Download Co-Infection

VIRAL HEPATITIS &
CO-INFECTION
James Hand
Clinical Nurse Manager for HIV & Hepatitis Research
Barts Health NHS Trust
The cause of liver disease
• Hepatotoxic antiretroviral drugs?
• Substance misuse (Alcohol/rec drugs)
• Fatty Liver Disease?
• Hepatitis co-infection?
What does the liver do?
• Produces bile
• Breaking down food to
create and store energy
• Stores vitamins and
minerals including iron
• Breaks down and eliminates
toxins
• Produces hormones and
proteins for most of the
chemical reactions in the
body such as clotting
Hepatotoxicity of ARVs
•
Early ARVs cause hepato-toxicity
• Nevirapine – acute liver
failure (+/- rash)
• Ritonavir – low dose less of
a problem
• D4T – lactic acidosis but
little use anyway
• DDI – non cirrhotic portal
hypertension
• Darunavir, Tipranavir –
case reports of toxicity
although rare
• Drugs used for
opportunistic infections
Benhamou Y Hepatology 2001
John M AIDS 1998
Labarga P CID 2007
• Alcohol & liver disease is well documented
• Alcoholic liver disease is the commonest form of
cirrhosis in the western world
• Non-Alcoholic Fatty Liver Disease
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Increasing waistlines
Insulin resistance
More common in men
Prevalence increasing
The cause of liver disease
• Hepatotoxic antiretroviral drugs?
• Substance Misuse (Alcohol)
• Fatty Liver Disease?
• Hepatitis Co-infection?
What is Hepatitis?
• ‘Hepa’ = Liver
• ‘titis’ = inflammation
• Caused by several agents
– Toxins
– Drugs
– Alcohol
– Obesity
– Viruses
HEPATITIS B
CO-INFECTION
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Hepatitis B (HBV) = DNA VIRUS
• Approx 350 million people
worldwide (WHO)
• 50 to 100 times more infective
than HIV
• Able to survive outside the body
for up to 7 days
• Controllable & Preventable
• Very effective vaccine
• Not directly damaging to the liver despite millions of virons
being produced daily.
• Immune response to infection causes inflammation and
scaring (Fibrosis)
• Build up of fibrosis over time leads to cirrhosis and also
hepatocellular carcinoma (HCC)
• If initial immune response does not clear the virus, repeated
episodes of inflammation once the virus enters the ‘chronic
stage’ is the main cause of the damage
• Vertical transmission results in an increased rate of
chronic infection (95% of children progress to
chronic)
• HBV caught in adulthood – Higher chance of ‘selfclearing’ (approx. 80%)
• HIV co-infection reduces the chance of clearing to
nearer 60% - increasing the prevalence of chronic
HBV transmitted in adulthood.
Transmission Routes
• All body fluids
• Vertical transmission
• Contaminated medical equipment
• IV Drug use
• Sexual exposure
HBV/HIV
• Up to 20% of HIV infected individuals have evidence of
current or past infection with HBV
• HBV does not affect natural history of HIV or the
associated treatment response
• However HIV does have an impact on HBV infection by
worsening the prognosis of HBV
•Increased risk of cirrhosis/ESLD
•Increased risk of death
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Why cant we cure HBV?
• Latent, non-replicating viral genomes
• Persist within reservoirs for each of these
infections, and high levels of viral replication
typically resume soon after cessation of
antiviral therapy, even after years of
treatment
Serology of hepatitis B
• Anti HBc – Hepatitis B core antibody
• HBsAg – Hepatitis B Surface Anitgen
• Anti HBs- Hepatitis B Surface Antibody
• HBeAg – envelope antigen indicating high infectivity
and replication
• Anti-HBe – envelope antibody indicative of low
replication
• HBV DNA (viral load) actively replicating virus
Vaccinating HIV+ Patients
Can delay vaccination till CD4 >200
25% response with CD4 < 200
80% response with CD4 >500
» Balance of risks
» Course can be repeated for non-responders with
double dose
Non responders
• Annual markers for HBV infection
• Check markers again before starting ARVs
• Educate on exposure risks
Evaluation of the HIV co-infected patient
• HIV status
• CD4 count/ARVs
• HBV status
• eAg, HBV DNA
• Liver status
• ALT (AST),Albumin, INR, AFP, scan, biopsy
• Other infections
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HAV status (vaccinate)
Life style
Infection risks (vaccinate contacts),
Alcohol abstinence
Treatment of chronic HBV
• Treatment in HBV infection aims:
– Suppress Viral replication
– Reduces inflammation
– Prevent fibrosis progressions
– Prevent development of Cirrhosis
When to treat?
