Research Letter AIDS 2015, 29:977–979
Telaprevir decreases estimated glomerular filtration rate in HIV-hepatitis C virus coinfected patients Eva Van den Eynde, Jordi Curto, Elena Ferrer, Arkaitz Imaz, Maria Saumoy, Silvana Di Yacovo, Antonia Vila and Daniel Podzamczer We investigated kidney function outcome in 24 chronic hepatitis C genotype 1 patients coinfected with HIV receiving telaprevir in a single tertiary care hospital in Spain. A statistically significant median (interquartile range) decrease in estimated glomerular filtration rate (eGFR, ml/min/1.73 m2) relative to baseline [93.6 (73.0– 109.0)] was seen at weeks 4 [86.5 (34.0–112.0), P U 0.014], 8 [90.0 (49.0–111.0), P U 0.026] and 12 [89.5 (54.0–113.0), P U 0.017]. These changes reversed after telaprevir discontinuation. Patients presenting an eGFR decrease had a higher risk of haematological toxicity. An estimated glomerular filtration rate (eGFR) decrease during telaprevir (TVR) treatment was recently reported in hepatitis C virus (HCV)-infected patients [1–3], which has been correlated with higher ribavirin (RBV) plasma levels and increased risk of anaemia [4–6]. We designed a retrospective study to investigate the kidney function outcome in HCV/HIV-coinfected patients receiving TVR and an attempt to identify any correlation between changes in eGFR and the development of anaemia. Adult HIV-infected patients with chronic HCV genotype 1 infection starting TVR (1150 mg/day) along with pegylated interferon (PegIFN) and RBV in a single tertiary care hospital in Spain were evaluated. Clinical and biological data at TVR initiation and at every following visit during 48 weeks were retrospectively recorded from medical files. The eGFR was calculated by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. Wilcoxon’s signed-rank test for repeated measures was used for comparisons between follow-up and baseline results. We investigated the association between the antiretroviral drugs used and the presence of comorbidities with eGFR changes via the Mann–Whitney U-test. Pearson coefficient and linear regression were used to determine any correlation between the severity of the decreases in haemoglobin and eGFR at week 12. For all statistical analyses, P values less than or equal to 0.05 were considered significant.
Twenty-four HIV-positive patients started TVR in combination with PegIFN and RBV. One patient stopped therapy after 1 week because of PegIFN-related adverse events and was excluded from the analysis. Mean age was 48.9 years and 91.3% were men, 20 out of 23 (87%) had severe fibrosis/cirrhosis and 52.2% were treatment-naive. Among the 11 treatment-experienced patients, four (36.4%) were prior relapsers and seven (63.6%) prior nonresponders. Three patients discontinued therapy after 4 weeks because of intolerance to PegIFN in two cases and acute renal failure in one case (previously reported in this journal) [7]. A statistically significant median (interquartile range) reduction in eGFR (ml/min/1.73 m2) was seen relative to the baseline value [93.6 (73.0–109.0)] at weeks 4 [86.5 (34.0–112.0), P ¼ 0.014], 8 [90.0 (49.0–111.0), P ¼ 0.026] and 12 [89.5 (54.0–113.0), P ¼ 0.017]. These changes reversed after TVR discontinuation, as was seen at week 24 [92.0 (59.0–120.0), P ¼ 0.465] (Fig. 1a). The renal dysfunction caused by TVR was associated with the haemoglobin decrease at treatment-week 12 (Fig. 1b) (haemoglobin change at week 12, 3.86 mg/ dl þ 0.05x eGFR change at week 12; P ¼ 0.026). Neither the baseline fibrosis stage, the antiretroviral companion drugs, nor the patients’ risk factors for renal failure were associated with the eGFR decrease from baseline to week 12 (data not shown). We found a reversible eGFR decline during TVR therapy in HIV-HCV coinfected patients that is in keeping with the results of recent reports in HCV-monoinfected patients [1–3]. In a large real-life study, 6.6% of patients taking TVR experienced a decrease in eGFR to less than 60 ml/min compared with 0.9% of patients taking dual therapy [1]. In all patients, renal function improved after discontinuation of TVR. In another study, LoustaudRatti et