Il trattamento dell’infezione da HCV nel paziente HIV ... · HCV in CKD pats. • We recommend...

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


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)


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



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.


******

***

SOF: Contraindicated for eGFR < 30 ml/min

RBV: Dose reduction for eGFR < 50 ml/min for AE* *

*

**

Kidney safe regimens


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

Il trattamento dell’infezione da HCV nel paziente HIV ... · HCV in CKD pats. • We recommend...

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