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ledipasvir treatment for HCV infection: Much Ado About Nothing?
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LETTER TO THE EDITOR
Co-administration of tenofovir plus protease inhibitor based antiretroviral therapy during sofosbuvir/ledipasvir treatment for HCV infection: Much Ado About Nothing? KEYWORDS Tenofovir; Hepatitis C virus; Sofosbuvir/ledipasvir
Dear Editor, The recent development of direct acting agents (DAAs) targeting hepatitis C virus (HCV) has revolutionised the outcome of HCV chronic infection, improving significantly the possibility of sustained viral response (SVR), also in HIV/HCV co-infected patients. Among DAAs, sofosbuvir/ledipasvir (SOF/LDV) is widely used for treatment of HCV genotype 1 and 4 and, in the case of HIV/HCV co-infection, can be safely co-administrated with almost all antiretrovirals [1]. However, European Guidelines recommend caution if the concomitant combined antiretroviral therapy (cART) contains tenofovir (TDF) and either ritonavir or cobicistat [1]. The warning is due to an increase in TDF concentrations in presence of these pharmacokinetic enhancers, added to the increase of TDF concentration caused by LDV itself [2—4]. Consequently, phase II/III trials did not allow the coadministration of TDF plus boosted protease inhibitors (bPI) within SOF/LDV [5,6]; then, no randomised controlled clinical trial explored the association. Considering the lack of data, current guidelines discourage the co-administration of TDF plus bPI and SOF/LDV [1] and recommend cART switching before starting SOF/LDV and, when not feasible, frequent renal function monitoring [1]. However, in real-life experience, patients in TDF and bPI containing regimens, in some cases, had already experienced multiple therapeutic lines or treatment failures, so that pre-emptive switch is not always feasible. In the context of the SCOLTA project (Surveillance Cohort Long-Term Toxicity Antiretrovirals), [7] we evaluated
the renal tolerability of the SOF/LDV in association with TDF and/or PIs in terms of eGFR variations, number of drug discontinuations and any renal adverse event. We have prospectively followed-up all HCV infected patients aged > 18 years who started a course of SOF/LDV treatment in 2015—2016. Patients have been followed up and performed blood tests in each centre, on the basis of clinical need and medical judgement. Clinical and laboratory data were collected in a common database every three months, until 12 weeks after the end of treatment. Glomerular filtration rate (eGFR) has been estimated on the basis of CKD-EPI equation [8]. Patients were described using frequency (%) for categorical variables and median (interquartile range, IQR) or mean (standard deviation, SD) for continuous variables. Comparisons among groups were performed using, respectively, the chi-square, Mann—Whitney U or t-test. During the study period 152 HCV infected patients, 26 females (17.1%), received a course of SOF/LDV treatment. Among them, 73 (48.0%) had a negative serology for HIV, whilst 79 (52.0%) were co-infected with HIV/HCV. Risk factors for infection were previous intravenous drug use in 41.7%, blood transfusions in 4.6%, unprotected intercourse in 4.0%, unapparent parenteral exposure in 0.7%, while were not known in the remaining patients (49.0%). Most patients (109, 71.7%) have been treated for 12 weeks and ribavirin was added to SOF/LDV as a part of anti-HCV treatment in 104 (68.4%) patients, in accordance with current guidelines recommendations [1]. Among the 79 HIV/HCV co-infected patients, 12 (15.2%) were female and 18 (22.8%) had a detectable HIV-RNA at the beginning of SOF/LDV treatment. At baseline, their mean CD4 T-cell count was 588 (standard deviation, SD ± 284). All 79 were in cART and 6 changed their cART by discontinuing either a PI or TDF (3 and 3 patients, respectively) before starting SOF/LDV. At the beginning of the HCV treatment, 47 patients (59.5%) were taking TDF and 34 (43.0%) a bPI; 17 were on both TDF and bPI. No patient was in cobicistat. The frequency of bPI treatment and mean age were similar in patients taking TDF and patients with TDF-sparing cART (P = 0.17 and P = 0.37), whereas monoinfected subjects were slightly older (P < 0.0001). At baseline, the overall median eGFR was 103.9 (IQR 83—124 ml/min), not significantly different among groups. At the moment of data extraction, 104 patients had
