Abstract
We evaluate the impact of ledipasvir on both tenofovir plasma trough concentration and estimated glomerular renal function in human immunodeficiency virus–hepatitis C virus coinfected patients receiving a tenofovir‐based antiretroviral regimen and treated with ledipasvir/sofosbuvir. Twenty‐six patients [81% male, median age: 51 years; hepatitis C virus genotype 1(75%)/4(15%)] were included. Tenofovir trough concentration (interquartile range) increased from 78 ng ml–1 (53–110) at baseline to 141 ng ml–1 (72–176) at 1 month (P = 0.003). No significant difference on estimated glomerular renal function using both Cockroft–Gault and Modification of Diet in Renal Disease formulae, respectively, [median (interquartile range)] was observed between baseline [101.3 ml min–1 (91.1–114.1); 95.6 ml min–1 (86.5–111.2)], 1 month [102.4 ml min–1 (89.8–112.9), P = 0.26; 92.5 ml min–1 (88.1–114.3), P = 0.27], end‐of‐treatment [96.5 ml min–1 (82.4–115.4), P = 0.39; 95.4 ml min–1 (84.2–105.4), P = 0.16] and 12 weeks after the end of treatment [100.5 ml min–1 (83.3–111.9), P = 0.24; 93.4 ml min–1 (82.2–103.5), P = 0.16]. Three patients progressed from chronic kidney disease stage 1 to stage 2 at 12 weeks post‐treatment. A significant increase in tenofovir exposure through P‐glycoprotein inhibition by ledipasvir was confirmed without significant impact on glomerular renal function in our population with normal renal function or mild renal impairment.
Keywords: drug–drug interaction, human immunodeficiency virus–hepatitis C virus coinfection, ledipasvir, renal function, tenofovir
What is Already Known about this Subject
Ledipasvir increases tenofovir trough concentration (Ctrough) in healthy volunteers by inhibiting P‐glycoprotein.
Tenofovir nephrotoxicity is concentration‐dependant and tenofovir Ctrough has been correlated with a glomerular renal function decrease.
Guidelines for hepatitis C virus treatment recommend caution when tenofovir disoproxil fumarate‐based regimens are combined to ledipasvir/sofosbuvir with frequent renal monitoring and/or dose adjustment.
What this Study Adds
A significant increase in tenofovir Ctrough was confirmed in human immunodeficiency virus–hepatitis C virus coinfected patients treated with ledipasvir/sofosbuvir.
No significant impact on glomerular renal function was observed, which might confirm ledipasvir/sofosbuvir as being a safe treatment at least for patients with normal renal function or mild renal impairment.
Introduction
Ledipasvir (LDV) is a hepatitis C virus (HCV) NS5A inhibitor, given once‐daily with sofosbuvir (SOF), an HCV NS5B nucleotide polymerase inhibitor, in an oral fixed‐dose (90/400 mg) combination tablet. LDV/SOF indicated with or without ribavirin for the treatment of chronic HCV infection is one of the most prescribed regimens for HCV genotype 1 and 4 infections 1, 2.
LDV/SOF may be safely coadministered with almost all antiretroviral drugs. Bilirubin monitoring along with therapeutic drug monitoring is recommended with atazanavir/r due to increased exposure of atazanavir by LDV 3. LDV and SOF are not metabolized through cytochrome P450 (CYP) isoforms but are both substrates for intestinal P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP) transporters 4. LDV is also a weak inhibitor of both P‐gp and BCRP leading to a few drug–drug interactions 4, 5. Thus, caution is warranted with well‐studied P‐gp substrates such as digoxin and dabigatran, but also potentially with other drugs, in part, transported by these proteins such as tenofovir disoproxil fumarate (TDF). In healthy volunteers, LDV increases tenofovir (TFV) exposure, ranging from 40 to 98% for the area under the curve and from 59 to 163% for the trough concentration (Ctrough), in combination with efavirenz, rilpivirine, dolutegravir or darunavir/ritonavir 6, 7. To date, no pharmacokinetic data have been reported in human immunodeficiency virus (HIV)– HCV coinfected patients. Therefore, higher TFV exposures may be observed in patients receiving LDV/SOF combined to TDF‐based regimens and therefore may increase the risk of renal toxicity. As TFV plasma concentration has been positively correlated with either a decrease in the glomerular renal function or the risk of tubulopathy 8, 9, 10, renal monitoring is currently recommended when LDV/SOF is associated with TDF‐based regimen if other alternatives are not available 1, 2.