al. [2] found that eGFR significantly decreased with TVR (mean nadir decrease at week 8, 17.0 18.9 ml/min/1.73 m2) and returned to baseline at week 16. Mauss et al. [1] were the first to describe a correlation between an eGFR drop and low haemoglobin concentrations. The authors suggested that this could be a result of RBVaccumulation consequent to impaired renal drug elimination. Two studies subsequently confirmed that the TVR-induced decrease in renal function leads to an increase in serum RBV concentration and a higher risk of anaemia [4,5]. Similarly, in the ANRS HC26 TelapreVIH study, to our knowledge, the only cohort examining changes in kidney
DOI:10.1097/QAD.0000000000000643
ISSN 0269-9370 Copyright Q 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
977
AIDS
2015, Vol 29 No 8 (a)
Median eGFR
Median creatinine
125
2.5
0.465* 0.017* 0.026* 0.014*
2.0
94
90
87
75
1.5 1.00
0.98
0.92
50
92
90
0.97
0.93
1.0
0.036*
Creatinine (mg/dL)
eGFR (mL/min/1.73 m2)
100
0.109*
25
0.5
0.040* 0.862*
TVR stopped
0 Baseline n = 23
4 n = 22
0.0 12 n = 20
8 n = 14
24 n = 22
Weeks *Wilcoxon signed-rank test for repeated measures to compare from baseline
(b) –1
Change hemoglobin (mg/dL) (week 12-baseline)
978
Change Hb week12-baseline = –3.86 + 0.05 x change eGFR week 12-baseline (p = 0.026)
–2
–3
–4
–5
–6
–7 –60
–40
–20
0
20
40
Change eGFR (mL/min/1.73 m2) (week 12-baseline)
Fig. 1. Renal function outcome. (a) Estimated glomerular filtration rate (eGFR) and creatinine changes. (b) Correlation between eGFR changes and haemoglobin level.
function in HIV patients receiving TVR, a reversible eGFR decline was also found during the first 8 weeks of triple therapy, which was associated with a significant rise in the RBV trough concentration and a higher risk of haematological toxicity [6]. In keeping with these data, the haemoglobin changes seen in our study also correlated with the magnitude of the eGFR decrease, likely due to a rise in serum RBV levels. However, as ours is a retrospective study, we do not have
data on plasma RBV concentrations and, regrettably, we cannot confirm this point. TVR has shown in-vitro inhibition of drug transporters expressed in the kidney, which interacts with proximal tubular creatinine secretion [8]. That has also been described in association with other drugs used for the treatment of HIV, which have demonstrated to decrease the eGFR by the inhibition of the organic cation transporter 2 (OCT2) (dolutegravir and rilpivirine) or the
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Research Letter
multidrug and toxin extrusion transporter 1 (MATE1) (cobicistat), without affecting the actual glomerular filtration [9,10]. This mechanism has been suggested as the reason for the elevations in plasma creatinine during TVR therapy [11], but true renal failure cannot be ruled out because there are no studies available in which simultaneous measurement of iohexol clearance has been performed. With the emergence of new direct antiviral agents (DAAs) for HCV with better efficacy and tolerability profiles, continued massive use of TVR seems unlikely. Nevertheless, because of the high cost of the new DAAs, triple therapy with first-generation protease inhibitors may remain the best treatment choice in countries with limited resources. Furthermore, particularly in the setting of HIVcoinfection, the use of several of the new DAAs may be limited by pharmacokinetic/pharmacodinamic interactions with the antiretroviral drugs. In these very few selected cases, TVR might still be the most suitable option. In conclusion, even though only a small number of patients were evaluated, TVR treatment was significantly associated with a reversible decrease in eGFR in this HIVpositive population. The improvements in renal function after discontinuation of the HCV protease inhibitor strongly argue for a causal relationship. Patients presenting an eGFR decrease during TVR therapy had a higher risk of haematological toxicity. On the basis of our results and the recently published data reported above, we believe that it would be advisable to closely monitor kidney function in patients receiving TVR.