http://dx.doi.org/10.1016/j.clinre.2017.03.006 2210-7401/© 2017 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Taramasso L, et al. Co-administration of tenofovir plus protease inhibitor based antiretroviral therapy during sofosbuvir/ledipasvir treatment for HCV infection: Much Ado About Nothing? Clin Res Hepatol Gastroenterol (2017), http://dx.doi.org/10.1016/j.clinre.2017.03.006
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CLINRE-996; No. of Pages 4
xxx.e2 Table 1
Letter to the editor Change from baseline and outcome of treatment (if available). HCV (n = 73, 48.0%)
HIV/HCV on TDF-sparing cART (n = 32, 21.1%)
HIV/HCV on TDF-containing cART (n = 47, 30.9%)
P
107 (88—125) 101 (84—134) 106 (94—128)
112 (75—142) 96 (62—120) 90 (59—127)
88 (75—117) 81 (71—99) 84 (71—117)
0.19 0.01 0.14
Change from BL (mean ± SD) EoT 4.1 ± 30.8 FU 12 4.0 ± 27.7
−2.2 ± 17.8 −2.1 ± 18.9
−3.2 ± 17.3 −0.7 ± 25.7
0.36 0.69
CD4 (mean ± SD) BL EoT FU 12
615 ± 199 590 ± 323 595 ± 215
570 ± 295 553 ± 336 566 ± 283
0.50 0.70 0.77
Change from BL (mean ± SD) EoT FU 12
−35 ± 127 40 ± 141
−11 ± 121 18 ± 96
0.50 0.59
Outcome (n = 72) Treatment failure Relapse SVR 12
n = 16 2 (12.5) 1 (6.2) 13 (81.2)
n = 25 0 2 (8.0) 23 (92.0)
0.09
eGFR (median, IQR) BL EoT FU 12
— — —
n = 31 0 1 (3.2) 30 (96.8)
TDF: tenofovir; PI: protease inhibitor; cART: combined antiretroviral regimen; SD: standard deviation; IQR: interquartile range; EoT: end of treatment; FU 12: follow-up at 12 weeks after the end of treatment; SVR 12: sustained virologic response at 12 weeks.
Figure 1 Percentage change of estimated glomeralur filtration rate (eGFR) at the end of treatment (EoT) and after 12 weeks follow-up (FU12), compared to baseline (BL), according to HIV co-infection and class antiretroviral regimen. PI = protease inhibitor; TDF = tenofovir.
Please cite this article in press as: Taramasso L, et al. Co-administration of tenofovir plus protease inhibitor based antiretroviral therapy during sofosbuvir/ledipasvir treatment for HCV infection: Much Ado About Nothing? Clin Res Hepatol Gastroenterol (2017), http://dx.doi.org/10.1016/j.clinre.2017.03.006
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Letter to the editor completed the treatment and were subsequently analysed and 72 had already completed a 12 weeks follow-up (FU12) after the end of treatment (EoT), while the others were still on SOF/LDV. At EoT, mean change from baseline was 0.23 ml/min (SD 24.3, P = 0.92), and 1.0 ml/min at FU12 (SD 25.1, P = 0.75. The variation of eGFR was not significant in any of the groups considered at any time-point (Table 1). To account for differences in baseline eGFR, we also calculated the percentage changes from baseline: mean percentage difference was 1.2 (SD 22.5, P = 0.59), ranging from 4.5 (SD 25.2) in HCV mono-infected subjects to −3.4 (SD 15.2, P = 0.13) in HCV/HIV co-infected on a TDF-containing regimen (Fig. 1). An additional analysis in HIV infected patients who were in treatment with a bPI, either in combination or not with TDF, found no statistically significant variation of GFR. Focusing on EoT, we found that, on average, subjects on TDF-containing/without bPI regimens experienced the highest percentage filtration loss: −5.3 (SD 15.8). We also evaluated if the frequency of a loss >5% was different by groups: consistently with the analysis on variables in continuous, it was more frequent in TDF-containing regimens. When we split the groups between those who took bPI and those who did not, the comparison was not significant (P = 0.33). Two