Transcript HIV/HCV Co-infection Jurgen Rockstroh - UK-CAB

HIV/HCV Co-infection
Dr Ranjababu Kulasegaram
Guy’s & St Thomas’ Hospital
London
4th UK-CAAB - Hepatitis
coinfection
4th UK-CAAB - Hepatitis
coinfection
HIV/HCV Co-infection
• Epidemiology
• Impact of HIV on HCV
• Impact of HCV on HIV
• Management issues
• Future
4th UK-CAAB - Hepatitis
coinfection
Epidemiology
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• 3 % of the world population
• UK estimated prevalence 200,000-400,000 people
0.04% of blood donors
0.4-0.6% of ANC in London
• Changing epidemiological pattern – incidence
(IVDU, Blood)
4th UK-CAAB - Hepatitis
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Extrahepatic manifestations
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Dermatological- PCT, lichen planus
Renal- MPGN
Haematology- Essential mixed cryoglobulinaemia
B cell lymphoma
Endocrine – Type 2 Diabetes
Autoimmune, peripheral neuropathy, PAN,uveitis, corneal
ulceration, sialadenitis
4th UK-CAAB - Hepatitis
coinfection
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4th UK-CAAB - Hepatitis
coinfection
HIV/HCV
• Europe
30% of HIV pts are co-infected
• Germany
15-20% of the 40,000 HIV pts
• Spain
45% of the 130,000 HIV pts
• USA
30% of the 800,000 HIV pts
» IVDU 60-90%
» Blood products prior to 1985 85%
» Sexual transmission
<5%
Mother to child transmission
HIV/HCV
Hepatology
4th UK-CAAB
- Hepatitis
coinfection
<6%
15-20%
Yeung et al 2001
HIV/HCV
HIV
HCV
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ss RNA 9000 nt
11 clades
chronic infection 100%
109-1010 virions /day
integration in host
genome
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coinfection
ss RNA 9500 nt
6 clades
chronic infection 80%
1011-1012
no latent form - curable
Impact of HIV on HCV
4th UK-CAAB - Hepatitis
coinfection
4th UK-CAAB - Hepatitis
coinfection
4th UK-CAAB - Hepatitis
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HIV accelerates HCV liver disease especially when CD4
declines
• Within 10-15 yrs of infection
15-25% HIV/HCV cirrhosis
2.6-6.5% of those without HIV
• HCC appears to occur at a younger age
After shorter duration of HCV infection
4th UK-CAAB - Hepatitis
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4th UK-CAAB - Hepatitis
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Impact of HCV on HIV
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coinfection
Swiss Cohort Study
• HCV accelerates the progression of HIV
• Less likely to achieve CD4 cell increases on HAART
• (warrants further studies)
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coinfection
Management issues
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coinfection
Assessment
• HCV IgG Ab (EIA-3,RIBA)
• HBV, HAV screening and vaccination
• HCV RNA and genotyping
• LFT, coagulation screen, α fetoprotein
• U/S scan
• Liver biopsy
4th UK-CAAB - Hepatitis
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Liver biopsy
• Not yet a reliable non-invasive test to assess liver fibrosis
• Neither HCV RNA nor level of ALT correlates well with liver
inflammation and fibrosis
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HCV treatment
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AIMS of treatment
• Viral eradication
• Viral suppression
SVR (loss of detectable virus at
24 wks post treatment)
improving histology
Liver related outcomes Delay cirrhosis, prevent ESLD
and HCC
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Interferon
• Mid-1980s
• Antiviral, antiproliferative and antifibrotic activity
• Glycoproteins produced in vivo by leucocytes in response
to viral infection
• Commercially – by cell culture or recombinant technology
• Pegylated interferon – reduce clearance -> Longer half life
4th UK-CAAB - Hepatitis
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Optimizing Interferon  Kinetics
“optimised” IFN 
Serum
IFN 
Levels
(U/mL)
2nd Dose
Time
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1 week
Interferon
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Flu-like symptoms – transient
Fatigue, apathy, alopecia
Bone marrow suppression
Hypothyroidism, Hyperthyroidism
Depression, irritability
Severe-seizure,cardiac,renal failure,pulmonary
fibrosis,retinopathy,hearing impairment in <2%
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Ribavirin
Guanosine nucleoside analogue
Drug – drug interactions
• Inhibits intracellular phosphorylation of pyrimidine
analogue (AZT, d4T, ddC)
• Enhances the purines (ddI) - Toxicity
4th UK-CAAB - Hepatitis
coinfection
Ribavirin
• Dose dependent haemolysis
– Hb start to drop after the first week and stabilise by
week 4 of therapy ( mean drop 2.9g/dl)
• EPO
• Rash, pruritus, teratogenicity, insomnia, cardiovascular
deterioration, cough and dyspnoea
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When to treat?