Acknowledgements E.V. designed the study and drafted the manuscript. J.C. performed data analysis. E.F., A.I., M.S., S.D., A.V. and D.P. recruited patients and reviewed the manuscript.
Conflicts of interest Daniel Podzamczer has received research grants and/or honoraria for advisories and/or conferences from Boehringer Ingelheim, GSK, Viiv, Pfizer, BMS, Abbott, Gilead, Janssen and Merck; Elena Ferrer and Eva Van den Eynde have received honoraria for lectures from Boehringer Ingelheim, GSK, Viiv, Pfizer, BMS, Abbott, Gilead, Janssen and Merck. Arkaitz Imaz has received speakers’ fees, consultant fees or research funds from Abbott, Boehringer-Ingelheim, BMS, Gilead, Janssen, Merck and ViiV.
HIV Unit, Infectious Diseases Service, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain. Correspondence to Eva Van den Eynde, MD, PhD, HIV Unit, Infectious Disease Service. Antigua Escuela de Enfermeria 38 floor, Hospital Universitari de Bellvitge, C/ Feixa Llarga S/N, Hospitalet de Llobregat 08907, Barcelona, Spain. Tel: +3493335901 x2886; fax: +34932607669; e-mail: [email protected] Received: 9 December 2014; revised: 27 February 2015; accepted: 27 February 2015.
References 1. Mauss S, Hueppe D, Alshuth U. Renal impairment is frequent in chronic hepatitis C patients under triple therapy with telaprevir or boceprevir. Hepatology 2014; 59:46–48. 2. Loustaud-Ratti V, Rousseau A, Carrier P, Vong C, Chambaraud T, Jacques J, et al. eGFR decrease during antiviral C therapy with first generation protease inhibitors: a clinical significance? Liver Int 2015; 35:71–78. 3. Fukuda K, Imai Y, Hiramatsu N, Irishio K, Igura T, Sawai Y, et al. Renal impairment during the treatment of telaprevir with peginterferon and ribavirin in patients with chronic hepatitis C. Hepatol Res 2014; 44:1165–1171. 4. Tempestilli M, Lionetti R, D’Offizi G, Montalbano M, Giaffreda A, Fazio S, et al. Increased plasma concentration of ribavirin as a result of renal dysfunction in hepatitis C virus patients treated with telaprevir. Hepatology 2014; 60: 1109–1110. 5. Karino T, Ozeki I, Hige S, Kimura M, Arakawa T, Nakajima T, et al. Telaprevir impairs renal function and increases blood ribavirin concentration during telaprevir/pegylated interferon/ ribavirin therapy for chronic hepatitis C. J Viral Hepat 2014; 21:341–347. 6. Cotte L, Barrail-Tran A, Vincent C, Valantin MA, Fournier I, Lacombe K, et al. Telaprevir enhances ribavirin-induced anaemia through renal function impairment. Antivir Ther 2014; doi: 10.3851/IMP2929. [Epub ahead of print]. 7. Van den Eynde E, Ferrer E, Podzamczer D. Acute renal failure and liver toxicity in an HIV/hepatitis C coinfected patient receiving telaprevir and boosted atazanavir. AIDS 2014; 28:1538–1539. 8. Kunze A, Huwyler J, Camenisch G, Gutmann H. Interaction of the antiviral drug telaprevir with renal and hepatic drug transporters. Biochem Pharmacol 2012; 84:1096–1102. 9. 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. 10. Raffi F, Rachlis A, Stellbrink HJ, Hardy WD, Torti C, Orkin C, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, noninferiority SPRING-2 study. Lancet 2013; 381:735–743. 11. Loustaud-Ratti V, Carrier P, Vong C, Essig M. Renal impairment is frequent in chronic hepatitis C patients under triple therapy with telaprevir or boceprevir. Hepatology 2014; 59: 2426.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
979