patients had renal adverse events in course of HCV treatment that have been possibly attributed to SOF/LDV or ribavirin by the investigators: a case of creatinine elevation in a HIV/HCV co-infected patient taking bPI and not TDF and one episode of dark urines in a HIV/HCV co-infected patient who was not taking bPI nor TDF. Both patients did not discontinue any antiviral drug and the adverse events resolved spontaneously and without sequelae at following blood and urine tests. None of the study participants, including patients still on treatment, discontinued any of the antiviral drugs or experienced adverse events due to drug interactions during the follow-up. The main finding of the present study is that HIV-infected patients on treatment with both TDF and a bPI did not experience a statistically significant decline of GFR. Moreover, neither HIV/HCV on TDF-containing cART nor HIV/HCV on TDF-sparing cART patients experienced any significant difference in GFR value at any time-point. To date, no published data have ever demonstrated the clinical burden of SOF/LDV association with TDF and bPI, while data from two real-life cohorts addressing this issue have been presented in international conferences. Goncalves et al. [9] found that mean eGFR decreased in all groups of patients during treatment with SOF/LDV, mainly in patients taking TDF plus PI. Vivancos-Gallego et al. evaluated renal safety of ‘‘boosted TDF’’ (Elvitegravir/cobicistat/FTC/TDF or TDF with a bPI) without finding any significant difference in creatinine or eGFR, nor in 12 vs 24 weeks of SOF/LDV [10]. In our study the variation of GFR was not statistically significant in 17 patients treated with the same regimen, nor in the other groups of patients considered. Additionally, in our clinical experience no serious adverse events attributable to drug over-dosage have been found. Particularly, no Fanconi’s syndrome, the most feared acute adverse event in case of TDF over dosage, happened and no patient stopped cART or SOF/LDV for adverse event.
xxx.e3 A major limitation of this study is the small sample size. Our power to detect a significant difference in changes from baseline eGFR values between HCV mono- and HCV/HIV coinfected patients was 0.53, and 0.24 to detect differences between subjects on TDF and those on other regimens. Second, therapeutic drug monitoring has not been performed, thus we have no data on the real concentrations of TDF obtained in the patients in different cART associations. Even if further and larger studies are desirable, our data suggest that, in real-life circumstances where TDF use in association with a PI and SOF/LDV might be necessary, the association is feasible and reasonably safe, if performed under clinical control and regular monitoring of uranalysis and creatinine levels.
Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Acknowledgements We want to acknowledge all the members of Coordinamento Italiano Studio Allergie e Infezione da HIV (CISAI). Coordination: T. Quirino, P. Bonfanti and E. Ricci. Recruitment sites and investigators: C. Bellacosa and P. Maggi (Bari); L. Calza (Bologna); C. Abeli and B. Menzaghi (Busto Arsizio); B.M. Celesia (Catania); C. Grosso and A. Stagno (Cesena); F. Vichi and F. Mazzotta (Firenze, S. Maria Annunziata); C. Martinelli (Firenze, Careggi); G. Penco and G. Cassola (Genova, Galliera); A. Di Biagio, L. Taramasso, LA Nicolini (Genova, S. Martino); C. Dentone (San Remo); C. Molteni (Lecco); L. Palvarini and A. Scalzini (Mantova); L. Carenzi and G. Rizzardini (Milano, Ospedale Sacco, I Divisione); L. Valsecchi and L. Cordier (Milano, Ospedale Sacco, II Divisione); S. Rusconi, M. Franzetti and M. Galli (Milano, Ospedale Sacco, Clinica Malattie Infettive); M. Franzetti (Padova); G.V. De Socio and A. Sgrelli (Perugia); E. Mazzotta and G. Parruti (Pescara); G. Madeddu, P. Bagella and M. S. Mura (Sassari); R. Libertone and A. Antinori (Roma); S. Di Giambenedetto (Roma); G. Orofino, M. Guastavigna and P. Caramello (Torino).
