Seek to Treat update

Sammi: Good evening everybody and welcome to this evening’s Seek to Treat Update webinar. Just for those online, this is a repeat of a webinar that we have already done, so if you have already participated in this it will be the same content.

Okay, before we jump in I would like to make an Acknowledgement of Country. We recognise the traditional custodians of the land and sea on which we live and work and we pay our respects to Elders past, present and emerging.

Before we jump in I will just take you through some housekeeping quickly so you know how to interact with us and your control panel this evening. So you should all be able to see a control panel like the image that is currently on your screen. If you cannot, have a look in the top right hand corner of your screen for a small red arrow. If you click on that arrow, it will pop out the rest of your control panel and your control panel provides you will tools to select if you are listening via your microphone and speakers tonight, or if you have joined the audio via the telephone it also provides a chat box where you can send through questions and comments throughout the session. Everybody has been placed on listen-only mode tonight. This is to make sure that learning is not disrupted by any background noise. As I mentioned though, you do have a chat box and we do encourage you to send through your questions as they might arise. We will do our best to respond to all your questions but in the interest of time it is not always possible, so what we will do is at the end of the session we will post an email address where you can post through any unanswered questions and we will get back to you offline.

Okay, so I would like to introduce our presenters for this evening. We are joined by Dr Joseph Lawler and Dr Marie Healy. Joe was awarded his medical degree from the University of Sydney in 2004. He completed his advanced training in gastroenterology in 2011 having trained at RPAH and Liverpool Hospital in Sydney. He completed a clinical Fellowship in Liver Medicine and Liver Transplant Medicine at Mount Sinai Hospital in New York City in 2014 and he is now a consultant gastroenterologist and hepatologist in Sydney and Western New South Wales LHD. So welcome, Joe.

And our GP presenter and facilitator for this evening, is Dr Marie Healy. Marie has been a GP in Redfern for more than 20 years with experience and interests in aged and chronic care and Aboriginal health. Marie has also been an RACGP examiner for 15 years, so thanks for joining us, Marie.

I will hand over to Marie now who is going to take us through our learning outcomes for this evening and then we will move on with the rest of the presentation.

Marie: Thanks Sammi and good evening everyone. I hope you enjoy this important webinar that really goes through the basics of understanding hepatitis C, its treatment and why we are doing this. So we will go through the learning outcomes and we hope that by the end of this activity you should be able to discuss the justifications for identifying priority populations when assessing and managing HCV infection and we will go through that in a fair bit of detail. Demonstrate a sensitive and non-stigmatising approach to the diagnosis, assessment and management of chronic HCV infection, and we use a couple of role plays to facilitate that. Explain the new direct acting anti-viral hepatitis C treatment to patients including differences from the previous pangenotypic regimen. And explain the simplified recommendations for on-treatment monitoring for patients. And we hope that the role plays will help, you know consolidate those learning outcomes.

So why treat hepatitis C? Why are we doing this? We are aiming for cure and if we cure people we decrease transmission. So there is a public health benefit that we have got to be interested in but we also want improved clinical outcomes for our patients. And that means that for the individual, curing hepatitis C will reduce the progression of liver disease and increase liver-related and overall survival. For those with cirrhosis there are other benefits including reducing the risks of complications such as clinical decompensation, variceal bleeding, liver cancer and the need for liver transplant. Not all patients with cirrhosis however achieve these clinical improvements, in particular those with decompensated cirrhosis so it can be argued that we should treat all patients with mild disease before they develop cirrhosis. There is emerging evidence that curing hepatitis C can improve patient-reported outcomes such as quality of life which will not surprise you, neurocognitive function, fatigue and work productivity. Extrahepatic manifestations such as cryoglobulinaemia – I have to get my tongue around these things, but cryoglobulinaemia, insulin resistance and cardiovascular disease also have a potential for improvement with treatment. So there are so many reasons and, so we will look at the people who we need to screen and consider testing for so that we can sort of get as many people treated as possible.