Treat HCV before HIV treatment?
• Likely to help avoid Hepatotoxicity
• Less drug interactions – toxicity (TDM), adherence
• Response to HAART – better immune reconstitution
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4th UK-CAAB - Hepatitis
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On HAART and HCV treatment
Drug interactions
• Anaemia (AZT & ribavirin)
• Mitochondrial toxicity-Lactic acidosis, pancreatitis,
lipodystrophy (ddI & ribavirin)
• Possible reduction in CD4 (due to interferon)
Compromise adherence
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Standard IFN -2b + RBV
as Initial Therapy
80%
US trial
International trial
60%
43%
40%
31%
35%
38%
19%
20%
13%
6%
0%
IFN 24 wk
IFN 48 wk
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McHutchison
IFN/RBV 24 wk
IFN/RBV 48 wk
JG et al. NEJM. 1998. Poynard T et al. Lancet. 1998
PEG-IFN -2a (40KD) + RBV
Combination Therapy
PEG-IFN -2a (40KD)/PBO
IFN -2b/RBV
SVR (%)
100
PEG-IFN -2a (40KD)/RBV
81
80
58
56
60
44
33
40
20
65
59
41
17
13
<2M
copies/mL
>2M
copies/mL
74
40
0
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Genotype 1
<2M
copies/mL
>2M
copies/mL
Genotype 2/3
Hoffmann-La Roche, data on file.
Pegylated interferon--2a (PEG) + ribavirin
(RBV) vs. interferon--2a (IFN) + RBV in
HCV/HIV co-infection (ACTG A5071) Chung et
al Abs LB15
IFN 6 MIU tiw x 12 weeks then 3
MIU x 36 weeks + 600 mg/day RBV
escalating to 1 g/day
133 patients
Randomised
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PEG 180 mcg qwk x 48 weeks + 600
mg/day RBV escalating to 1 g/day
Final version X March 2002
PEG + RBV vs. IFN + RBV in HCV/HIV coinfection (ACTG A5071) Chung et al Abs LB15
Proportion HCV RNA <60 IU at
week 24
 Total CD4 fell in both arms
 % CD4 and HIV RNA was
unchanged
Percentage <60 IU
100
p=0.0003
80
60
44%
PEG
IFN
40
20
0
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15%
 PEG had more grade 4 toxicity
(17 vs. 5, p=0.004)
 Discontinuations were similar in
both groups (15% vs. 12%)
 PEG + RBV was superior in HCV
RNA response
Final version X March 2002
PEG + RBV vs. IFN + RBV in HCV/HIV coinfection (ACTG A5071) Chung et al Abs LB15
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133 pts
CD4 >100 & VL <10,000 stable on HAART or CD4 >300 off ART
HCV RNA
Fibrosis score
 Virologic non responders – Liver biopsy – histologic
response
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Final version X March 2002
Transplantation
• Is an option in carefully selected patients.
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Future
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HCV specific protease inhibitors
Antifibrotic agents
Helicase inhibitor
Antisense oligonucleotides
Ribozymes
• ?Triple therapy
• Immunotherapy IL-2 ( 2/7 co infected pts SVR)
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Pegylated Interferons
• 40 kD PEGylated Interferon (Pegasys®, Roche)
• 12 kD PEGylated Interferon
(Viraferonpeg/PegintronTM, Schering Plough)
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Predictability of Response
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12 week predictability with 40 kD Peg
IFN -2a Ribavirin Combination
All PEG (40kD) Patients + RBV Patients
86%
YES
Week 12
PCR < 50 IU/mL or
14%
NO
2 log10 decline
Amplicor®
65%
SVR
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97%
NO SVR
Safety of Peg IFN alfa-2b (12kD) +
RBV
• Similar to Standard interferon
• Higher influenza like reactions
• Substantial  injection site reactions
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Manns et al, Lancet Vol 358.Pg 958 - 965