Hepatitis C plus HIV: How bad is it? - Virology contraindicated in CP B or C;DRV contraindicated in

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Hepatitis C plus HIV: How bad is it?

Hepatitis

Mortality in the Americas-PAHO

Sistema Regional de Mortalidad, 2015. Pan American Health Organization. http://www.paho.org

http://www.paho.org/

Estimated worldwide numbers of HIV/HCV co-infected individuals

Clausen LN et al. World J Gastroenterol 2014; 20:1213212143.

HIV 33 million

HCV130180 million

HIV/HCVco-

infection up to 10 million

Outbreaks in IDU & MSM

Global prevalence of HIV/HCV co-infection

Easterbrook P. International HIV/Viral Hepatitis Co-infection Satellite Meeting 2014. HCV, hepatitis C virus; IQR, inter-quartile ratio

2,500,000

2,000,000

1,500,000

1,000,000

500,000

0SouthEast Asia

Africa Eastern Europe

North America

Latin America

Western Pacific

Europe East Med

Burden of co-infection with HIV and HCV by region, 2013

Estimate Lower quartile Upper quartile

2.8 million(IQR: 1.65.9 million)

HCV :Natural History

10 to > 30 years

Progression of Liver Fibrosis Is Common in HIV Patients With HCV Coinfection1

A prospective cohort study assessed the incidence of liver fibrosis progression in coinfected patients (N=282)

On initial biopsy, 14% of patients had Metavir stage 2 fibrosis

After a median follow-up 2.5 years:

1. Konerman MA et al. Hepatology. 2014;59:767775.

Fibrosis progression

34%

Increase 2 Metavir stages

9%

FibrosisCirrhosis

LPS

HIV

HCV

Direct effect on stellatecells

Immune dysregulation Cytokine alteration Hepatocyte apoptosis

Higher HBV and HCV chronicity rate

Increased viral replication Decreased HCV-specific

immune response

HAART

HCC

Adapted from Ingiliz P, Rockstroh JK, Current Opinion in HIV and AIDS 2015

HBV

Pathogenesis of HCV-related Liver Disease in HIV Patients With HCV Coinfection1

HIV accelerates the progression of hepatic fibrosis via several T-cell independent mechanisms:

CCR4 = chemokine (C-C motif) receptor 5; CXCR4 = chemokine (C-X-C motif) receptor 4; NF-B = nuclear factor kappa B; TGF-1 = transforming growth factor beta 1; TLR-4 = toll-like receptor 4. 1. Sherman KE et al. Hepatology. 2014;59:307317.

Upregulation of HCV replication - via signalling through CXCR4 and CCR5 co-receptors on hepatocytes1Enhanced fibrogenesis- via augmentation of HCV-related increases in TGF-12NF-B activation- via generation of reactive oxygen species3Independent induction of hepatocyte apoptosis4Microbial translocation in the gut- via TLR-4 on hepatocytes and stellate cells5

9

HIV/HCV co-infection burden: Accelerated disease progression and morbidity

Prevalence, especially in some populations13

Compared with HCV mono-infected patients, patients co-infected with HIV display: viraemia (28-fold greater)1,4

infectivity increases risk of transmission from mother to child (20% vs 6%) and risk of sexual transmission (3% vs

Impact of HIV RNA, CD4, or Both on Liver Fibrosis Progression Rate

0

10

20

30

40

50

60

HIV RNA(copies/mL)

Est

imat

ed T

ime

From

HC

VIn

fect

ion

to C

irrh

osis

(yea

rs)

P=0.05 P=0.04

P=0.005 P=0.004 P=0.005

350(n=124)

Impact of ART on Overall Liver Mortalityin HIV/HCV-Coinfected Patients

Bonn cohort (1990-2002) 285 HIV/HCV coinfected

patients Liver-related mortality rates per

100 person-years HAART: 0.45 ART: 0.69 No therapy: 1.70

Predictors for liver-related mortality

No HAART Low CD4 cell count Increasing age

Qurishi N, et al. Lancet. 2003:362:1708-1713.

0,2

0,4

0,6

0,8

1

Days

Overall Mortality

Cum

ulat

ive

Surv

ival

0 1000 2000 3000 4000 5000 6000

ART

HAART*

0,2

0,4

0,6

0,8

1

Days

Liver-Related Mortality

Cum

ulat

ive

Surv

ival

0 1000 2000 3000 4000 5000 6000

HAART*

No therapy

ART

No therapy

*P=0.018

*P

What is the optimal treatment strategy in HIV/HCV co-infected patients?

Treat HCV first?

Treat HIV first?

Treat HIV/HCV simultaneously?

