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Il trattamento dell’infezione da HCV nel paziente HIV-positivo
nefropatico
Vincenzo Montinaro
U.O. Nefrologia
Azienda Ospedaliera «Pia Fondazione Card. G. Panico» – Tricase (LE)
Treatment of HCV in HIV pats with CKD – Key points
• HCV infection and hepatic diseases are relevant co-morbidities of HIV-infected people
• HCV in general population may promote CKD
• HCV in advanced CKD increase CV risk
• Unsatisfactory therapeutic regimens for treating HCV infection till recently
• Availability of DAA and possibility of global eradication of HCV
• In HIV and CKD, treatment for HCV eradication needs to face with drug-drug interaction (ARV) and nephrotoxicity of DAA
HCV AND CKD EPIDEMIOLOGY
Treatment of HCV in HIV patients with CKD
V. Montinaro
Prevalence of HIV and HCV co-infection and kidney disease
HCV
150 mln
HIV
37 mlnHIV/HCV
4-5 mln
Barreiro P et al: Antivir Res. 2014; 105:1-7
8 % of HIV/HCV Co-
infected
CKD
Ekrikpo UE et al: PLoS One 2018; 13(4) e0195443
Effects of the HCV+ status on the development of CKD
Fabrizi F et al: Dig Dis Sci 2015; 60:3801-13
Pats. N= 2,735,065
HCV+ N= 302,600 (11.1%)
Studies N=23
Renal Outcome in HCV+ Patients
Molnar MZ et al; Hepatology 2015; 61:1495-1502
1,031,049 US Veterans
HCV+ : 100,118
HCV- : 920,531 Basal: Follow-up median: 8.0 y.
age 54.5 ± 13.1; 22% black, 92% M
eGFR: 88 ± 16 ml/min/1.73 m2
HCV status and Renal Outcome
Molnar MZ et al; Hepatology 2015; 61:1495-1502
HCV Ab positive vs. Ab negative (Reference)
RNA Negative
Pats.
RNA Positive Pats.
HRs and 95% CI
Incidence of eGFR< 60
ml/min/1.73 m2
1.06 (0.91 – 1.23) 1.10 (1.05 – 1.16)
ESRD 1.52 (0.79 – 2.94) 1.62 (1.26 – 2.07)
ORs and 95% CI of ORs
Slope of steeper eGFR 1.06 (0.81 – 1.31) 1.23 (1.14 – 1.33)
Metanalysis on all-cause mortality in pats. HD/HCV
145,608 Dialysis pats. from 14 studies
Fabrizi F. et al: J Vir Hepatitis 2012; 19:601-7
Global prevalence of CKD among HIV-infected people
Estimation Prevalence (%)
(CI 95%)
Studies (N) Subjects (N)
MDRD 6.4 (5.2-7.7) 45 167,011
CKD-EPI 4.8 (2.9-7.1) 14 41,791
Cockcroft-Gault 12.3 (8.4-16.7) 19 59,414
CKD: GFR < 60 ml/min/1.73 m2
Ekrikpo UE et al: PLoS One 2018; 13(4) e0195443
Pats 209,078 from 60 countries
Prevalence of CKD in USA (USRDS 2018)
American J Kidney Dis 2019; 73: S1-S28
Hill NR, Fatoba ST, Oke JL, Hirst JA, O’Callaghan CA, et al. (2016) Global Prevalence of Chronic Kidney Disease – A Systematic
Review and Meta-Analysis. PLOS ONE 11(7): e0158765. https://doi.org/10.1371/journal.pone.0158765
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158765
Global prevalence of CKD by Age
Association of Hepatitis C viremia with progressive kidney disease.
SMART and ESPRIT
Studies [HIV+]
3,441 patsMocroft A, Neuhaus J, Peters L, Ryom L, Bickel M, et al. (2012) Hepatitis B and C Co-Infection
Are Independent Predictors of Progressive Kidney Disease in HIV-Positive, Antiretroviral-
Treated Adults. PLoS ONE 7(7): e40245. doi:10.1371/journal.pone.0040245
http://127.0.0.1:8081/plosone/article?id=info:doi/10.1371/journal.pone.0040245
Adjusted hazard ratio point estimates and 95% confidence intervals (CIs) for stage 3 chronic kidney disease (CKD), stage 5 CKD, and progressive CKD,
according to hepatitis C virus (HCV) exposure groups in human immunodeficiency virus (HIV)-infected subjects from NA-ACCORD.
Gregory M. Lucas et al. J Infect Dis. 2013;208:1240-1249
© The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].
Consortium: 63,023 pats.
HCV-: 52,602
HCV+: 9,508
HCV RNA neg: 913
HCV co-infection and CKD in HIV-infected people
CKD stage 1 or higher
Margolick JB et al: PLoS ONE 2014 9(2); e86311
CKD prevalence in HIV/HCV co-infected people
(No effect of HCV co-infection on CKD prevalence)
Ekrikpo UE et al: PLoS One 2018; 13(4) e0195443
Sub-Group eGFR
formula Studies
N
Pats N CKD
cases
N
Prevalence
(95%CI)
I2
(%)
P -
heterog
eneity
p-different
formulae
p-diff
sub-
groups
HIV/No HCV <0.001
MDRD 14 71,799 2,695 7.3 (5.6-9.3) 98.3 <0.001 0.74
CKD-EPI 4 29,286 842 3.5 (1.9-5.5) 98.2 <0.001
CG 1 433 101 23.3 (19.6-27.5) -
HIV/HCV 0.06
MDRD 14 11,183 598 7.6 (4.5-11.4) 97.1 <0.001
CKD-EPI 4 3,649 93 3.7 (1.8-6.2) 87.3 <0.001 0.78
CG 1 58 16 27.6 (17.8-40.2) -
Treatment of HCVTreatment of HCV in HIV patients with CKD
V. Montinaro
Clinical benefit linked to eradication of HCV infection in CKD
Fabrizi F, Messa P: CJASN 2018; 13:793-5
Evolution of antiviral therapies for HCV and HIV
Abutaleb A, Sherman KE: Hepatol Int 2018; 12: 500-9
SIN SIMIT
SIMI AISF
Italian Guidelines for Management of HCV in CKD
K-DIGO Guidelines for treatment of HCV in CKD pats.