Telaprevir decreases estimated glomerular filtration rate in HIV-hepatitis C virus coinfected patients Eva Van den Eynde, Jordi Curto, Elena Ferrer, Arkaitz Imaz, Maria Saumoy, Silvana Di Yacovo, Antonia Vila and Daniel Podzamczer We investigated kidney function outcome in 24 chronic hepatitis C genotype 1 patients coinfected with HIV receiving telaprevir in a single tertiary care hospital in Spain. A statistically significant median (interquartile range) decrease in estimated glomerular filtration rate (eGFR, ml/min/1.73 m2) relative to baseline [93.6 (73.0– 109.0)] was seen at weeks 4 [86.5 (34.0–112.0), P U 0.014], 8 [90.0 (49.0–111.0), P U 0.026] and 12 [89.5 (54.0–113.0), P U 0.017]. These changes reversed after telaprevir discontinuation. Patients presenting an eGFR decrease had a higher risk of haematological toxicity. An estimated glomerular filtration rate (eGFR) decrease during telaprevir (TVR) treatment was recently reported in hepatitis C virus (HCV)-infected patients [1–3], which has been correlated with higher ribavirin (RBV) plasma levels and increased risk of anaemia [4–6]. We designed a retrospective study to investigate the kidney function outcome in HCV/HIV-coinfected patients receiving TVR and an attempt to identify any correlation between changes in eGFR and the development of anaemia. Adult HIV-infected patients with chronic HCV genotype 1 infection starting TVR (1150 mg/day) along with pegylated interferon (PegIFN) and RBV in a single tertiary care hospital in Spain were evaluated. Clinical and biological data at TVR initiation and at every following visit during 48 weeks were retrospectively recorded from medical files. The eGFR was calculated by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. Wilcoxon’s signed-rank test for repeated measures was used for comparisons between follow-up and baseline results. We investigated the association between the antiretroviral drugs used and the presence of comorbidities with eGFR changes via the Mann–Whitney U-test. Pearson coefficient and linear regression were used to determine any correlation between the severity of the decreases in haemoglobin and eGFR at week 12. For all statistical analyses, P values less than or equal to 0.05 were considered significant.
Twenty-four HIV-positive patients started TVR in combination with PegIFN and RBV. One patient stopped therapy after 1 week because of PegIFN-related adverse events and was excluded from the analysis. Mean age was 48.9 years and 91.3% were men, 20 out of 23 (87%) had severe fibrosis/cirrhosis and 52.2% were treatment-naive. Among the 11 treatment-experienced patients, four (36.4%) were prior relapsers and seven (63.6%) prior nonresponders. Three patients discontinued therapy after 4 weeks because of intolerance to PegIFN in two cases and acute renal failure in one case (previously reported in this journal) [7]. A statistically significant median (interquartile range) reduction in eGFR (ml/min/1.73 m2) was seen relative to the baseline value [93.6 (73.0–109.0)] at weeks 4 [86.5 (34.0–112.0), P ¼ 0.014], 8 [90.0 (49.0–111.0), P ¼ 0.026] and 12 [89.5 (54.0–113.0), P ¼ 0.017]. These changes reversed after TVR discontinuation, as was seen at week 24 [92.0 (59.0–120.0), P ¼ 0.465] (Fig. 1a). The renal dysfunction caused by TVR was associated with the haemoglobin decrease at treatment-week 12 (Fig. 1b) (haemoglobin change at week 12, 3.86 mg/ dl þ 0.05x eGFR change at week 12; P ¼ 0.026). Neither the baseline fibrosis stage, the antiretroviral companion drugs, nor the patients’ risk factors for renal failure were associated with the eGFR decrease from baseline to week 12 (data not shown). We found a reversible eGFR decline during TVR therapy in HIV-HCV coinfected patients that is in keeping with the results of recent reports in HCV-monoinfected patients [1–3]. In a large real-life study, 6.6% of patients taking TVR experienced a decrease in eGFR to less than 60 ml/min compared with 0.9% of patients taking dual therapy [1]. In all patients, renal function improved after discontinuation of TVR. In another study, LoustaudRatti et al. [2] found that eGFR significantly decreased with TVR (mean nadir decrease at week 8, 17.0 18.9 ml/min/1.73 m2) and returned to baseline at week 16. Mauss et al. [1] were the first to describe a correlation between an eGFR drop and low haemoglobin concentrations. The authors suggested that this could be a result of RBVaccumulation consequent to impaired renal drug elimination. Two studies subsequently confirmed that the TVR-induced decrease in renal function leads to an increase in serum RBV concentration and a higher risk of anaemia [4,5]. Similarly, in the ANRS HC26 TelapreVIH study, to our knowledge, the only cohort examining changes in kidney