References [1] European Association for the Study of the Liver. EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol 2016 [Epub ahead of print]. [2] German P, Pang PS, West S, Han L, Sajwani K, Mathias A. Drug interactions between direct-acting anti HCV Antivirals sofosbuvir and ledipasvirand HIV antiretrovirals. In: 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. 2014. http://regist2.virologyeducation.com/2014/15HIVHEP PK/10 German.pdf [accessed 14.11.16]. [3] German P, Garrison K, Pang PS, Stamm LM, Ray AS, Shen G, et al. Abstract number: 82. Drug—Drug Interactions Between Anti-HCV Regimen Ledipasvir/Sofosbuvir and Antiretrovirals. In: CROI Conference 2017. 2016. http://www.croiconference. org/sessions/drug-drug-interactions-between-anti-hcvregimen-ledipasvirsofosbuvir-and-antiretrovirals [accessed 14.11.16].
Please cite this article in press as: Taramasso L, et al. Co-administration of tenofovir plus protease inhibitor based antiretroviral therapy during sofosbuvir/ledipasvir treatment for HCV infection: Much Ado About Nothing? Clin Res Hepatol Gastroenterol (2017), http://dx.doi.org/10.1016/j.clinre.2017.03.006
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xxx.e4 [4] Goicoechea M, Liu S, Best B, Sun S, Jain S, Kemper C, et al. Greater tenofovir-associated renal function decline with protease inhibitor-based versus nonnucleoside reverse-transcriptase inhibitor-based therapy. J Infect Dis 2008;197:102—8. [5] Naggie S, Cooper C, Saag M, Workowski K, Ruane P, Towner WJ, et al. Ledipasvir and Sofosbuvir for HCV in patients coinfected with HIV-1. N Engl J Med 2015;373:705—13. [6] Osinusi A, Townsend K, Kohli A, Nelson A, Seamon C, Meissner EG, et al. Virologic response following combined ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and HIV co-infection. JAMA 2015;313:1232—9. [7] Bonfanti P, Martinelli C, Ricci E, Carradori S, Parruti G, Armignacco O, et al. CISAI Group (Italian Coordinators for the Study of Allergies HIV Infection): an Italian approach to postmarketing monitoring: preliminary results from the SCOLTA (Surveillance Cohort Long-Term Toxicity Antiretrovirals) project on the safety of lopinavir/ritonavir. J Acquir Immune Defic Syndr 2005;39:317—20. [8] Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro III AF, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604—12. [9] Goncalves C, Soeiro C, Méndez J, Maia L, Martins S, Abreu MA, et al. Glomerular filtration rate change during HCV treatment with sofosbuvir/ledipasvir in HCV/HIV coinfected patients treated with tenofovir ± boosted PI. In: 12th International Workshop on Co-infection — HIV & Hepatitis. 2016. http://regist2.virology-education.com/2016/12coinfection/ ¸alves.pdf [accessed 14.11.16]. 16 Gonc [10] Vivancos-Gallego MJ, Moreno A, Pérez-Elias MJ, Quereda C, Díaz De Santiago A, Casado JL, et al. Abstract number: 452. Real-Life Renal Safety of Boosted TDF in HIV/HCV Patients on SOF/LDV. In: CROI Conference 2016. 2016. http://www. croiconference.org/sessions/real-life-renal-safety-boostedtdf-hivhcv-patients-sofldv [accessed 14.11.16].