The aim of our study was to evaluate the impact of LDV/SOF treatment on both TFV plasma Ctrough and glomerular renal function in a cohort of HIV‐HCV coinfected patients receiving a TDF‐based regimen.
Methods
Patients and study design
A retrospective and observational study was performed between January 2015 and June 2016 in an outpatient clinical unit following nearly 1000 HIV‐infected patients of whom 30% are HCV‐HIV coinfected. Data of patients receiving a TDF‐based antiretroviral therapy and initiating LDV/SOF for chronic HCV infection were collected from our electronic medical record NADIS, approved by the French Commission Nationale Informatique et Liberté (Registration number: 2001/762876/nadiscnil.doc). All patients signed informed consent before being included in the database 11. Serum HCV‐RNA was recorded at baseline, 1 month (M1), end of treatment (EOT) and 12 weeks post‐treatment (PT12). The virological outcome was evaluated through the sustained virological response defined as an undetectable HCV‐RNA et PT12.
Tenofovir plasma concentrations
TFV plasma Ctrough, quantified by a liquid chromatography–mass spectrometry method (limit of quantification: 10 ng ml–1; precision: 2.31% to 12.4%; accuracy: –10.1 to 3.42%), was collected as part of routine TDM, before initiation (baseline) of LDV/SOF when available and only if patients were on the same antiretroviral regimen. TFV Ctrough was determined at steady‐state, 1 month (M1) after LDV/SOF initiation, according to the recommendations of the French Association for Liver Study (Available at http://www.afef.asso.fr/ckfinder/userfiles/files/Interactions_DAA_ARV_dec2015.pdf.%20February%202016).
Glomerular renal function assessment
Glomerular renal function was assessed through estimated glomerular filtration rate (eGFR) using both Cockroft–Gault (CG) and Modification of Diet in Renal Disease's (MDRD) formulae at baseline, M1, EOT and PT12. Renal function staging was evaluated using the chronic kidney disease (CKD) classification (ml min–1 1.73m–2): stage 1 (>90), stage 2 (60–89), stage 3 (30–59), stage 4 (15–29), stage 5 (<15) 12.
Statistical analysis
Results are expressed as a median value (interquartile range) or n (%). TFV Ctrough before and after LDV/SOF initiation as well as eGFR values between baseline and the different endpoints of the follow‐up were compared using the nonparametric Wilcoxon rank‐sum test. TFV Ctrough was also compared only in patients for whom both values (baseline and M1) were available using the Wilcoxon matched pairs test. Analyses were performed using IBM SPSS Statistics 20 (IBM Corp., Armonk, New York, USA).
Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 13, and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 14.
Results
Patient characteristics and HCV treatment response
Data of 26 HIV‐HCV coinfected patients (81% male; 85% HCV genotype 1 coinfected) receiving LDV/SOF for 8 weeks (n = 1), 12 weeks (n = 23) or 24 weeks (n = 2) were analysed (Table 1). Three patients (11%) received ribavirin in combination with LDV/SOF. All patients were treated for their HIV infection with TDF/FTC combined to a non‐nucleoside reverse transcriptase inhibitor (rilpivirine n = 5; etravirine n = 3, efavirenz n = 1), or a boosted protease inhibitor (atazanavir/r n = 5; darunavir/r n = 4) or an integrase inhibitor (raltegravir n = 7; dolutegravir n = 1). At baseline, according to CKD stage classification, 20/26 (76.9%) were in stage 1, 5/26 (19.2%) in stage 2 and only one (3.8%) in stage 3.
Table 1.
