Transcript HEPATITIS C CO-INFECTION

HEPATITIS C
CO-INFECTION
2
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
Hepatitis C and HIV progression
www.thebody.com
Natural History of Hepatitis C
Virology of HCV
•
•
•
•
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?
30+ years mono-infected
10-15 years HIV co-infection
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
Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory
Committee Meeting, April 27-28, 2011, Silver Spring, MD.
Peg/RBV
/DAA
DAA’s
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
•
•
•
•
•
•
•
•
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
–
–
–
–
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