Letter to the editor Lucia Taramasso a,∗ Elena Ricci b Benedetto Maurizio Celesia c Paolo Bonfanti d Tiziana Quirino e Nicola Squillace f Laura Ambra Nicolini a Paolo Maggi g Canio Martinelli h Giuseppe Vittorio De Socio i a Antonio Di Biagio , on behalf CISAI Study Group a University of Genova (DISSAL), Infectious Diseases Clinic, IRCCS AOU San Martino-IST, Largo R. Benzi, 10, 16132 Genova, Italy b Epi2004, Luigi Sacco Hospital, Milano, Italy c Infectious Diseases Unit, University of Catania, ARNAS (Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione) Garibaldi, Catania, Italy d Infectious Diseases Unit, A. Manzoni Hospital, Lecco, Italy e Unit of Infectious Diseases, ASST della Valle Olona, Busto Arsizio Hospital, Busto Arsizio, Italy f Infectious Diseases Clinic, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy g Infectious Disease Clinic, University Hospital Policlinico, Bari, Italy h Unit of Infectious Diseases, Careggi Hospital, Firenze, Italy i Unit of Infectious Diseases, Santa Maria Hospital, Perugia, Italy ∗
Corresponding author. E-mail address: [email protected] (L. Taramasso)
Please cite this article in press as: Taramasso L, et al. Co-administration of tenofovir plus protease inhibitor based antiretroviral therapy during sofosbuvir/ledipasvir treatment for HCV infection: Much Ado About Nothing? Clin Res Hepatol Gastroenterol (2017), http://dx.doi.org/10.1016/j.clinre.2017.03.006
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Clinics and Research in Hepatology and Gastroenterology (2017) xxx, xxx.e1—xxx.e4
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LETTER TO THE EDITOR
Co-administration of tenofovir plus protease inhibitor based antiretroviral therapy during sofosbuvir/ledipasvir treatment for HCV infection: Much Ado About Nothing? KEYWORDS Tenofovir; Hepatitis C virus; Sofosbuvir/ledipasvir
Dear Editor, The recent development of direct acting agents (DAAs) targeting hepatitis C virus (HCV) has revolutionised the outcome of HCV chronic infection, improving significantly the possibility of sustained viral response (SVR), also in HIV/HCV co-infected patients. Among DAAs, sofosbuvir/ledipasvir (SOF/LDV) is widely used for treatment of HCV genotype 1 and 4 and, in the case of HIV/HCV co-infection, can be safely co-administrated with almost all antiretrovirals [1]. However, European Guidelines recommend caution if the concomitant combined antiretroviral therapy (cART) contains tenofovir (TDF) and either ritonavir or cobicistat [1]. The warning is due to an increase in TDF concentrations in presence of these pharmacokinetic enhancers, added to the increase of TDF concentration caused by LDV itself [2—4]. Consequently, phase II/III trials did not allow the coadministration of TDF plus boosted protease inhibitors (bPI) within SOF/LDV [5,6]; then, no randomised controlled clinical trial explored the association. Considering the lack of data, current guidelines discourage the co-administration of TDF plus bPI and SOF/LDV [1] and recommend cART switching before starting SOF/LDV and, when not feasible, frequent renal function monitoring [1]. However, in real-life experience, patients in TDF and bPI containing regimens, in some cases, had already experienced multiple therapeutic lines or treatment failures, so that pre-emptive switch is not always feasible. In the context of the SCOLTA project (Surveillance Cohort Long-Term Toxicity Antiretrovirals), [7] we evaluated