Baseline characteristics of the population
| Characteristic, n = 26 patients | Median (IQR) or n (%) |
|---|---|
| Age, years | 51.3 (49.1–54.9) |
| Sex, male | 21 (81) |
| HCV infection, years | 20.2 (16.8–22) |
| HCV genotype | |
| ‐ 1a/1b/not determined | 14 (54)/7 (27)/1 (4) |
| ‐ 4 | 4 (15) |
| HCV RNA, log UI ml –1 | 5.8 (5.1–6.2) |
| Fibrosis stage | |
| ‐ F0/F1 | 12 (46) |
| ‐ F2/F3 | 10 (39) |
| ‐ F4 | 4 (15) |
| Child–Pugh score | |
| ‐ A | 21 (80.8) |
| ‐ B | 4 (15.4) |
| ‐ unknown | 1 (3.8) |
| HIV infection, years | 26.3 (20.1–27.8) |
| CDC stage | |
| ‐ A | 8 (30.8) |
| ‐ B | 15 (57.7) |
| ‐ C | 3 (11.5) |
| CD4, cells mm –3 | 857 (501–1028) |
| ‐ 200–500 | 6 (23) |
| ‐ >500 | 20 (77) |
| Plasma HIV RNA < 50 copies ml –1 | 24 (92) |
| ARV exposition, years | 18.5 (16.3–20.8) |
| ‐ TDF exposition, years | 7.1 (4.0–9.9) |
| ARV treatment | |
| ‐ TDF/FTC + II | 8 (30.8) |
| ‐ TDF/FTC + NNRTI | 9 (34.6) |
| ‐ TDF/FTC + boosted PI | 9 (34.6) |
| Risk factors of nephrotoxicity | |
| ‐ Diabetes | 3 (11.5) |
| ‐ High blood pressure | 4 (15.4) |
ARV, antiretroviral; FTC, emtricitabine; II, integrase inhibitor; HCV; hepatitis C virus; HIV, human immunodeficiency virus; NNRTI, non‐nucleoside reverse transcriptase inhibitors; PI, protease inhibitor; TDF, tenofovir disoproxil fumarate.
All patients completed their HCV treatment and sustained virological response was achieved in 24/26 (92%) patients. Two patients (infected by genotype 4 and 1a) treated for 12 weeks, relapsed at week 4 after EOT.
Impact of ledipasvir on tenofovir Ctrough
On the whole population, the median (IQR; n) TFV Ctrough increased significantly from 78 ng ml–1 (53–110; 25) at baseline to 141 ng ml–1 (72–176; 15) 1 month after LDV/SOF initiation (P = 0.003). Among patients for which TFV Ctrough was available both at baseline and M1 (n = 15), a significant increase of 55% in the mean (± standard deviation) TFV Ctrough was observed: 84.1 (± 30.4) ng ml–1 at baseline vs. 131 (± 55.3) ng ml–1 at M1 (P = 0.003).
Evolution of the glomerular renal function during LDV/SOF treatment
MDRD and CG eGFR values were, respectively: 95.6 (86.5–111.2; 26) and 101.3 (91.1–114.1; 26) at baseline; 92.5 (88.1–114.3; 25) and 102.4 (89.8–112.9; 25) at M1; 95.4 (84.2–105.4; 26) and 96.5 (82.4–115.4; 25) at EOT; and 93.4 (82.2–103.5; 26) and 100.5 (83.3–111.9; 21) at PT12. No significant difference was observed on eGFR, regardless of the formula used, over the treatment duration (Figure 1).
Figure 1.
Estimated glomerular renal function (eGFR) evolution during hepatitis C virus treatment with ledipasvir (LDV)/sofosbuvir (SOF). MDRD, Modification of Diet in Renal Disease
Among the 17 patients with CKD stage 1 at baseline, five progressed to CKD stage 2 during HCV treatment (four at M1 and one at EOT). Two out of these five returned to stage 1 while three only remained at stage 2 at PT12. None of the nine patients with CKD stage 2 at baseline progressed to stage 3 during HCV therapy; two of them were classified stage 1 at EOT and PT12. The CKD staging was similar using either CG or MDRD eGFR.
Discussion
Our results are the first to report data on both TFV exposure and glomerular renal function after 12 or 24 weeks of LDV/SOF therapy in a cohort of HIV‐HCV coinfected patients receiving a TDF‐based regimen. In our population, TFV exposure was significantly increased by 80%, confirming a significant drug–drug interaction between LDV and TDF through intestinal P‐gp inhibition. The median TFV Ctrough, within the expected range at baseline (40–90 ng ml–1), has become potentially nephrotoxic after LDV/SOF initiation and higher than usually observed with boosted regimen, which is approximately increased by 20–30% 8, 9, 10, 15. This result is consistent with those previously described in healthy volunteers, reporting an increase in TFV Ctrough ranging from 40 to 98%, according to the third antiretroviral agent prescribed 6, 7. As ritonavir inhibits P‐gp, boosted regimen may also increase TFV exposure. Unfortunately, the limited number of patients for each class did not allow us to assess the degree of the interaction between boosted and nonboosted regimens.