DOI:10.1097/QAD.0000000000000643
ISSN 0269-9370 Copyright Q 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
977
AIDS
2015, Vol 29 No 8 (a)
Median eGFR
Median creatinine
125
2.5
0.465* 0.017* 0.026* 0.014*
2.0
94
90
87
75
1.5 1.00
0.98
0.92
50
92
90
0.97
0.93
1.0
0.036*
Creatinine (mg/dL)
eGFR (mL/min/1.73 m2)
100
0.109*
25
0.5
0.040* 0.862*
TVR stopped
0 Baseline n = 23
4 n = 22
0.0 12 n = 20
8 n = 14
24 n = 22
Weeks *Wilcoxon signed-rank test for repeated measures to compare from baseline
(b) –1
Change hemoglobin (mg/dL) (week 12-baseline)
978
Change Hb week12-baseline = –3.86 + 0.05 x change eGFR week 12-baseline (p = 0.026)
–2
–3
–4
–5
–6
–7 –60
–40
–20
0
20
40
Change eGFR (mL/min/1.73 m2) (week 12-baseline)
Fig. 1. Renal function outcome. (a) Estimated glomerular filtration rate (eGFR) and creatinine changes. (b) Correlation between eGFR changes and haemoglobin level.
function in HIV patients receiving TVR, a reversible eGFR decline was also found during the first 8 weeks of triple therapy, which was associated with a significant rise in the RBV trough concentration and a higher risk of haematological toxicity [6]. In keeping with these data, the haemoglobin changes seen in our study also correlated with the magnitude of the eGFR decrease, likely due to a rise in serum RBV levels. However, as ours is a retrospective study, we do not have
data on plasma RBV concentrations and, regrettably, we cannot confirm this point. TVR has shown in-vitro inhibition of drug transporters expressed in the kidney, which interacts with proximal tubular creatinine secretion [8]. That has also been described in association with other drugs used for the treatment of HIV, which have demonstrated to decrease the eGFR by the inhibition of the organic cation transporter 2 (OCT2) (dolutegravir and rilpivirine) or the
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Research Letter
multidrug and toxin extrusion transporter 1 (MATE1) (cobicistat), without affecting the actual glomerular filtration [9,10]. This mechanism has been suggested as the reason for the elevations in plasma creatinine during TVR therapy [11], but true renal failure cannot be ruled out because there are no studies available in which simultaneous measurement of iohexol clearance has been performed. With the emergence of new direct antiviral agents (DAAs) for HCV with better efficacy and tolerability profiles, continued massive use of TVR seems unlikely. Nevertheless, because of the high cost of the new DAAs, triple therapy with first-generation protease inhibitors may remain the best treatment choice in countries with limited resources. Furthermore, particularly in the setting of HIVcoinfection, the use of several of the new DAAs may be limited by pharmacokinetic/pharmacodinamic interactions with the antiretroviral drugs. In these very few selected cases, TVR might still be the most suitable option. In conclusion, even though only a small number of patients were evaluated, TVR treatment was significantly associated with a reversible decrease in eGFR in this HIVpositive population. The improvements in renal function after discontinuation of the HCV protease inhibitor strongly argue for a causal relationship. Patients presenting an eGFR decrease during TVR therapy had a higher risk of haematological toxicity. On the basis of our results and the recently published data reported above, we believe that it would be advisable to closely monitor kidney function in patients receiving TVR.