the renal tolerability of the SOF/LDV in association with TDF and/or PIs in terms of eGFR variations, number of drug discontinuations and any renal adverse event. We have prospectively followed-up all HCV infected patients aged > 18 years who started a course of SOF/LDV treatment in 2015—2016. Patients have been followed up and performed blood tests in each centre, on the basis of clinical need and medical judgement. Clinical and laboratory data were collected in a common database every three months, until 12 weeks after the end of treatment. Glomerular filtration rate (eGFR) has been estimated on the basis of CKD-EPI equation [8]. Patients were described using frequency (%) for categorical variables and median (interquartile range, IQR) or mean (standard deviation, SD) for continuous variables. Comparisons among groups were performed using, respectively, the chi-square, Mann—Whitney U or t-test. During the study period 152 HCV infected patients, 26 females (17.1%), received a course of SOF/LDV treatment. Among them, 73 (48.0%) had a negative serology for HIV, whilst 79 (52.0%) were co-infected with HIV/HCV. Risk factors for infection were previous intravenous drug use in 41.7%, blood transfusions in 4.6%, unprotected intercourse in 4.0%, unapparent parenteral exposure in 0.7%, while were not known in the remaining patients (49.0%). Most patients (109, 71.7%) have been treated for 12 weeks and ribavirin was added to SOF/LDV as a part of anti-HCV treatment in 104 (68.4%) patients, in accordance with current guidelines recommendations [1]. Among the 79 HIV/HCV co-infected patients, 12 (15.2%) were female and 18 (22.8%) had a detectable HIV-RNA at the beginning of SOF/LDV treatment. At baseline, their mean CD4 T-cell count was 588 (standard deviation, SD ± 284). All 79 were in cART and 6 changed their cART by discontinuing either a PI or TDF (3 and 3 patients, respectively) before starting SOF/LDV. At the beginning of the HCV treatment, 47 patients (59.5%) were taking TDF and 34 (43.0%) a bPI; 17 were on both TDF and bPI. No patient was in cobicistat. The frequency of bPI treatment and mean age were similar in patients taking TDF and patients with TDF-sparing cART (P = 0.17 and P = 0.37), whereas monoinfected subjects were slightly older (P < 0.0001). At baseline, the overall median eGFR was 103.9 (IQR 83—124 ml/min), not significantly different among groups. At the moment of data extraction, 104 patients had
http://dx.doi.org/10.1016/j.clinre.2017.03.006 2210-7401/© 2017 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Taramasso L, et al. Co-administration of tenofovir plus protease inhibitor based antiretroviral therapy during sofosbuvir/ledipasvir treatment for HCV infection: Much Ado About Nothing? Clin Res Hepatol Gastroenterol (2017), http://dx.doi.org/10.1016/j.clinre.2017.03.006
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CLINRE-996; No. of Pages 4
xxx.e2 Table 1
Letter to the editor Change from baseline and outcome of treatment (if available). HCV (n = 73, 48.0%)
HIV/HCV on TDF-sparing cART (n = 32, 21.1%)
HIV/HCV on TDF-containing cART (n = 47, 30.9%)
P
107 (88—125) 101 (84—134) 106 (94—128)
112 (75—142) 96 (62—120) 90 (59—127)
88 (75—117) 81 (71—99) 84 (71—117)
0.19 0.01 0.14
Change from BL (mean ± SD) EoT 4.1 ± 30.8 FU 12 4.0 ± 27.7
−2.2 ± 17.8 −2.1 ± 18.9
−3.2 ± 17.3 −0.7 ± 25.7
0.36 0.69
CD4 (mean ± SD) BL EoT FU 12
615 ± 199 590 ± 323 595 ± 215
570 ± 295 553 ± 336 566 ± 283
0.50 0.70 0.77
Change from BL (mean ± SD) EoT FU 12
−35 ± 127 40 ± 141
−11 ± 121 18 ± 96
0.50 0.59
Outcome (n = 72) Treatment failure Relapse SVR 12
n = 16 2 (12.5) 1 (6.2) 13 (81.2)
n = 25 0 2 (8.0) 23 (92.0)
0.09
eGFR (median, IQR) BL EoT FU 12
— — —
n = 31 0 1 (3.2) 30 (96.8)
TDF: tenofovir; PI: protease inhibitor; cART: combined antiretroviral regimen; SD: standard deviation; IQR: interquartile range; EoT: end of treatment; FU 12: follow-up at 12 weeks after the end of treatment; SVR 12: sustained virologic response at 12 weeks.