TFV undergoes renal clearance by both glomerular filtration and active tubular secretion 16. TDF‐induced nephrotoxicity is well known and characterized by a delayed onset of gradual decrease in eGFR and/or signs of tubular dysfunction but some cases of acute renal injury have also been reported 17, 18, 19. TFV plasma concentrations and cumulative exposition of TDF have been independently associated with an increased risk of kidney disease 8, 9, 10, along with baseline serum creatinine, low body weight, or protease inhibitor‐containing regimens 20. Therefore, in France, TDM of TDF is recommended particularly for all patients with impaired renal function 21. Guidelines for the treatment of HCV recommend caution when TDF‐based regimens are combined to LDV/SOF, with frequent renal monitoring and/or dose adjustment if other alternatives are not available but also to avoid this combination when eGFR is less than 60 ml min–1 (CKD stage ≥3) 1, 2. However, given the shorter treatment duration and the cumulative and concentration‐dependant mechanism of TDF‐induced nephrotoxicity, the risk of developing acute and/or severe renal injury might be expected to be limited.
In our HIV‐HCV coinfected population receiving a TDF‐based regimen, LDV/SOF did not significantly impact glomerular renal function. Indeed, eGFR, evaluated with both MDRD and CG formula, was not significantly modified during LDV/SOF therapy. It is important to note that the majority of our population (17/26) had a normal renal function at baseline. Only nine (35%) patients presented mild renal impairment according to the CKD classification and very few (10–15%) presented concomitant risk factors of nephrotoxicity such as diabetes or high blood pressure.
However, minor changes in the CKD stage were observed with deterioration of the renal function from CKD stage 1 to stage 2 reported in five patients during LDV/SOF therapy, of whom three remained at stage 2 at PT12. These three patients did not present additional risk factor of nephrotoxicity but two of them presented a slightly elevated TFV Ctrough at baseline (102 and 105 ng ml–1, respectively). No deterioration of the renal function was observed among patients with a CKD stage 2 at baseline.
Our results are consistent with recent data reporting no significant impact of LDV/SOF on the renal function in 69 patients with a baseline eGFR ≥70 ml min–1, without difference between patients receiving a boosted‐ or nonboosted‐TDF regimen 22. In this study, eGFR decreased below 70 ml min–1 in five patients but only one, on boosted‐TDF regimen, stopped TDF due to renal impairment after 74 days of therapy. Unfortunately, no pharmacokinetic data, particularly in the one who had to stop treatment, were available.
A case of acute kidney injury was recently reported in an HIV‐HCV coinfected cirrhotic patient, after 8 weeks of LDV/SOF, presenting a baseline eGFR at 62 ml min–1 23. A multifactorial aetiology was suggested as several risk factors of nephrotoxicity were present, along with occasional use of ibuprofen and evidence of acute tubular necrosis on the renal biopsy.
Despite these encouraging results, several limitations of the study must be highlighted. First given the small number of patients and the heterogeneity of the population, caution should be maintained regarding the safety of LDV/SOF in combination with TDF‐based regimen. Therefore, we need to confirm these preliminary results on a larger population, allowing stratification on the baseline eGFR. Another limit of our study is the lack of data concerning the markers of tubulopathy, in particular the protein:creatinine ratio and glycosuria. Unfortunately, we did not collect enough data to assess the tubular function thoroughly.
Tenofovir alafenamide (TAF), the new prodrug of TFV, decreased TFV plasma exposure by 90% allowing a better tolerance profile on kidney function even in patients with impaired renal function 24, 25. No clinically significant interaction was observed when TAF was coadministered with LDV/SOF in healthy volunteers with a TFV Ctrough still approximately 80% below the concentration range observed with the current TDF prodrug 7.
In summary, our results showed no significant impact on the glomerular renal function, after 8, 12 or 24 weeks of LDV/SOF, in a cohort of HIV‐HCV coinfected patients with normal renal function or mild renal impairment, although a significant increase in TFV exposure, due to P‐gp inhibition by LDV was confirmed. These results suggest that the short treatment duration with LDV/SOF, usually 12 weeks but further reduced to 8 weeks for HCV genotype 1 with low HCV‐RNA, could be considered as safe, at least for patients with an eGFR > 60 ml min–1. However, in case of high TFV Ctrough at baseline or after LDV/SOF initiation, the issue of a therapeutic intervention such as TDF dose‐adjustment or switching to TAF may be raised on a case‐by‐case according to the presence of other risk factors.
