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