0123456789

10

HIV Suppression Is Associated with Less Hepatic Necroinflammatory Activity

Mehta SH et al. Hepatology 2005

Activ

ity S

core

Viral LoadUndetectable

Viral LoadDetectable

**

Liver Toxicity due to HAART

14-20% of patients will develop elevated liver enzymes. 2-10% of patients will need to interrupt HAART due to

severe liver injury. Risk factors: Viral hepatitis B or C First regimen Nevirapine Full dose ritonavir Female sex

J Infect Dis 2002; 186:23-31

Avoid mitochondrial toxicity

ARVs and Liver Disease

Slide credit: clinicaloptions.comDHHS Guidelines. January 2016. DTG/3TC/ABC [package insert]. 2016.

ART Drug Class Liver Toxicity

NRTI

Reported with most NRTIs Steatosis most common with ZDV, d4T, or ddI ddI: Prolonged exposure linked to noncirrhotic portal HTN, esophageal varices Flares: HIV/HBV-coinfected pts may develop severe hepatic flares when TDF, 3TC, and

FTC are withdrawn or when HBV resistance develops Dose adjust ABC

NNRTI

NVP > other NNRTIs NVP: Severe hepatotoxicity associated with skin rash or hypersensitivity. Risk greater for

women with pre-NVP CD4+ cell count > 250 cells/mm3 and men with pre-NVP CD4+ cell count > 400 cells/mm3. NVP in pts with hepatic insufficiency (CP B or C)

Use EFV with caution in liver disease

PI

All PIs: Drug-induced hepatitis and hepatic decompensation have been reported; greatest frequency with TPV/RTV

TPV/RTV contraindicated in CP B or C; DRV contraindicated in CP C Dose adjust ATV, FPV, IDV No boosting in CP B or C

INSTI DTG/3TC/ABC associated with severe acute exacerbations of hepatitis, which are

primarily described in HBV-coinfected pts DTG and EVG not recommended in CP C

http://www.clinicaloptions.com/oncology

Antiretroviral therapy reduces the rate of hepatic decompensation among HIV- and hepatitis C virus-coinfected veterans

Objective: To evaluate 10,090 HIV/HCV-co-infected

males from the Veterans Aging CohortStudy Virtual Cohort, who had notinitiated ART at entry, for incidenthepatic decompensation between1996 and 2010

Results: Initiation of ART significantly reduced the rate of hepatic decompensation

by 2841% on average

Anderson JP, et al. Clin Infect Dis 2014; 58(5): 71927.17

HCV Disease Progression Remains Faster in Coinfected Patients, Despite Effective ART

ART, antiretroviral therapy; HCV, hepatitis C virus; HIV, human immunodeficiency virus.

1. Adapted from: Lo Re 3rd V, et al. Ann Intern Med 2014;160:36979.

If HIV RNA 1000 copies/mL: +82% excess risk

If CD4 < 200/mm2: +203% excess riskIf CD4 > 200/mm2: 5663% excess risk

Time to hepatic decomposition (years)

HCV-monoinfected patientsAntiretroviral-treatment patients coinfected withHIV/HCV: HIV RNA level < 1000 copies/mLAntiretroviral-treatment patients coinfected withHIV/HCV: HIV RNA level 1000 copies/mL

0.1

0.2

0.0

0.0760.0690.048

0 1 2 3 4 5 6 7 8 9 10

Cum

ulat

ive

inci

denc

e

0.081

0.0690.048

0 1 2 3 4 5 6 7 8 9 10

HCV-monoinfected patientsAntiretroviral-treatment patients coinfected withHIV/HCV: CD4 count < 0.200 x 109 cells/LAntiretroviral-treatment patients coinfected withHIV/HCV: CD4 count 109 cells/L

Cum

ulat

ive

inci

denc

eTime to hepatic decomposition (years)

0.1

0.2

0.0

18

100%

?

19911989

FDA approves RBV to combine with IFN

FDA approves IFN as the first therapy

Discovery of HCV

New Era of HCV Therapy

NS3 inhibitor2 Inhibits activity of NS3

protease Prevents processing of HCV

proteins required for replication

NS5B inhibitor(s)2 Inhibits NS5B RNA

replicase Prevents replication of

viral genome

NS5A inhibitor2 Inhibits activity of NS5A, a

multifunctional protein Prevents viral replication

HCV life cycle

HCV virion

New HCV virion

PEG-IFN lambda3 Type III pegylated

interferon Expression of receptor is

more limited than Alfa, should lead to improved tolerability and safety

1. Manns MP, et al. Nat Rev Drug Discov 2007;6:9911000. 2. Rice C. Top Antivir Med 2011;19(3):11720. 3. Donnelly R, et al. Trends Immunol 2011;32(9):44350. 4. Gallay P, Lin K. Drug Des Devel Ther 2013;7:105-15.

Endocytosis

SR-B1

CD81

Cytoplasm

Liver cell

ER

Maturation

Nucleus

Uncoating

RNA replication

Virionassembly

Golgi

Adapted from reference 1

ER Lumen Adapted from reference 2

Cytoplasm

NS4A NS4B

Cyclophilin Ainhibitor4 Inhibition of

cyclophilin A reduces HCV replication

-previr