Acknowledgements E.V. designed the study and drafted the manuscript. J.C. performed data analysis. E.F., A.I., M.S., S.D., A.V. and D.P. recruited patients and reviewed the manuscript.
Conflicts of interest Daniel Podzamczer has received research grants and/or honoraria for advisories and/or conferences from Boehringer Ingelheim, GSK, Viiv, Pfizer, BMS, Abbott, Gilead, Janssen and Merck; Elena Ferrer and Eva Van den Eynde have received honoraria for lectures from Boehringer Ingelheim, GSK, Viiv, Pfizer, BMS, Abbott, Gilead, Janssen and Merck. Arkaitz Imaz has received speakers’ fees, consultant fees or research funds from Abbott, Boehringer-Ingelheim, BMS, Gilead, Janssen, Merck and ViiV.
HIV Unit, Infectious Diseases Service, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain. Correspondence to Eva Van den Eynde, MD, PhD, HIV Unit, Infectious Disease Service. Antigua Escuela de Enfermeria 38 floor, Hospital Universitari de Bellvitge, C/ Feixa Llarga S/N, Hospitalet de Llobregat 08907, Barcelona, Spain. Tel: +3493335901 x2886; fax: +34932607669; e-mail: [email protected] Received: 9 December 2014; revised: 27 February 2015; accepted: 27 February 2015.
References 1. Mauss S, Hueppe D, Alshuth U. Renal impairment is frequent in chronic hepatitis C patients under triple therapy with telaprevir or boceprevir. Hepatology 2014; 59:46–48. 2. Loustaud-Ratti V, Rousseau A, Carrier P, Vong C, Chambaraud T, Jacques J, et al. eGFR decrease during antiviral C therapy with first generation protease inhibitors: a clinical significance? Liver Int 2015; 35:71–78. 3. Fukuda K, Imai Y, Hiramatsu N, Irishio K, Igura T, Sawai Y, et al. Renal impairment during the treatment of telaprevir with peginterferon and ribavirin in patients with chronic hepatitis C. Hepatol Res 2014; 44:1165–1171. 4. Tempestilli M, Lionetti R, D’Offizi G, Montalbano M, Giaffreda A, Fazio S, et al. Increased plasma concentration of ribavirin as a result of renal dysfunction in hepatitis C virus patients treated with telaprevir. Hepatology 2014; 60: 1109–1110. 5. Karino T, Ozeki I, Hige S, Kimura M, Arakawa T, Nakajima T, et al. Telaprevir impairs renal function and increases blood ribavirin concentration during telaprevir/pegylated interferon/ ribavirin therapy for chronic hepatitis C. J Viral Hepat 2014; 21:341–347. 6. Cotte L, Barrail-Tran A, Vincent C, Valantin MA, Fournier I, Lacombe K, et al. Telaprevir enhances ribavirin-induced anaemia through renal function impairment. Antivir Ther 2014; doi: 10.3851/IMP2929. [Epub ahead of print]. 7. Van den Eynde E, Ferrer E, Podzamczer D. Acute renal failure and liver toxicity in an HIV/hepatitis C coinfected patient receiving telaprevir and boosted atazanavir. AIDS 2014; 28:1538–1539. 8. Kunze A, Huwyler J, Camenisch G, Gutmann H. Interaction of the antiviral drug telaprevir with renal and hepatic drug transporters. Biochem Pharmacol 2012; 84:1096–1102. 9. 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. 10. Raffi F, Rachlis A, Stellbrink HJ, Hardy WD, Torti C, Orkin C, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, noninferiority SPRING-2 study. Lancet 2013; 381:735–743. 11. Loustaud-Ratti V, Carrier P, Vong C, Essig M. Renal impairment is frequent in chronic hepatitis C patients under triple therapy with telaprevir or boceprevir. Hepatology 2014; 59: 2426.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
979
