HEPATITIS C CO-INFECTION
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
• 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.comNatural 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 re-
infection 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 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
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
What does progression look like?
30+ years mono-infected
10-15 years HIV co-infection
Stages of fibrosis
Treatment options
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
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
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
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
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.
No Free Lunch
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
How do we decide who to treat now and who can wait?
Waiting game?
• Stage of liver damage
• Availability of drugs
• Prior treatment response
• Cost !!!
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.
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