of HIV-1 infection.N Engl J Med 2013; 369: 1807–1818.
6. Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy ofraltegravir-based versus efavirenz-based combination therapy in treatment-na¨ıve patients with HIV-1 infection: a multi- centre, double-blind randomized controlled trial. Lancet (London, England) 2009; 374: 796–806.
7. Clotet B, Feinberg J, van Lunzen J, et al. Once-daily dolu-tegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study. Lancet (London, England) 2014; 383: 2222–2231.
8. DeJesus E, Rockstroh JK, Henry K, et al. Co-formulatedelvitegravir, cobicistat, emtricitabine, and tenofovir disoproxilfumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet (London, England) 2012; 379:2429–2438.
9. Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy andtolerability of 3 nonnucleoside reverse transcriptase inhibitor- sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med 2014; 161: 461–471.
10. Elzi L, Erb S, Furrer H, et al. Adverse events of raltegravir anddolutegravir. AIDS (London, England) 2017; 31: 1853–1858.
11. Penafiel J, de Lazzari E, Padilla M, et al. Tolerability of in-tegrase inhibitors in a real-life setting. J Antimicrob Che- mother 2017; 72(6): 1752–1759.
12. Hoffmann C, Welz T, Sabranski M, et al. Higher rates ofneuropsychiatric adverse events leading to dolutegravir discon- tinuation in women and older patients. HIV Med 2017; 18: 56–63.
13. de Boer M, van den Berk G, van Holten N, et al. Intoleranceof dolutegravir-containing combination antiretroviral therapy regimens in real-life clinical practice. AIDS (London, Eng- land) 2016; 30: 2831–2834.
14. Menard A, Montagnac C, Solas C, et al. Neuropsychiatricadverse effects on dolutegravir: an emerging concern in Europe. AIDS (London, England) 2017; 31: 1201–1203.
15. Cuzin L, Pugliese P, Katlama C, et al. Integrase strand transferinhibitors and neuropsychiatric adverse events in a large pro- spective cohort. J Antimicrob Chemother 2019; 74: 754–760.
16. Llibre JM, Montoliu A, Miro JM, et al. Discontinuation ofdolutegravir, elvitegravir/cobicistat and raltegravir because of toxicity in a prospective cohort. HIV Med 2019; 20: 237–247.
17. Tao X, Lu Y, Zhou Y, et al. Efficacy and safety of the regimenscontaining tenofovir alafenamide versus tenofovir disoproxil fumarate in fixed-dose single-tablet regimens for initial treatment of HIV-1 infection: A meta-analysis of randomized controlled trials. Int J Infect Dis 2020; 93: 108–117.
18. Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir,cobicistat, emtricitabine, and tenofovir versus co-formulated efa- virenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet 2012; 379(9835): 2439–2448.
19. Pozniak A, Markowitz M, Mills A, et al. Switching to co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of non-nucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir in virologically suppressed adults with HIV (STRATEGY-NNRTI): 48 week results of a randomised, open-label, phase 3b non-inferioritytrial. Lancet Infect Dis 2014; 14(7): 590–599.
20. Arribas JR, Pialoux G, Gathe J, et al. Simplification to co-formulated elvitegravir, cobicistat, emtricitabine, and teno- fovir versus continuation of ritonavir-boosted protease inhibitor with emtricitabine and tenofovir in adults with vi- rologically suppressed HIV (STRATEGY-PI): 48 week results of a randomised, open-label, phase 3b, non-inferiority trial.Lancet Infect Dis 2014; 14(7): 581–589.
21. Post FA, Winston J, Andrade-Villanueva JF, et al. Elvitegravir/cobicistat/emtricitabine/tenofovir DF in HIV-infected patients with mild-to-moderate renal impairment. J Acquir Immune Defic Syndr 2015; 68(3): 310–313.Tabak et al. 569
22. Natale E and Marsocci A. Are clinical trial results transferable in the real life? Monaldi Arch Chest Dis 2016; 84(1–2): 733. DOI: 10.4081/monaldi.2015.733
23. Collins R, Bowman L, Landray M, et al. The magic of ran- domization versus the myth of real-world evidence. N Engl J Med 2020; 382(7): 674–678.
24. Chronic kidney disease, classification. National KidneyFoundation. https://www.kidney.org/professionals/guidelines/guidelines_commentaries/chronic-kidney-disease-classification (Last accessed 20 July 2020).
25. National Cholesterol Education Program. Guidelines, https:// www.nhlbi.nih.gov/files/docs/guidelines/atglance.pdf (last accessed 10 May, 2020).