Moreover, due to the lack of data, caution is advised in patients with moderate or severe renal impairment and/or at higher risk of nephrotoxicity who would receive LDV/SOF and monitoring both TFV exposure and renal safety remains highly recommended.
Lastly, same concerns are likely to arise with the new anti‐NS5A velpatasvir, which also inhibits P‐gp and therefore increases TFV exposure to the same extent as LDV 26.
Competing interests
There are no competing interests to declare.
Contributors
C.S.: pharmacologist, coordinators of the pharmacokinetic study; tenofovir monitoring, data acquisition and interpretation; main writer of the manuscript. O.‐R.V.: methodology, data acquisition, statistical analysis and participation in the redaction. S.B., O.F.‐Z. and I.P.‐M.: investigators, recruitment of the patients and revision of the article. C.T.: virologist and revision of the article. S.Q. and B.L.: pharmacologists, contribution to the pharmacokinetic analysis and revision of the article.
Solas, C. , Bregigeon, S. , Faucher‐Zaegel, O. , Quaranta, S. , Obry‐Roguet, V. , Tamalet, C. , Lacarelle, B. , and Poizot‐Martin, I. (2018) Ledipasvir and tenofovir drug interaction in human immunodeficiency virus–hepatitis C virus coinfected patients: Impact on tenofovir trough concentrations and renal safety. Br J Clin Pharmacol, 84: 404–409. doi: 10.1111/bcp.13450.
References
- 1. AASLD/IDSA HCV Guidance Panel . Hepatitis C guidance: AASLD‐IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology 2015; 62: 932–954. [DOI] [PubMed] [Google Scholar]
- 2. European Association for the Study of the Liver . EASL recommendations on treatment of hepatitis C 2016. J Hepatol 2017; 66: 153–194. [DOI] [PubMed] [Google Scholar]
- 3. El‐Sherif O, Khoo S, Solas C. Key drug–drug interactions with direct‐acting antiviral in HIV‐HCV coinfection. Curr Opin HIV AIDS 2015; 10: 348–354. [DOI] [PubMed] [Google Scholar]
- 4. European Medicines Agency . Harvoni. Summary of Product characteristics. Available at http://www.ema.europa.eu/docs/fr_FR/document_library/EPAR_-_Product_Information/human/003850/WC500177995.pdf (last accessed 13 January 2017).
- 5. German P, Pang PS, Fang L, Chung D, Mathias A. Drug–drug interaction profile of the fixed‐dose combination tablet ledipasvir/sofosbuvir. Hepatology 2014; 60 (Suppl 1): 1976. [Google Scholar]
- 6. German P, Pang P, West S, Han L, Sajwani K, Mathias A. Drug interactions between direct‐acting anti‐HCV antivirals sofosbuvir and ledipasvir and HIV antiretrovirals [abstract O_06]. Presented at: 15th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy. Washington, 2014.
- 7. Garrisson K, Custodio J, Pang P, Das M, Cheng F, Ma G, et al Drug interactions between anti‐HCV antivirals ledipasvir/sofosbuvir and integrase strand transfer inhibitor–based regimens [abstract 71]. Presented at: 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy. Washington, 2015.
