HEPATITIS C CO-INFECTION Now we are going to Discuss HCV co-infection 1

Hepatitis C (HCV) = RNA VIRUS 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’ So Hep C - Has a large worldwide prevelence – 150Million Lasts for up to 3 weeks outside the human body Can be cured however traditional therapies have been limited although as we discuss newer treatment options are in the pipeline 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 Unlike Hepatitis B – Very few people actually clear the virus during the acute phase The virus can actively replicate but patients can remain asymptomatic for 30+ years Prevalence rates in IVDU’s are incredibly high It is good to recognise that the Period of drug use may have ended many years before diagnosis and so dispite increased awareness campaigns patients may not consider themselves at risk 3

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 re-infection and there is no vaccine 5

Transmission Routes Drug use Blood Transfusions Vertical Transmission High Risk sexual activity (MSM) Contaminated medical equipment Why just drug use and not specifically IVDU? Well….. HCV exposure can also include transmission through sharing of snorting equipment such as notes & straws with cocaine, as well as through injecting drugs. Increasing incidence of hep C transmission with men who have sex with men in many cities with an increase in aknowledged transmission through non-traumatic sexual intercourse – (ie not just fisting) Contaminated medical equipment – A good example of this is the prolific spread of genotype 4 hcv in egypt through mass immunisation against leishmeniesis in the 1980’s 6

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 So the majority of people infected with HCV report no signs or symptoms of infection. Interestingly a lot of what we have learnt about HCV infection has come from the HIV positive population. Previously it was rare to catch an actue infection of Hepatitis C however regular hepatitis serology monitoring of HIV patients has increased and we are now witnessing timepoints when patients contract Hep C and what we are observing is that like with hepatitis B – a high ALT during the acute phase indicates self clearence of the virus. 7

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 The main markers for detecting HCV are Antibody tests, Viral load tests and indicative Liver enzyme tests. As a general rule of thumb – if the patients ALT is over twice the normal value then we should be ruling out Hepatitis C Viral load assays can detect HCV Viremia within 3 weeks where as an antibody test can take up to 6 months. 8

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 Now lets look at Prevelence data of Co-infection: worldwide prevelence of co-infection with HCV is super high – in the UK we are seeing just less than 10% although this is growing due to an epidemic amongst gay men in our cities. European figures show anywhere up to 50% What is being studied in greater detail though is how these two viruses interact. 9

Effect of HCV on HIV Controversial 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 So does hep C effect the prognosis of HIV? Well its controversial – The swiss cohort says yes, the eurosida cohort says no…. Ultimately its difficult to interpret because often these study patients aquired their HCV before they contracted HIV Making it difficult to translate these result s now that we are treating patients who contract hcv after their hiv infection. 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 Well this we do know with some certainty. HIV accelerates the progress of liver disease shortening the time it takes to cirrhosis. interestingly co-infected patients have higher HCV viral loads – which leads to higher infectivity Clifford G. AIDS 2008 Mohsen A. Gut 2003 Smit C. AIDS 2006 11

What does progression look like? So again – what does progression look like? Well the immune assault on the liver over time leads to fibrosis and eventually cirrhosis. 30+ years mono-infected 10-15 years HIV co-infection 12

Stages of fibrosis Im not sure how this slide will come out We can assess the stage of liver damage by looking at the appearance of the liver cells. Historically (and what is the still gold standard) this would be by biopsy. Two scoring systems ISHAK and METAVIR are used – Either a score out of 6 (with 6 being cirrhotic and the worst) or F0 to F4 with F4 being the worst. And along side viral loads and genotype, Fibrosis is an indicator of predictive treatment outcome. Obviously if your liver is so stiff and damaged… it cant work efectively at clearing the virus even with successful treatment. 13

Treatment options Ok so lets get onto treatment options – but before we do does anyone have any questions so far? 14

The Good News DAAs 2014 100 2011 PegIFN 90+ 80 RBV 2001 Standard IFN 70+ 1998 60 55 SVR (%) 1991 42 39 40 34 DAA, direct-acting antiviral; HCV, hepatitis C virus; IFN, interferon; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. So, in the west we are very familiar with the rapid progress of HCV therapy over the last number of years, and it really has been a dramatic change in the treatment landscape. And I think it’s an exciting time to be in this field, where we see treatments going from cure rates of under 10% with standard interferon through expectations of over 90% treatment efficacy now. 20 16 6 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. 15

Traditional Therapies Pegylated interferon & Ribivirin Low Cure Rates Side Effects Toxicity Management So historically we have used two drugs to treat Hep C – Interferon and Ribivirin. Firstly Interferon is used to surmount an immune response to the virus, and ribivirin is used as a broad acting anti-viral. They don’t have direct activity against the HCV virus but are shown to work all be it in low percentages – however this is all we have had until recently. The side effect of these two drugs are well known – Depression, Psychosis, Anaemia, Low platelets, Neutropenia – the list goes on. And as nurses our biggest challenge has been the support of patients undergoing treatment including the encouragement of these individuals not to pull out half way through. 16

Therapy ‘response guided’ Null responders Partial responders Relapsers High drop-out rate due to side effects Different genotypes have different cure rates And this therapy is response guided – HCV RNA is monitored throughout treatment and if it doesn’t drop by certain time points then we know its not likely to work and so courses of treatment are stopped. 17

Managing Side Effects Pegylated Interferon Ribivirin Lowers Hb Flu-like symptoms Rash Lowers Hb Fatigue Neutropenia Flu-like symptoms Depression Psychosis Lowers Platelets Weight Loss So here we can see some of the main side effect associated with traditional therapies for HCV. And our jobs as nurses is to Help patients manage these symptoms 18