• HBV DNA > 2000
• Evidence of Fibrosis
• CD4 < 500
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Treatment of chronic HBV
• Treatment with Tenofovir/FTC as part of HIV regimen is gold
standard
• 3TC is effective but risk of developing resistance is higher
• It is important to maintain anti-HBV properties if switching
ARV’s.
• Consider Entecavir if unable to use Tenofovir.
HEPATITIS C
CO-INFECTION
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Hepatitis C (HCV) = RNA VIRUS
• Worldwide prevalence of
Approx 150million
• Able to survive outside the
body for up to 3 weeks
• Ongoing improvements in
treatment options
• Can be ‘cured’
• Only approx. 20% clear the virus spontaneously
• Chronic hepatitis C can remain asymptomatic for
30+yrs
• Prevalence higher than 50% in IVDU’s in Europe
• Adequate treatment can clear the virus fully – no
DNA integration or viral reserve
Virology of HCV
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First identified in 1989
Prior to that known as non A non B Hepatitis
A small (50nm) enveloped single stranded RNA virus
Replicates within the hepatocytes of the liver but
also found in most other organs
• 6 major genotypes (1-6) with subtypes
• Initial infection often asymptomatic
• Antibodies provide no protection against reinfection and there is no vaccine
Transmission Routes
• Drug use
• Blood Transfusions
• Vertical Transmission
• High Risk sexual activity (MSM)
• Contaminated medical equipment
Signs & Symptoms
• Majority report little or no symptoms of early infection
• If any symptoms are present, usually non specific e.g. lethargy,
nausea, muscle aches & pains
• Rarely jaundice
• Raised Alanine Transaminase (ALT) or transaminitis due to immune
response
• High ALT often sign of likely self clearance
Diagnosis & Serology
• Diagnostic bloods
• Raised ALT
• HCV Ab
• HCV PCR (viral load)
• General rule ALT 2.5 >normal ?HCV
• Detectable by viral load within 1 – 3 weeks
• Detectable by Antibody can take up to 24 weeks
HCV/HIV
•
Approx 25% of HIV+ patients are
infected with HCV worldwide
• EuroSIDA 33.9%
• Southern Europe nearly
50%
• US 16% - 25%
•
Increasing incidence of acute HCV
infection in young men (MSM)
•
Interactions between Viruses
Effect of HCV on HIV
Controversial
•
Swiss cohort – some effect
•
EUROSIDA – no effect on HIV
disease
•
However – data in studies is often
difficult to interperate:
• HCV increases AIDS/death
• Failure to increase CD4 with
ARVs
• No effect on HIV VL
suppression
• HCV acquired first in studies
• Now more likely to be
caught later
Law et al AIDS 2004
Stebbing J. CID 2005
Sullivan P. AIDS 2006
Effect of HIV on HCV
• Definitely accelerates progress:
• Median time to cirrhosis
23 v 32 years
• Higher HCV viraemia in
co infected
Clifford G. AIDS 2008
Mohsen A. Gut 2003
Smit C. AIDS 2006
What does progression look like?
Stages of fibrosis
Treatment options
The Good News
100
PegIFN
80
2014
2011
90+
2001
RBV
Standard
IFN
DAAs
70+
1998
55
60
1991
42
40
34
39
16
20
6
0
IFN
6 mos
IFN
12 mos
IFN/RBV
6 mos
IFN/RBV
12 mos
PegIFN
12 mos
PegIFN/
RBV
Peg/RBV
/DAA
DAA’s
Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting,
April 27-28, 2011, Silver Spring, MD.
Traditional Therapies
• Pegylated interferon & Ribivirin
• Low Cure Rates
• Side Effects
• Toxicity Management
• Therapy ‘response guided’
– Null responders
– Partial responders
– Relapsers
• High drop-out rate due to side effects
• Different genotypes have different cure rates
Managing Side Effects
Pegylated Interferon
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Lowers Hb
Fatigue
Neutropenia
Flu-like symptoms
Depression
Psychosis
Lowers Platelets
Weight Loss
Ribivirin
• Lowers Hb
• Flu-like symptoms
• Rash
• Fatigue Management
• Check Bloods regularly and dose reduce drug
• Encourage small regular exercise
• Flu-like Symptoms
• Regular Paracetamol
• Dose Interferon at Night
• Rash
• Emollients!
