4th UK-CAAB - Hep atitis coinfectio n HIV/HCV Co-infection Dr Ranjababu Kulasegaram Guy’s & St Thomas’ Hospital London
4th UK-CAAB - Hepatitis coinfection
HIV/HCV Co-infection
Dr Ranjababu KulasegaramGuy’s & St Thomas’ Hospital
London
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
• 3 % of the world population
• UK estimated prevalence 200,000-400,000 people 0.04% of blood donors0.4-0.6% of ANC in London
• Changing epidemiological pattern – incidence (IVDU, Blood)
4th UK-CAAB - Hepatitis coinfection
Extrahepatic manifestations
• 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
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 <6%HIV/HCV 15-20%
Yeung et al 2001 Hepatology
4th UK-CAAB - Hepatitis coinfection
HIV/HCV
HIV
• ss RNA 9000 nt• 11 clades• chronic infection 100%• 109-1010 virions /day• integration in host
genome
HCV
• ss RNA 9500 nt• 6 clades• chronic infection 80%• 1011-1012
• no latent form - curable
4th UK-CAAB - Hepatitis coinfection
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 coinfection
Swiss Cohort Study
• HCV accelerates the progression of HIV
• Less likely to achieve CD4 cell increases on HAART
• (warrants further studies)
4th UK-CAAB - Hepatitis 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 coinfection
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
4th UK-CAAB - Hepatitis coinfection
AIMS of treatment
• Viral eradication SVR (loss of detectable virus at 24 wks post treatment)
• Viral suppression improving histology
Liver related outcomes Delay cirrhosis, prevent ESLD and HCC
4th UK-CAAB - Hepatitis coinfection
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 coinfection
Time
Serum IFN Levels (U/mL)
“optimised” IFN
Optimizing Interferon Kinetics
1 week
2nd Dose
4th UK-CAAB - Hepatitis coinfection
Interferon
• 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%
4th UK-CAAB - Hepatitis coinfection
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
4th UK-CAAB - Hepatitis coinfection
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
4th UK-CAAB - Hepatitis coinfection
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
4th UK-CAAB - Hepatitis coinfection
Standard IFN -2b + RBVas Initial Therapy
20%20%
40%40%
60%60%
80%80%
IFN 24 wkIFN 24 wk IFN 48 wkIFN 48 wk IFN/RBV 24 wkIFN/RBV 24 wk IFN/RBV 48 wkIFN/RBV 48 wk
Vir
olog
ic R
espo
nse
(%
)V
irol
ogic
Res
pon
se (
%)
McHutchison JG et al. NEJM. 1998. Poynard T et al. Lancet. 1998
6%6%13%13%
31%31%38%38%
19%19%
35%35%
43%43%
0%0%
US trialUS trialInternational trialInternational trial
4th UK-CAAB - Hepatitis coinfection
PEG-IFN -2a (40KD) + RBV Combination Therapy
17
4456
13
3341
5865
81
40
5974
0
20
40
60
80
100
< 2 Mcopies/mL
> 2 Mcopies/mL
< 2 Mcopies/mL
> 2 Mcopies/mL
PEG-IFN -2a (40KD)/PBO
IFN -2b/RBV
PEG-IFN -2a (40KD)/RBV
Genotype 1 Genotype 2/3Hoffmann-La Roche, data on file.
SVR
(%
)
4th UK-CAAB - Hepatitis coinfection
Final version X March 2002
Pegylated interferon--2 ( ) + a PEG ribavirin( ) . RBV vs interferon--2 ( ) + a IFN RBV in
/ HCV HIV co- ( 5071) infection ACTG A Chung et
al 15Abs LB
133 patients
6 IFN MIU tiw 12 3 x weeks then 36 + 600 / MIU x weeks mg day RBV
1 /escalating to g day
180 PEG mcg qwk 48 + 600 x weeks/ 1 /mg day RBV escalating to g day
Randomised
4th UK-CAAB - Hepatitis coinfection
Final version X March 2002
Ø Total CD4 fell in both arms
Ø % CD4 and HIV RNA was unchanged
Ø PEG had more grade 4 toxicity (17 vs. 5, p=0.004)
Ø Discontinuations were similar in both groups (15% vs. 12%)
Ø PEG + RBV was superior in HCV RNA response
PEG + RBV vs. IFN + RBV in HCV/HIV co-infection (ACTG A5071) Chung et al Abs LB15
Proportion HCV RNA <60 IU at week 24
0
20
40
60
80
100
Percentage <60 IU
PEG
IFN
44%
15%
p=0.0003
4th UK-CAAB - Hepatitis coinfection
Final version X March 2002
Ø 133 pts
Ø CD4 >100 & VL <10,000 stable on HAART or CD4 >300 off ART
Ø HCV RNA
Ø Fibrosis score
Ø Virologic non responders – Liver biopsy – histologicresponse
PEG + RBV vs. IFN + RBV in HCV/HIV co-infection (ACTG A5071) Chung et al Abs LB15
4th UK-CAAB - Hepatitis coinfection
Future
• HCV specific protease inhibitors• Antifibrotic agents• Helicase inhibitor• Antisense oligonucleotides• Ribozymes
• ?Triple therapy• Immunotherapy IL-2 ( 2/7 co infected pts SVR)
4th UK-CAAB - Hepatitis coinfection
Pegylated Interferons
• 40 kD PEGylated Interferon (Pegasys®, Roche)
• 12 kD PEGylated Interferon
(Viraferonpeg/PegintronTM, Schering Plough)
4th UK-CAAB - Hepatitis coinfection
12 week predictability with 40 kD Peg12 week predictability with 40 kD PegIFN IFN -2a Ribavirin Combination-2a Ribavirin Combination
All All PEG (40kD)PEG (40kD) Patients + RBV Patients Patients + RBV Patients
65%65%
YESYES86%86%
SVRSVR
97%97%
NONO14%14%
NO SVRNO SVR
Week 12Week 12PCR < 50 IU/mL or PCR < 50 IU/mL or
2 log2 log1010 decline decline
Amplicor®Amplicor®