So there are priority populations that we need to be looking at when we are screening for hepatitis C and there are groups of individuals that are at higher risk of acquiring hepatitis C who should be screened. All people who inject drugs or have ever injected drugs, should be offered screening if they have not been tested. Ongoing use and people who have maybe only used a few times are important considerations here and sometimes these people slip through the net. People who have ever been in custody. Aboriginal and Torres Strait Islander people with risk factors for HCV infection which does unfortunately include the previous. There is a higher rate of incarceration in Aboriginal and Torres Strait Islander people. And other groups of people you can see on the slide should be considered, so people with evidence of liver disease, with HIV or hepatitis B or healthcare workers who practice exposure-prone procedures. A discussion around testing can be triggered by possible markers of HCV infection such as abnormal liver function tests and it is also important to be mindful of other medical and social problems that might co-exist in some high risk populations. You may need to make specific efforts to engage these groups. They would be people who have ongoing drug use for example. So stigma and fear of discrimination may prevent some people from being tested. So it is a good thing to think about.

Joe: Yes I thought we would spend some time going into some of the reasons behind why we focus on these priority populations, because I think it does warrant some understanding to justify the prioritisation of these groups. So clearly people who inject drugs carry the most significant risk factor for acquiring infection, so it is a really important group. And it is important to realise also that active injecting drug use is not a contraindication to hepatitis C treatment with these new DAA treatments. So we know that people that are actively using drugs through the needle and syringe programs in Australia, that we are actually having some success in reducing the prevalence of hepatitis C. So yes, hepatitis C antibody prevalence has declined from 54% in this population in 2013 to 49% in 2017. And the treatment uptake for the preceding 12 months has increased from 1% to 3% in the pre-DAA era to 22% in 2016 and up to 36% in 2017 which is a pretty remarkable increase and that reflects the successful treatments that we have got available now. So treating this population is really critical to preventing hepatitis C transmission within this population as Marie mentioned before. And, you know A, the achievement of the goal of HCV eradication or elimination in Australia.

Marie: So I guess these people who are actively using are really at risk of passing on the higher risk. You really do want to treat them, don’t you?

Joe: Absolutely so it is a form of prevention. And so to dispel the antipathy to treating this population, we look to the data and we know from meta-analyses of real world data that treatment of this population of people who inject drugs have treatment outcomes that are the same as people who do not or are not actively using drugs. So overall, treatment completion rates exceed 97% which is excellent and overall SVR or cure rates are around 90%.

Marie: Yes, so some assumptions that we might have made…

Joe: I think we need to dispel them.

Marie: Yes, yes. Yes the numbers tell us differently.

Joe: Now in most policy documents you will see that Aboriginal and Torres Strait Islander people are nominated as priority populations when treating hepatitis C. And you know, we all know that the Aboriginal and Torres Strait Islander population makes up 3% of the total Australian population but these people represent 9% of all hepatitis C infections that were reported between 2012 and 2016. So the other concerning thing is that the rate of diagnosis in Aboriginal and Torres Strait Islander people is nearly four times that of non-indigenous people. And most concerning, is in the five years to 2016 the HCV notification rates in this population increased by 25% but were stable in non-Aboriginal people. So in 2016 also, Aboriginal and Torres Strait Islander people had lower rates of treatment of the virus, so 18% in that population compared to 23% in the non-indigenous population. So you were going to talk about some of the other risk factors that describe or might even attribute some of the increased risk for infection for this population.

Marie: Yes. So there is in the Aboriginal and Torres Strait Islander population, there is a higher rate of receptive sharing of needles and a higher rate of receptive sharing of drug preparation equipment. So that is swabs, water, spoon, that sort of thing. There are higher rates of daily injection in this population and higher rates, which is important as I mentioned before, a higher rate of lifetime incarceration in the preceding 12 months. So this puts this priority population at significant risk given as Joe said it is only 3% of the population but there are much higher rates of incarceration in this population out of proportion with the general population. They are 27% of the total Australian prisoner population. And being Aboriginal or Torres Strait Islander is a risk factor for hepatitis C infection, but being a prisoner or an ex-prisoner is a really big risk factor. So, it is a really important thing to look out for when you are looking at screening people. And asking that question, has there ever been a risk factor such as incarceration.

Joe: And it can be a difficult question to ask.

Marie: Yes, it can be, but a really important one.

Joe: And that is a segue into the other priority population that is highlighted in policy documents. So, the National Prison Entrants’ Survey of 2016 identified hepatitis C antibody prevalence at rates between 22% and 44%. And most of those who had the hepatitis C antibody have a history of injecting drug use as their main risk factor beyond being in prison. Now, it might come as a surprise to some of you, but it should not be to most, that risk behaviours associated with hepatitis C transmission in prison include tattooing and injecting drug use. So injecting drug use does occur in prisons and it is often highly unsafe injecting behaviour with shared needles and shared paraphernalia that really increases that risk of HCV transmission.

