4th UK-CAAB - Hepatitis coinfection HIV/HCV Co-infection Dr Ranjababu Kulasegaram Guy’s & St...

4th UK-CAAB - Hepatitis coinfection

HIV/HCV Co-infection

Dr Ranjababu KulasegaramGuy’s & St Thomas’ Hospital

London


HIV/HCV Co-infection

• Epidemiology

• Impact of HIV on HCV

• Impact of HCV on HIV

• Management issues

• Future


Epidemiology


• 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)


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


•


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


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


Impact of HIV on HCV


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


Impact of HCV on HIV


Swiss Cohort Study

• HCV accelerates the progression of HIV

• Less likely to achieve CD4 cell increases on HAART

• (warrants further studies)


Management issues


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


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


HCV treatment


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


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


Time

Serum IFN Levels (U/mL)

“optimised” IFN

Optimizing Interferon Kinetics

1 week

2nd Dose


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%


Ribavirin

Guanosine nucleoside analogue

Drug – drug interactions• Inhibits intracellular phosphorylation of pyrimidine

analogue (AZT, d4T, ddC)

• Enhances the purines (ddI) - Toxicity


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


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


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


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


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

(%

)


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



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



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


Transplantation

• Is an option in carefully selected patients.


Future

• HCV specific protease inhibitors• Antifibrotic agents• Helicase inhibitor• Antisense oligonucleotides• Ribozymes

• ?Triple therapy• Immunotherapy IL-2 ( 2/7 co infected pts SVR)


Pegylated Interferons

• 40 kD PEGylated Interferon (Pegasys®, Roche)

• 12 kD PEGylated Interferon

(Viraferonpeg/PegintronTM, Schering Plough)


Predictability of Response


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®


Safety of Peg IFN alfa-2b (12kD) + RBV

• Similar to Standard interferon

• Higher influenza like reactions

• Substantial injection site reactions

Manns et al, Lancet Vol 358.Pg 958 - 965

4th UK-CAAB - Hepatitis coinfection HIV/HCV Co-infection Dr Ranjababu Kulasegaram Guy’s & St...

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