Figure 1 Percentage change of estimated glomeralur filtration rate (eGFR) at the end of treatment (EoT) and after 12 weeks follow-up (FU12), compared to baseline (BL), according to HIV co-infection and class antiretroviral regimen. PI = protease inhibitor; TDF = tenofovir.
Please cite this article in press as: Taramasso L, et al. Co-administration of tenofovir plus protease inhibitor based antiretroviral therapy during sofosbuvir/ledipasvir treatment for HCV infection: Much Ado About Nothing? Clin Res Hepatol Gastroenterol (2017), http://dx.doi.org/10.1016/j.clinre.2017.03.006
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Letter to the editor completed the treatment and were subsequently analysed and 72 had already completed a 12 weeks follow-up (FU12) after the end of treatment (EoT), while the others were still on SOF/LDV. At EoT, mean change from baseline was 0.23 ml/min (SD 24.3, P = 0.92), and 1.0 ml/min at FU12 (SD 25.1, P = 0.75. The variation of eGFR was not significant in any of the groups considered at any time-point (Table 1). To account for differences in baseline eGFR, we also calculated the percentage changes from baseline: mean percentage difference was 1.2 (SD 22.5, P = 0.59), ranging from 4.5 (SD 25.2) in HCV mono-infected subjects to −3.4 (SD 15.2, P = 0.13) in HCV/HIV co-infected on a TDF-containing regimen (Fig. 1). An additional analysis in HIV infected patients who were in treatment with a bPI, either in combination or not with TDF, found no statistically significant variation of GFR. Focusing on EoT, we found that, on average, subjects on TDF-containing/without bPI regimens experienced the highest percentage filtration loss: −5.3 (SD 15.8). We also evaluated if the frequency of a loss >5% was different by groups: consistently with the analysis on variables in continuous, it was more frequent in TDF-containing regimens. When we split the groups between those who took bPI and those who did not, the comparison was not significant (P = 0.33). Two patients had renal adverse events in course of HCV treatment that have been possibly attributed to SOF/LDV or ribavirin by the investigators: a case of creatinine elevation in a HIV/HCV co-infected patient taking bPI and not TDF and one episode of dark urines in a HIV/HCV co-infected patient who was not taking bPI nor TDF. Both patients did not discontinue any antiviral drug and the adverse events resolved spontaneously and without sequelae at following blood and urine tests. None of the study participants, including patients still on treatment, discontinued any of the antiviral drugs or experienced adverse events due to drug interactions during the follow-up. The main finding of the present study is that HIV-infected patients on treatment with both TDF and a bPI did not experience a statistically significant decline of GFR. Moreover, neither HIV/HCV on TDF-containing cART nor HIV/HCV on TDF-sparing cART patients experienced any significant difference in GFR value at any time-point. To date, no published data have ever demonstrated the clinical burden of SOF/LDV association with TDF and bPI, while data from two real-life cohorts addressing this issue have been presented in international conferences. Goncalves et al. [9] found that mean eGFR decreased in all groups of patients during treatment with SOF/LDV, mainly in patients taking TDF plus PI. Vivancos-Gallego et al. evaluated renal safety of ‘‘boosted TDF’’ (Elvitegravir/cobicistat/FTC/TDF or TDF with a bPI) without finding any significant difference in creatinine or eGFR, nor in 12 vs 24 weeks of SOF/LDV [10]. In our study the variation of GFR was not statistically significant in 17 patients treated with the same regimen, nor in the other groups of patients considered. Additionally, in our clinical experience no serious adverse events attributable to drug over-dosage have been found. Particularly, no Fanconi’s syndrome, the most feared acute adverse event in case of TDF over dosage, happened and no patient stopped cART or SOF/LDV for adverse event.
xxx.e3 A major limitation of this study is the small sample size. Our power to detect a significant difference in changes from baseline eGFR values between HCV mono- and HCV/HIV coinfected patients was 0.53, and 0.24 to detect differences between subjects on TDF and those on other regimens. Second, therapeutic drug monitoring has not been performed, thus we have no data on the real concentrations of TDF obtained in the patients in different cART associations. Even if further and larger studies are desirable, our data suggest that, in real-life circumstances where TDF use in association with a PI and SOF/LDV might be necessary, the association is feasible and reasonably safe, if performed under clinical control and regular monitoring of uranalysis and creatinine levels.
Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Acknowledgements We want to acknowledge all the members of Coordinamento Italiano Studio Allergie e Infezione da HIV (CISAI). Coordination: T. Quirino, P. Bonfanti and E. Ricci. Recruitment sites and investigators: C. Bellacosa and P. Maggi (Bari); L. Calza (Bologna); C. Abeli and B. Menzaghi (Busto Arsizio); B.M. Celesia (Catania); C. Grosso and A. Stagno (Cesena); F. Vichi and F. Mazzotta (Firenze, S. Maria Annunziata); C. Martinelli (Firenze, Careggi); G. Penco and G. Cassola (Genova, Galliera); A. Di Biagio, L. Taramasso, LA Nicolini (Genova, S. Martino); C. Dentone (San Remo); C. Molteni (Lecco); L. Palvarini and A. Scalzini (Mantova); L. Carenzi and G. Rizzardini (Milano, Ospedale Sacco, I Divisione); L. Valsecchi and L. Cordier (Milano, Ospedale Sacco, II Divisione); S. Rusconi, M. Franzetti and M. Galli (Milano, Ospedale Sacco, Clinica Malattie Infettive); M. Franzetti (Padova); G.V. De Socio and A. Sgrelli (Perugia); E. Mazzotta and G. Parruti (Pescara); G. Madeddu, P. Bagella and M. S. Mura (Sassari); R. Libertone and A. Antinori (Roma); S. Di Giambenedetto (Roma); G. Orofino, M. Guastavigna and P. Caramello (Torino).
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Please cite this article in press as: Taramasso L, et al. Co-administration of tenofovir plus protease inhibitor based antiretroviral therapy during sofosbuvir/ledipasvir treatment for HCV infection: Much Ado About Nothing? Clin Res Hepatol Gastroenterol (2017), http://dx.doi.org/10.1016/j.clinre.2017.03.006
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Letter to the editor Lucia Taramasso a,∗ Elena Ricci b Benedetto Maurizio Celesia c Paolo Bonfanti d Tiziana Quirino e Nicola Squillace f Laura Ambra Nicolini a Paolo Maggi g Canio Martinelli h Giuseppe Vittorio De Socio i a Antonio Di Biagio , on behalf CISAI Study Group a University of Genova (DISSAL), Infectious Diseases Clinic, IRCCS AOU San Martino-IST, Largo R. Benzi, 10, 16132 Genova, Italy b Epi2004, Luigi Sacco Hospital, Milano, Italy c Infectious Diseases Unit, University of Catania, ARNAS (Azienda Ospedaliera di Rilievo Nazionale e di Alta Specializzazione) Garibaldi, Catania, Italy d Infectious Diseases Unit, A. Manzoni Hospital, Lecco, Italy e Unit of Infectious Diseases, ASST della Valle Olona, Busto Arsizio Hospital, Busto Arsizio, Italy f Infectious Diseases Clinic, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy g Infectious Disease Clinic, University Hospital Policlinico, Bari, Italy h Unit of Infectious Diseases, Careggi Hospital, Firenze, Italy i Unit of Infectious Diseases, Santa Maria Hospital, Perugia, Italy ∗
Corresponding author. E-mail address: [email protected] (L. Taramasso)
Please cite this article in press as: Taramasso L, et al. Co-administration of tenofovir plus protease inhibitor based antiretroviral therapy during sofosbuvir/ledipasvir treatment for HCV infection: Much Ado About Nothing? Clin Res Hepatol Gastroenterol (2017), http://dx.doi.org/10.1016/j.clinre.2017.03.006