And moving onto another priority population. So migrants from high prevalence countries. And I think it is really important when we are you know in a multi-cultural country such as Australia that we do think about the countries of birth of our patients. So looking to Africa, the hepatitis C prevalence is as high as 4% or just over 4% in Western Africa and nearly 8% in Central Africa. In Egypt, Egypt has the highest hepatitis C prevalence in the world with up to 10% of the population being infected and that comes from, and they are all the same, mostly the same genotype, genotype 4 which is a less common genotype in Australia. And this results from a mass schistosomiasis treatment program from the 50s through to the 80s and there was an iatrogenic spread of the virus. So that is really important to remember.

Marie: Are they treating, have they got you know, a big treatment program there now?

Joe: They do. They do. Yes and that is a publically funded treatment program.

Marie: So we might see that change too over time.

Joe: Absolutely. Now, in sub-Saharan countries, the transmission risks are different to the rest of the world. So compared to the transmission risks that we have been talking about to this point, there are a little different. So therapeutic injections with re-used syringes and unsterilised needles in vaccination campaigns are responsible for infection rates in Cameroon for instance, and that was for treatment of the trypanosomiasis, the sleeping sickness from the tsetse fly. And that program ran from the 20s to the 60s. There is also the risk of vertical transmission in HIV and Hep C co-infected mothers and we know HIV prevalence in Africa is quite different to here in Australia and there are traditional practices such as circumcision and scarification rituals with re-used instruments that can promote transmission.

Marie: I might just go back to, there is a question here about do the comments on Aboriginal people apply only in urban areas? Is there also a significant risk in remote parts of our country?

Joe: Look I do not think we have the granular data, but I know from the regional work that I do in Western New South Wales that the risk factors are very similar to an urban population, so I do think particularly given the incarceration rates and that is across the country, I think it is just something to be mindful of and to always question.

Marie: Yes, yes.

Joe: So Pakistan is another important country and Pakistan has the second largest hep C burden in all the world, and there are seven million people in Pakistan that were chronically infected at that time of 2013. And that represents one tenth of the global burden of SCV. Transmission here is drive by multiple risk factors and that includes community risk factors and practices such as barbering and piercing and health care practices such as blood transfusions and medical injections, as well as injecting drug use.

Marie: Okay. So talking about priority populations, we thought we would talk about sexual transmission.

Joe: Because this comes up. It is just one of those questions that comes up all the time.

Marie: It does, yes. And you know it is often used as part of sexual health screening and you just wonder about the evidence there. But there is a very low risk in monogamous heterosexual couples, 0.07% per year. So that was over 190 thousand sexual contacts.

Joe: For one transmission.

Marie: Yes, yes, so that is a pretty good confidence.

Joe: So very different from hepatitis B.

Marie: Yes, definitely. But there is a higher risk in men who have sex with men. And this is driven by things such as HIV co-infection, higher risk sexual activities and the use of sex toys or group sex and mucosally administered recreational drugs that may occur in that setting. So there is a difference in subgroups there for sexual risk and that is an important thing again. The questions might be embarrassing but it is important to put them out there because we are talking about a disease that has significant morbidity. So to recap. When to test for hepatitis C virus. So, a patient may come in and request the test. I think it is important to explore why they want to, but that is a good thing. They might have abnormal liver function tests, symptoms or signs of liver disease. You may have a concern because of some clinical indicators or history, jaundice, acute hepatitis and the presence of risk factors. So they are listed there on the right. And they are: considering the priority populations that we have just discussed and injecting drug use, the sharing of equipment, birth in a high prevalence country such as Pakistan, Egypt, unsterile tattooing, body piercing and those other ones that are down here, but down the bottom sexual transmission is rare, but think about men who have sex with men and people who are HIV positive.

