HEPATITIS C CO-INFECTION. Hepatitis C (HCV) = RNA VIRUS Worldwide prevalence of Approx 150million...
Transcript of HEPATITIS C CO-INFECTION. Hepatitis C (HCV) = RNA VIRUS Worldwide prevalence of Approx 150million...
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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’
2
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• 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
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Hepatitis C and HIV progression
www.thebody.comNatural History of Hepatitis C
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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 re-
infection and there is no vaccine
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Transmission Routes• Drug use
• Blood Transfusions
• Vertical Transmission
• High Risk sexual activity (MSM)
• Contaminated medical equipment
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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
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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
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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
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Effect of HCV on HIVControversial
• Swiss cohort – some effect• HCV increases AIDS/death• Failure to increase CD4 with
ARVs• No effect on HIV VL
suppression
• EUROSIDA – no effect on HIV disease
• However – data in studies is often difficult to interperate:
• HCV acquired first in studies• Now more likely to be
caught later Law et al AIDS 2004Stebbing J. CID 2005Sullivan P. AIDS 2006
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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 2008Mohsen A. Gut 2003
Smit C. AIDS 2006
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What does progression look like?
30+ years mono-infected
10-15 years HIV co-infection
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Stages of fibrosis
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Treatment options
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Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD.
SV
R (
%)
IFN6 mos
PegIFN/ RBV
IFN12 mos
IFN/RBV12 mos
PegIFN12 mos
2001
1998
2011
StandardIFN
RBV
PegIFN
1991
DAAs
Peg/RBV/DAA
IFN/RBV6 mos
6
16
3442 39
55
70+
0
20
40
60
80
100
DAA’s
90+
2014
The Good News
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Traditional Therapies
• Pegylated interferon & Ribivirin
• Low Cure Rates
• Side Effects
• Toxicity Management
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• Therapy ‘response guided’ – Null responders– Partial responders– Relapsers
• High drop-out rate due to side effects
• Different genotypes have different cure rates
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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
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• 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
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• Anxiety/Depression
• Psychiatry input• Anti-depressants (watch for interactions)• Counselling
Ultimately its about encouraging patients to Continue on therapy for as long as possible
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HCV Life Cycle and DAA Targets
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
Receptor bindingand endocytosis
Fusion and
uncoating
Transportand release
(+) RNATranslation
andpolyprotein processing
RNA replication
Virionassembly
Membranousweb
ER lumen
LD
LDER lumen
LD
NS3/4 protease inhibitors
NS5B polymerase inhibitors
Nucleoside/nucleotide
Nonnucleoside
Block replication complex formation, assembly
NS5A inhibitors
RNA replication
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So what does this mean?
• Different classes of drugs developed
• Protease Inhibitors• NS5B Polymerase inhibitors• NS5A Replication Assembly Complex inhibitors
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A Major Advance: The first PI’s for Hep C
0
20
40
60
80
100S
VR
(%
)
PegIFN/RBVBOC or TVR + PegIFN/RBV
38-44
63-75
Poordad F, et al. N Engl J Med. 2011;364:1195-1206.
Jacobson IM et al. N Engl J Med. 2011;364:2405-2416.
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No Free Lunch
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Upcoming Agents• Polymerase Inhibitors
– Sofosbuvir– ABT-072– ABT-333– BMS-791325
• CypA Inhibitors– Alisporivir
• PIs - Simeprevir- Faldaprevir- Asunaprevir- ABT-450- MK5172- Danoprevir- GS-9451
• NS5A inhibitors- Daclatasvir- Ledipasvir- ABT-267
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How do we decide who to treat now and who can wait?
Waiting game?
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• Stage of liver damage
• Availability of drugs
• Prior treatment response
• Cost !!!
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96
Example of Nuc Backbone + PI in Trt-Naive Pts and Nulls (COSMOS)
SVR1
2 (%
)
F0-F2 Fibrosis
100
80
60
40
20
0
96 93
26/27
13/14
SMV (PI) + SOF (Nuc) + RBV 12 wks SMV (PI) + SOF (Nuc) 12 wks
SVR4
(%)
F3/F4 Fibrosis
100
26/27
14/14
78% GT1a
50% Q80K
94% non-CC
All nulls
78% GT1a
40% Q80K
79% non-CC
47% F4
54% Null
Jacobson I, et al. AASLD 2013. Abstract LB-3.
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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
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