• Anti-histimines
• Anxiety/Depression
• Psychiatry input
• Anti-depressants (watch for interactions)
• Counselling
Ultimately its about encouraging patients to
Continue on therapy for as long as possible
HCV Life Cycle and DAA Targets
NS5A inhibitors
Block replication complex formation, assembly
Receptor binding
and endocytosis
Transport
and release
Fusion
and
uncoating
Translation
and
polyprotein
processing
(+) RNA
ER lumen
LD
LD
LD
NS3/4 protease
inhibitors
Membranous
web
ER lumen
Virion
assembly
NS5B polymerase
inhibitors
RNA
replication
Nucleoside/nucleotide
RNA replication
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
Nonnucleoside
So what does this mean?
• Different classes of drugs developed
• Protease Inhibitors
• NS5B Polymerase inhibitors
• NS5A Replication Assembly Complex inhibitors
A Major Advance:
The first PI’s for Hep C
100
63-75
SVR (%)
80
60
38-44
40
Poordad F, et al. N Engl J Med.
2011;364:1195-1206.
Jacobson IM et al. N Engl J
Med. 2011;364:2405-2416.
20
0
PegIFN/RBV
BOC or TVR +
PegIFN/RBV
No Free Lunch
Upcoming Agents
• PIs
- Simeprevir
- Faldaprevir
- Asunaprevir
- ABT-450
- MK5172
- Danoprevir
- GS-9451
• NS5A inhibitors
- Daclatasvir
- Ledipasvir
- ABT-267
• Polymerase Inhibitors
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Sofosbuvir
ABT-072
ABT-333
BMS-791325
• CypA Inhibitors
– Alisporivir
Waiting game?
How do we decide who to treat now and who
can wait?
• Stage of liver damage
• Availability of drugs
• Prior treatment response
• Cost !!!
Example of Nuc Backbone + PI in
Trt-Naive Pts and Nulls (COSMOS)
SMV (PI) + SOF (Nuc) + RBV 12 wks
100
 All nulls
93
100
 78% GT1a
60
40
20
0
 40% Q80K
SVR4 (%)
SVR12 (%)
 94% non-CC
96
80
 78% GT1a
 50% Q80K
96
SMV (PI) + SOF (Nuc) 12 wks
26/
27
13/
14
F0-F2 Fibrosis
Jacobson I, et al. AASLD 2013. Abstract LB-3.
 79% non-CC
 47% F4
26/
27
14/
14
F3/F4 Fibrosis
 54% Null
Summary
• Viral Hepatitis shares many transmission routes with HIV
• Treatment options are available for both B & C however only
C can be cured
• Side effects of current treatments require good nursing
management
• New therapies are coming but are expensive
Case Study
HEPATITIS C / HIV
CO-INFECTION Case Study
James Hand
HIV/HCV Clinical Research Manager
34yr MSM
• HIV+ past 3 years (routine screening)
• Initial CD4 = 570
• Present CD4 = 400
• HIV viral load = 92,000
• Not had any antiretrovirals to date
• Partner (also HIV+) for past 3 years turns out to be HCV+
• ‘Plenty of unprotected sex…’
Question…….?
“How would it be best to check if he has
become infected with hep C?”
•
1. Hepatitis C antibody
2. Abnormal LFTs
3. Hepatitis C PCR (i.e. viral load)
4. Hepatitis C Antibody & Viral Load
FINDINGS…….
• HCV confirmed…..
• Hep C Ab+
• Genotype 1a
• HCV viral load 1,250,000
• ALT 52
• Other LFT and clotting normal
• Examination Unremarkable
Assessing the patient:
What factors are relevant?
Various factors may make his liver even worse:
• Alcohol
• Other drugs/recreational drugs
• Other liver disease e.g. HBV
• Degree of liver fibrosis
• Weight & insulin resistance
• Black African race
Question?
When trying to assess his degree of liver fibrosis which of
the following techniques are as good in co-infection as
mono-infection?
1. Commercial blood assays – e.g. Fibrotest
2. Fibroscan
3. Liver Biopsy
4. Ultrasound
Liver Fibrosis Staging
Patient asks…..
• Is this really bad news?
• Will my HIV make it worse?
Patient asks….
‘Can you cure me?’
What should we treat first –
HIV or Hep C?
• Liver Biopsy Score = 2/6
• Probably some fibrosis
• CD4 = 400
• HIV VL = 92,000 (WT)
• Not had ARVs
A balance of what to treat first
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REASONS TO TREAT HCV FIRST
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REASONS TO TREAT HIV FIRST
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Can we wait?
Drug-drug interactions
If get a rash/adverse event what
is the cause?
Increased hepatotoxicity with
ARVs if HCV+
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Can we wait?
Response to HCV Rx better at
higher CD4
Response to HCV Rx better
when HIV controlled
CD4 will drop with PEG-IFN
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