So, how to test for hepatitis C virus. So, the HCV antibody test is a screening test remember, and it indicates exposure to HCV at some point. So, if somebody has had exposure to hepatitis C their antibody test is positive and it will stay positive. So it may indicate one of three scenarios. They could have an acute infection, given the right context or risk factors. They may have a chronic infection by definition, we say that is greater than six months. Or it may be infection that has cleared spontaneously which can happen in 20% to 30% of cases or with anti-viral treatment. So to confirm chronic hepatitis C you need to check for evidence of viraemia. The test to use is the HCV PCR. There are two types, the qualitative one which just tells you if virus is detectable. The quantitative one is the viral load or the HCV RNA level. And you must specify this on the pathology form. Under Medicare, a patient can have one quantitative PCR test if not on treatment, and four if they are on treatment per year. So, if they have chronic hepatitis C, you should also test for Medicare requirements for the HCV genotype, and this helps to dictate treatment. Although we do have pangenotypic regimes it is still recommended because it is not only a PBS requirement, but there are different regimens for different genotypes and you may not use the pangenotypic regimen because of comorbidities such as renal failure and drug interactions. And it can also help to define re-infection. So there is a point to knowing the genotype, because that is an important thing for working out the next round of treatment for example, if it is re-infection.

Joe: So this slide jus summarises what Marie has just said, looking at the appropriate algorithms. Testing when you approaching somebody, moving from screening to diagnosis of hepatitis C. So reiterating that the hepatitis C antibody test is the first step. If that is negative then you can stop there. They do not have hepatitis C, or chronic hepatitis C. If you are worried about acute hepatitis C you might test again later, but at this point in time you can stop there. If that test is positive, you need to order the RNA test. So the detected viraemia in the blood. If the RNA is not detected, there is no evidence of current hepatitis C infection and that could represent as you have just said, spontaneous clearance of clearance with treatment. Moving on to the right further. If the HCV RNA is detected, that indicates current hepatitis C infection and that would be the prompt to provide care or provide a link to care. And remember that we do define chronic hepatitis C as evidence of hepatitis C infection for more than six months.

Marie: So, now Joe is a hepatologist and so we will discuss now from my point of view as a GP when I might consult with him or refer a patient to him or a specialist. And so, while as a GP I am comfortable with these medications and comfortable with the assessment, there are patients who have special requirements and those people with advanced fibrosis or cirrhosis, you do need to be linked in with a specialist for treatment and then monitoring. So they will need things like endoscopies and all of those sort of six monthly checks as well. People with extra hepatic manifestations can be tricky. So you might either consult with them or treat them with the assistance of a specialist. Patients with complex comorbidities, patients with HIV or hepatitis B virus co-infection are important considerations. Patients who have failed first line direct acting anti-virals. Now patients with renal impairment, and it will depend on their level of renal impairment, that is at the more severe end.

Joe: So I think we could say with a GFR less than 30. That would be a trigger. So if they are hovering around that and you are worried it might go south.

Marie: And I guess if it stable and above that you might…

Joe: You would be happy.

Marie: Yes. And patients for the potential clinical trials of new HCV treatment regimens and patients with acute HCV. So they are the basic things that you would think about in terms of referring to a specialist.

Is there a question there?

Joe: Sorry yes, there is a question. In high risk patients, can all three tests – I think meaning the hepatitis C antibody, the HCVRNA and the genotype – be all asked for at a single consult? Look I think it is going to depend on your pathology lab but the RNA will be charged if the antibody is not detected and the genotype will not be done if there is no RNA. So, it would be worthwhile checking with your laboratory. And it could come down to the specification of the clinical indications in your clinical history box.

Marie: Yes, okay. Thank you. So, the PBS requirements. The patient must be aged 18 years or older. So we are only dealing in this webinar with adult patients. The treatment criteria are, they must be treated by a medical practitioner or authorised nurse practitioner experienced in the treatment of chronic hepatitis C infection. So that means that you have had 10 treatments with supervision of a specialist basically. Information that must be provided on the application are, the hepatitis C virus genotype and their cirrhotic status, that is, do they have cirrhosis or not? And the patient’s medical records must document evidence of chronic hepatitis C infection and evidence of the genotype. So that is the information that you will really need to have on hand when you ring up to prescribe it to. Alright?

Joe: So we are going to run through a couple of role plays now to demonstrate how to integrate screening and testing into your consultations in general practice. And after each sort of section of dialogue, we are going to ask for your feedback. So take note of the things you think were done poorly or things that were done well, and what you think you might integrate into your own consultations.

Marie: Okay, so I will be playing Angie and I am a 32-year-old married school teacher. Should you describe me Joe, maybe?