- 8. Rodríguez‐Nóvoa S, Labarga P, D'avolio A, Barreiroa P, Albalatec M, Vispo E, et al Impairment in kidney tubular function in patients receiving tenofovir is associated with higher tenofovir plasma concentrations. AIDS 2010; 24: 1064–1066. [DOI] [PubMed] [Google Scholar]
- 9. Ezinga M, Wetzels JFM, Bosch MEW, van der Ven AJ, Burger DM. Long‐term treatment with tenofovir: prevalence of kidney tubular dysfunction and its association with tenofovir plasma concentration. Antivir Ther 2014; 19: 765–771. [DOI] [PubMed] [Google Scholar]
- 10. Poizot‐Martin I, Solas C, Allemand J, Obry‐Roguet V, Pradel V, Bregigeon S, et al Renal impairment in patients receiving a tenofovir‐cART regimen: impact of tenofovir trough concentration. J Acquir Immune Defic Syndr 2013; 62: 375–380. [DOI] [PubMed] [Google Scholar]
- 11. Pugliese P, Cuzin L, Cabié A, Poizot‐Martin I, Allavena C, Duvivier C, et al A large French prospective cohort of HIV‐infected patients: the Nadis cohort. HIV Med 2009; 10: 504–511. [DOI] [PubMed] [Google Scholar]
- 12. Goolsby MJ. National Kidney Foundation guidelines for chronic kidney disease: evaluation, classification, and stratification. J Am Acad Nurse Pract 2002; 14: 238–242. [DOI] [PubMed] [Google Scholar]
- 13. Southan C, Sharman JL, Benson HE, Faccenda E, Pawson AJ, Alexander SPH, et al The IUPHAR/BPS guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. Nucl Acids Res 2016; 44: D1054–D1068. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Alexander SPH, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, et al The concise guide to PHARMACOLOGY 2015/16: transporters. Br J Pharmacol 2015; 172: 6110–6202. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. European Medicines Agency . Viread. Summary of Product characteristics. Available at http://www.ema.europa.eu/docs/fr_FR/document_library/EPAR_-_Product_Information/human/000419/WC500051737.pdf (last accessed 05 January 2017).
- 16. Ray AS, Cihlar T, Robinson KL, Tong L, Vela JE, Fuller MD, et al Mechanism of active renal tubular efflux of tenofovir. Antimicrob Agents Chemother 2006; 50: 3297–3304. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Fernandez‐Fernandez B, Montoya‐Ferrer A, Sanz AB, Sanchez‐Nino MD, Izquierdo MC, Poveda J, et al Tenofovir nephrotoxicity: 2011 update. AIDS Res Treat 2011; 2011: 354908: 11 pages. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Schaaf B, Aries SP, Kramme E, Steinhoff J, Dalhoff K. Acute renal failure associated with tenofovir treatment in a patient with acquired immunodeficiency syndrome. Clin Infect Dis 2003; 37: e41–e43. [DOI] [PubMed] [Google Scholar]
- 19. Zimmermann AE, Pizzoferrato T, Bedford J, Morris A, Hoffman R, Braden G. Tenofovir‐associated acute and chronic kidney disease: a case of multiple drug interactions. Clin Infect Dis 2006; 42: 283–290. [DOI] [PubMed] [Google Scholar]
- 20. Baxi SM, Greenblatt RM, Bacchetti P, Scherzer R, Minkoff H, Huang Y, et al Common clinical conditions ‐ age, low BMI, ritonavir use, mild renal impairment – affect tenofovir pharmacokinetics in a large cohort of HIV‐infected women. AIDS 2014; 28: 59–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Morlat P. Prise en charge médicale des personnes vivant avec le VIH. Recommandations du groupe d'experts. Paris, FRANCE: Ministère des affaires sociales et de la Santé. Conseil national du Sida. Agence nationale de recherches sur le sida et les hépatites virales. Rapport 2013. Available at http://social-sante.gouv.fr/IMG/pdf/Rapport_Morlat_2013_Mise_en_ligne.pdf (last accessed 5 January 2017)
- 22. Vivancos‐Gallego MJ, Moreno A, Pérez‐Elias MJ, Quereda C, Díaz De Santiago A, Casado JL, et al Real‐life renal safety of “boosted TDF” in HIV/HCV‐patients on SOF/LDV [abstract 452]. Presented at: 23rd Conference on Retroviruses and Opportunistic Infections. Boston, 2016.
- 23. Bunnell KL, Vibhakar S, Glowacki RC, Gallagher MA, Osei AM, Huhn G. Nephrotoxicity associated with concomitant use of ledipasvir‐sofosbuvir and tenofovir in a patient with hepatitis C virus and human immunodeficiency virus coinfection. Pharmacotherapy 2016; 36: e148–e153. [DOI] [PubMed] [Google Scholar]
- 24. 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. [DOI] [PubMed] [Google Scholar]
- 25. Pozniak A, Arribas JR, Gathe J, Gupta SK, Post FA, Bloch M, et al 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Mogalian E, Stamm LM, Osinusi A, Shen G, Sajwani K, McNally J, et al Drug interaction studies between sofosbuvir/velpatasvir and boosted HIV ARV regimens [abstract 100]. Presented at: 23rd Conference on Retroviruses and Opportunistic Infections. Boston, 2016.