Hepatitis C plus HIV: How bad is it?
Mortality in the Americas-PAHO
Sistema Regional de Mortalidad, 2015. Pan American Health Organization. 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
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
Africa Eastern Europe
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.
Increase 2 Metavir stages
Direct effect on stellatecells
Immune dysregulation Cytokine alteration Hepatocyte apoptosis
Higher HBV and HCV chronicity rate
Increased viral replication Decreased HCV-specific
Adapted from Ingiliz P, Rockstroh JK, Current Opinion in HIV and AIDS 2015
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
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
P=0.005 P=0.004 P=0.005
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 1000 2000 3000 4000 5000 6000
0 1000 2000 3000 4000 5000 6000
What is the optimal treatment strategy in HIV/HCV co-infected patients?
Treat HCV first?
Treat HIV first?
Treat HIV/HCV simultaneously?
HIV Suppression Is Associated with Less Hepatic Necroinflammatory Activity
Mehta SH et al. Hepatology 2005
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
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
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
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
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 2 3 4 5 6 7 8 9 10
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
eTime to hepatic decomposition (years)
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
NS5A inhibitor2 Inhibits activity of NS5A, a
multifunctional protein Prevents viral replication
HCV life cycle
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.
Adapted from reference 1
ER Lumen Adapted from reference 2
Cyclophilin Ainhibitor4 Inhibition of
cyclophilin A reduces HCV replication