Joe: So Marie has recently, oh sorry, Angie. Angie has recently attended for a full check-up prior to starting a family. Physical examination is pretty unremarkable and BMI is healthy. She has got some mild asthma that she has been treating and she only uses Salbutamol occasionally and otherwise is well. So no other regular medications apart from the oral contraceptive pill. She describes her social alcohol intake as 2 to 3 drinks on Friday and Saturday nights, so not too excessive. She was born in Australia and she is not indigenous. So Angie has come in today to chat about her blood test results which were full blood count, rubella serology and iron studies, and these were all normal. Of concern was something that you picked up on, was the basic biochemistry has revealed that she has mildly elevated LFTs with a GGT at 56 and transaminases are up a bit. So ALT is 50 and AST is 42 with a normal ALP, bilirubin and albumin.

So thanks for coming back, Angie. Your bloods were mostly normal but there was a mild elevation in your liver enzymes. Are you aware of any liver issues you might have?

Marie: I do not know of anything wrong. I do not drink a lot. Is it serious? What does it mean?

Joe: Well Angie, as I said, the abnormalities are only mild but they could be significant. Have you, your partner or anyone in your family ever had liver problems or hepatitis? For instance, have they ever been unwell with a yellowing of their skin?

Marie: No, not that I know of.

Joe: Well in that case, what we normally do is look for causes of liver strain. And this would involve taking another blood test for hepatitis B and hepatitis C. Do you know if you have ever had hepatitis before?

Marie: Well how do I know? I do not usually get sick or have blood tests.

Joe: Well look, people can be exposed to hepatitis in a number of ways like through blood transfusions several years ago, tattoos, body piercings, sexual activity rarely and injecting drug use, even if it was years ago.

Marie: Oh no, I did inject speed with a boyfriend when I was 19, but it was only twice. I have put that behind me. Could that be an issue now? I feel okay.

Joe: Well I think it is important to make sure you are healthy, especially if you are planning a family. It would be sensible to go ahead and check if you have been exposed to hepatitis B or hepatitis C. Hepatitis exposure can occur with only a couple of shared injections. Even if you do not feel unwell, it is important to check out what is going on with your liver.

Marie: Oh no I am really nervous now. I have never discussed that part of my life with my family or husband.

Joe: Look, I can understand your anxiety. The test result will come back soon, so I can see you again in two days. I am glad you came in for your check-up. Remember that pregnant women are checked for hepatitis anyway, so checking things out now could avoid a surprise later on. I will tell you that hepatitis results are notified to the public health unit, so if any test is positive, it is recorded, but not with your name and this is just part of keeping statistics for public health reasons.

Marie: Oh that is okay. Should I have the test today?

Joe: Look I will refer you for an antibody test for hepatitis A, hepatitis B and hepatitis C, and that will tell me whether you have been exposed to those viruses in the past. I will see you back here in two days and we will work out if the test will help us in sorting out this liver issue.

So, what do you think the GP did well? What do you think I did well? Did Angie have a good understanding of testing for hepatitis C? And what was the outcome?

Marie: Well, I think that I felt that I could ask questions you know. I do not think there was any sort of you know, it was just look we have got a problem and we have to sort through what the problem is. You know, I thought was a fairly logical discussion really.

Joe: You were able to comfortably discuss your distant history of injecting drug use and I think that is really important.

Marie: Yes, yes. You know, that is probably burning in me.

Joe: So, any suggestions or comments for improvements? I mean, I think the pregnancy discussion is really important.

Marie: I think so, yes.

Joe: You know, the hepatitis B and C screening is part of antenatal care so it is important to be aware that that is another trigger for screening.

Marie: Yes. And certainly you know the test, the fact that the tests are coming back quickly and that she will have some certainty is a good thing.

Joe: Yes, and the GP has provided a pathway for the testing.

Marie: Yes, yes.

Joe: So look seeing there are no comments or judgements coming in from the audience, so I think we will move on.

Marie: Here is one. So maybe confidentiality could have been provided. Yes, I think that the doctor has stated that look it would be notified to the Public Health Unit only, but I think that was his point, but not with the name.

Joe: Yes, and supporting any patient with any discussions when disclosing to family members and partners and things, that is an important discussion to participate in. But of course highlighting confidentiality is a really important point.

Marie: Yes, definitely. Yes.

Joe: So we wanted to sort of highlight a couple of changes to the Gastroenterological Society HCV consensus statement. So, GESA initially published a statement in September 2018, sorry published their updated version in September 2018 with a few key points that we could highlight for the general practitioners in the community who are considering prescribing treatment. So there were new PBS listings of pangenotypic regimens; Maviret which is glecaprevir and pibrentasvir in 2018 and then Vosevi which is sofosbuvir, velpatasvir and voxilaprevir which was listed in 2019, just this year.