• We recommend that all CKD patients infected with HCV be evaluated for antiviral therapy (1A)
• We recommend an interferon-free regimen (1A)
• We recommend that the choice of specific regimen be based on HCV genotype (and subtype), viral load, prior treatment history, drug–drug interactions, glomerular filtration rate (GFR), stage of hepatic fibrosis, kidney and liver transplant candidacy, and comorbidities (1A)
• We recommend that patients with GFR > 30 ml/min/1.73 m2 (CKD G1– G3b) be treated with any licensed DAA-based regimen (1A )
• Patients with GFR < 30 ml/min/1.73 m2 (CKD G4–G5D) should be treated with a ribavirin-free DAA-based regimen
KDIGO Guidelines 2018 for HCV – Kidney Int Supplement 8(3): Oct. 2018
HCV treatment algorithm by CKD stage
KDIGO Guidelines 2018 for HCV – Kidney Int Supplement 8(3): Oct. 2018
KDIGO Guidelines 2018 for HCV – Kidney Int Supplement 8(3): Oct. 2018
Treatment of HCV in CKD stage 4-5
Efficacy and tolerability of PrOD in HCV eradication in CKD
Sise ME: Kidney Int Reports 2019; 4:191-3
Effect of HCV eradication on renal function
in pats with CKD (post hoc analysis of pats
treated with PrOD)
11 phase 3 CT
HCV GT 1
Pats w/o decomp. chirrosis
Pats N 1033 (w/o RBV)
Pats N 2534 (w RBV)
Bernstein DE et al: Kidney Int Reports 2018; e-pubbl Oct. 16, 2018
GZR/EBR for treatment of HCV in CKD stage 4-5
• Elbasvir: NS5A replication complex inhibitor
• Grazoprevir: New NS3/4 protease inhibitor
• Registered for Genotypes GT 1 and 4
• Both metabolized by CYP3A and excreted in feces,
< 1% by kidney
• GZR substrate of OATP1B 1/3 (inhibitors: enalapril, statins, digoxins, some ARB) → hyperbilirubinemia
• Strong CYP3A inducers are contraindicated (rifampin, phenytoin, St John’s wort)
Grazoprevir/Elbasvir treatment of HCV
In pats. with advanced CKD
(C-SURFER Study)
12-wk course in pats with GT 1
76% pats in HD
Common AE
No acceleration of progression of CKD
Roth D. et al: Lancet 2015; 386:1537-45
Effect of Grazoprevir/Elbasvir treatment on eGFR
Reddy KR et al: Hepatol Res 2017; 47:1340-5
Retrospective pooled analysis
of pats. enrolled in trials
Phase II or III with ELB/GRZ
Cohort study from real-life
experience
EXPEDITION-4Glecaprevir NS3/4A
Pibrentasvir NS5A
Major intervention studies of treatment of HCV in pats with HIV – impact on CKD pats.
Abutaleb A, Sherman KE: Hepatol Int 2018; 12: 500-9
******
***
SOF: Contraindicated for eGFR < 30 ml/min
RBV: Dose reduction for eGFR < 50 ml/min for AE* *
*
**
Kidney safe regimens
Abutaleb A, Sherman KE: Hepatol Int 2018; 12: 500-9
ART and DAA PK interaction
Adapted from AASLD/IDSA/IAS-USA
Effect of DAA on TFV plasma levels
ION-4 study: 4/335 pats ↑ Screat > 0.4 mg/dl*
Adapted from AASLD/IDSA/IAS-USA guidelines
K-DIGO Guidelines 2018 for treatment of
HCV in advanced CKD
* RPV@, RAL@, DTG@, MVC@, TAF@
& RPV@, RAL@, DTG@, EVG/COBI@,
MVC@, TAF@§
# RAL@, DTG@, TAF
@ Kidney safe@ Not recommended (no data) in advanced RF@ Dose reduction if eGFR < 80 ml/min and
inhibitors of CYP3A4§ Can be associated as E/C/F/TAF in HD pats1
1 Eron JJ et al: Lancet HIV Dec 13, 2018 [ahead of print]
*
*
*
&
&
&
&
&
#
#
PK of E/C/F/TAF in HD pats and NRF pats
Eron JJ et al: Lancet HIV Dec 13, 2018 [ahead of print]
• HIV pats. coinfected with HCV may undergo significant kidney damage
• It is not clear whether HCV increases risk of developing CKD in HIV pats.
• HCV in HIV pats needs to be eradicated
• “Kidney friendly” regimens in advanced CKD include GRZ/EBV and GLE/PIB
• Drug-drug interaction with ART
• Good association with INSTIs and E/C/F/TAF
Summary and Conclusions