Fatigue Management Flu-like Symptoms Rash Check Bloods regularly and dose reduce drug Encourage small regular exercise Flu-like Symptoms Regular Paracetamol Dose Interferon at Night Rash Emollients! Anti-histimines 19

Anxiety/Depression Psychiatry input Anti-depressants (watch for interactions) Counselling Ultimately its about encouraging patients to Continue on therapy for as long as possible 20

HCV Life Cycle and DAA Targets Block replication complex formation, assembly NS5A inhibitors Receptor binding and endocytosis Transport and release Fusion and uncoating Translation and polyprotein processing ER lumen (+) RNA Virion assembly LD LD Then in 2006 something amazing happened – after years of research the replication cycle of HCV was finally cracked! And I know it all looks quite complex but what does it actually mean……. Well, one of the advantages of cracking this lifecycle is that, unlike some of other virus, (HBV, for example) hepatitis C has a number of potential targets for drug development, and this has led to multiple classes of direct-acting antivirals being developed.   NS3/4 protease inhibitors LD Membranous web NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside RNA replication ER lumen RNA replication Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000. 21

So what does this mean? Different classes of drugs developed Protease Inhibitors NS5B Polymerase inhibitors NS5A Replication Assembly Complex inhibitors Well – what does this mean – just like understanding the HIV lifecycle led us to develop different HIV drugs – PIs/NRTIs etc Understanding the HCV lifecycle has led to the development of Direct Acting Antivirals – leading to better treatment options. 22

A Major Advance: The first PI’s for Hep C 100 63-75 80 60 38-44 SVR (%) 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. So the first generation Pis – Telaprevir and Bocepravir – were licensed in 2012 the benefits seen with these agents when added to peginterferon and ribavirin have lead to a significant improvement in SVR rates over peginterferon and ribavirin alone in both treatment-naive patients and in patients who previously failed treatment with peginterferon and ribavirin. 20 BOC or TVR + PegIFN/RBV PegIFN/RBV 23

No Free Lunch But unfortunately with these new agents, although they have improved efficacy, they have come with a host of other side effects, predominantly more anemia and rash. And of course, interferon is still required, so all of the interferon-associated side effects that we were already familiar with. So, clearly treatment’s more effective, but it’s certainly more difficult with the first-generation protease inhibitors and the nurses role has increased again! More side effect management! 24

Upcoming Agents Polymerase Inhibitors PIs CypA 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 But what we have now in phase 3 studies are drugs that are showing very little in the way of side effects – and here are just a few. When added as a single agent to interferon and ribiviron are significantly shortening treatment times and massively increasing cure rates. Sofosbuvir for example with peg and rbv for 12 weeks is curing nearer 90% of people. Of course we are pushing our patients through 3 months of the traditional side effects but as sofosbuvir is pretty clean were not adding to that. What is exciting though is the move towards interferon free reigimes – wether with or without ribivirin. So the work now is looking at what classes work well together with what genotypes so it is very much like the first days of HIV research and its very exciting. 25

How do we decide who to treat now and who can wait? Waiting game? How do we decide who to treat now and who can wait? So what does this mean for patients – well Currently we are in limbo – we have patients who don’t want treatment with interferon – or have failed treatment with peg/RBV or have no damage to their livers so can afford to wait for these new therapies. The question is How do we decide who can wait and who cant? 26

Prior treatment response Cost !!! Stage of liver damage Availability of drugs Prior treatment response Cost !!! Ultimately it comes down to the stage of liver damage. We do not want and should not be letting our patients get cirrhotic – Transplants are out of the question for many and especially co-infected patients. But also the availability of drugs – Healthcare services in different countries vary widely. The cost of these new drugs is going to be enormous – 50K euros PLUS for a 3 month course of treatment (Sofosbuvir/Peg/Rbv). then there is prior treatment response – people who have failed peg/rbv have done much better with telaprevir and bocepravir and altthough the side effects are pretty harsh we have pushed people through treatment successfully because we realistically know they wont get access to the newer drugs for some time and their livers are deteriorating. 27

Example of Nuc Backbone + PI in Trt-Naive Pts and Nulls (COSMOS) SMV (PI) + SOF (Nuc) + RBV 12 wks SMV (PI) + SOF (Nuc) 12 wks 100 100 96 96 93 78% GT1a 40% Q80K 79% non-CC 47% F4 54% Null 80 78% GT1a 50% Q80K 94% non-CC All nulls 60 SVR12 (%) SVR4 (%) 40 Now I want to end on some positive news – The cosmos trial – (although very small numbers of patients) looked at completely interferon free treatment for people who have been previously hard to treat. GT 1a – traditionally hard. Nearly 50% had failed the first PI’s showing the Q80K mutation, Most of them had genetic variations that made them dificult to treat most had not responded to prior therapy. And so what you see here from the COSMOS trial is the combination of two new agents either with or without ribavirin for just 12 weeks show Cure rates of virtually 100% So Its an exciting time and new drugs are apon us, in different combinations and this is just one small example. But they will be expensive and hard to access but one hopeful point is that with so many drug companies bringing new agents to the table competition will keep prices down.   20 26/ 27 13/ 14 26/ 27 14/ 14 F0-F2 Fibrosis F3/F4 Fibrosis Jacobson I, et al. AASLD 2013. Abstract LB-3. 28

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 So in summary – Viral Hepatitis shares many transmission routes with HIV and casues acute and chronic damage to your liver. Treatment options for both B & C are available however only C can be effectivly Cured with treatments Whilst Hep B treatments can be included within HIV treatment reigimes, Hep C treatments are separate and have many side effects As Nurses we need to understand and anticipate the side effects of HCV treatment so that we can manage them effectivly – Good rash management, HB monitoring etc. New therapies are coming – but are expensive and access will be difficult 29

Ok so here is our chance for a quick breather – and any questions on hep C before we go onto a case study? 30