26. Jaeckle M, Khaykin P, Haberl A, et al. Efficacy of raltegravir- containing regimens in antiretroviral-naive and -experienced individuals in routine clinical practice. Int J STD AIDS 2016; 27: 1170–1179.
27. Jacobson K and Ogbuagu O. Integrase inhibitor-basedregimens result in more rapid virologic suppression rates among treatment-naive human immunodeficiency virus- infected patients compared to non-nucleoside and protease inhibitor-based regimens in a real-world clinical setting: a retrospective cohort study. Medicine 2018; 97: e13016.
28. Naumann U, Moll A, Schleehauf D, et al. Similar efficacy and tolerability of raltegravir-based antiretroviral therapy in HIV- infected patients, irrespective of age group, burden of co-morbidities and concomitant medication: real-life analysis of the German ‘WIP’ cohort. Int J STD AIDS 2017; 28: 893–901.
29. Brehm TT, Franz M, Hüfner A, et al. Safety and efficacy ofelvitegravir, dolutegravir, and raltegravir in a real-world co- hort of treatment-na¨ıve and -experienced patients. Medicine (Baltimore) 2019; 98(32): e16721.
30. Squires K, Bekker L-G, Eron JJ, et al. Safety, tolerability, and efficacy of raltegravir in a diverse cohort of HIV-infected patients: 48-week results from the REALMRK study. AIDS Res Hum Retroviruses 2013; 29: 859–870.
31. Kanters S, Vitoria M, Doherty M, et al. Comparative efficacyand safety of first-line antiretroviral therapy for the treatment of HIV infection: a systematic review and network meta- analysis. Lancet HIV 2016; 3: e510–e520.
32. Lee FJ, Amin J and Carr A. Efficacy of initial antiretroviraltherapy for HIV-1 infection in adults: a systematic review and meta-analysis of 114 studies with up to 144 weeks’ follow-up. PLoS One 2014; 9: e97482.
33. Bangsberg DR, Ragland K, Monk A, et al. A single tablet regimen is associated with higher adherence and viral sup- pression than multiple tablet regimens in HIV+ homeless and marginally housed people. AIDS 2010; 24(18): 2835–2840.DOI: 10.1097/QAD.0b013e328340a209
34. Airoldi M, Zaccarelli M, Bisi L, et al. One-pill once-a-day HAART: a simplification strategy that improves adherence and quality of life of HIV-infected subjects. Patient Prefer Adherence 2010; 4: 115–125.
35. Surial B, Ledergerber B, Calmy A, et al. Changes in renalfunction after switching from TDF to TAF in HIV-infected individuals: a prospective cohort study. J Infect Dis 2020; 222(4): 637–645.
36. DeJesus E, Haas B, Segal-Maurer S, et al. Superior efficacyand 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(4): 337–342.
37. Turner D, Drak D, O’Connor CC, et al. Renal functionchange after switching tenofovir disoproxil fumarate fortenofovir alafenamide in the HIV-positive patients of a metropolitan sexual health service. AIDS Res Ther 2019; 16(1): 40.
38. Lacey A, Savinelli S, Barco EA, et al. Investigating the effect of antiretroviral switch to tenofovir alafenamide on lipid profiles in people living with HIV within the UCDID Cohort. AIDS 2020; 34(8): 1161–1170. DOI: 10.1097/QAD.0000000000002541
39. Schwarze-Zander C, Piduhn H, Boesecke C, et al. Switching tenofovir disoproxil fumarate to tenofovir alafenamide in a real life setting: what are the implications? HIV Med 2020; 21(6): 378–385. DOI: 10.1111/hiv.12840
40. Kauppinen KJ, Kivela P and Sutinen J. Switching from te-nofovir disoproxil fumarate to tenofovir alafenamide signif- icantly worsens the lipid profile in a real-world setting. AIDS Patient Care STDS 2019; 33(12): 500–506.
41. Milinkovic A, Berger F, Arenas-Pinto A, et al. Lipidchanges due to tenofovir alafenamide are reversible by switching back to tenofovir disoproxil fumarate. AIDS 2019; 33(15): 2387–2391. DOI: 10.1097/QAD.0000000000002350
42. Huhn GD, Shamblaw DJ, Baril JG, et al. Atheroscleroticcardiovascular disease risk profile of Cobicistat tenofovir alafenamide versus tenofovir disoproxil fumarate. Open Forum Infect Dis 2019; 7(1): ofz472.