The recommendations for on-treatment monitoring have changed and been simplified, particularly during treatment, and the recommendations for management for people with hepatitis C and renal impairment have been updated.

Marie: So it certainly has been, you have got more choice and it is simplified as well, and there that one of the GPs who does a lot of antenatal work does recommend routine testing for pre-conception work up and I think that is a good point because they would be tested anyway in pregnancy.

Joe: Absolutely. I do not think we talk about it later, but we have covered it in other topics, but these medications are contraindicated in pregnancy so if people were concerned about medical transmission, treatment could be provided before conception safely.

Marie: Yes.

Joe: So we wanted to go through some of those changes to the consensus statement. So Maviret is an interesting addition to the armamentarium against hepatitis C, and this was listed in August last year. So it is fixed dose combination pills of protease inhibitor, NS3/4A inhibitor and a non-structural protein inhibitor, NS5A. The medication is pangenotypic, so it can be used in genotypes one through six. It is three pills taken daily. So in those three pills there are the two drugs, for the three pills taken every day. The big change is that non-cirrhotic treatment naïve patients with hepatitis C of any genotype, can be treated for eight weeks with cure rates equivalent to 12 weeks. So it is a really important thing to remember, is that truncating that 12 week treatment to eight weeks can be a blessing. But in people with cirrhosis you do need to use 12 weeks of treatment and of course that would be in the context of specialist care and then also there is a 16 week regimen for treatment experienced, so DAA experienced and protease inhibitor exposed patients with genotype 3 infection. So you know, that is a specialist. But overall, the SVR or cure rates are better than 95% for all genotypes, so that is really promising. And you will see if you are all familiar with the HCV consensus statement, it is a great document to have, and there are some wall charts there you can print out for your practice that have very quick, easy to access summaries for your prescribing. So you can see here that it is highlighted in the second row glecaprevir and pibrentasvir for all genotypes for eight weeks with no cirrhosis and 12 weeks for cirrhotic patients.

So the other really important thing about this listing is that it can be safely used in renal failure, and renal failure as defined by a GFR of less than 30, and again people with all genotypes treated for 12 weeks with a GFR of less than 30 have a cure rate of 98%. And I should just point out that any sofosbuvir-based treatments which you will see in Harvoni which is the sofosbuvir, oh sorry, Epclusa, the Harvoni velpatasvir regimen cannot be used in renal failure. The key here is that is that this drug Maviret cannot be used in patients with advanced liver disease because the protease inhibitor is metabolised in the liver and can cause liver toxicity in that context.

Marie: So where do you draw the line between, I suppose if they are being treated by a specialist you guys draw the line between cirrhosis and advanced liver disease.

Joe: Well it is a clinical and biochemical assessment. So we are using all those scoring assessments like the Child Pugh score and the MELD score. But in general practice, it is really about identifying the presence or the absence of cirrhosis and we have talked about that, and it will come up in the next case I think. We revisit the role of FibroScan, so transient elastography and also the role of the AST platelets ratio index.

Just another point about the Maviret is that it is incompatible with ethinyloestradiol-containing oral contraceptives, so that could be an issue. So alternative contraceptives could be sought or you use another anti-viral regimen.

Marie: Yes.

Joe: So the recommendations for on-treatment monitoring during the DAA therapy has been simplified. So, at the moment we get baseline blood tests before treatment is commenced and we have been through those tests before. But now there are no routine on-treatment monitoring recommendations which is great. What is critical and what we have to remember is that the SVR bloods are still required. So, 12 weeks following treatment completion is when we assess for a cure. Okay?

Marie: Now this was just a question. Yes, Mirena and Implanon are okay.

Joe: That is correct, yes.

Marie: Because they are progesterone based.

Joe: That is correct.

Marie: So we might talk a little bit more about the on-treatment and post-treatment monitoring with the changes to the consensus statement. So, at week nought, or before treatment, you do your pre-treatment blood test including liver function tests, the HCV PCR and then you just do your tests 12 weeks post-treatment. Now, this is repeating your liver function tests and your PCR. But look, for some populations and for certain sub-groups there may be more intensive monitoring required. You know, if you have got somebody with a little bit of renal impairment or other issues.

Joe: If you are concerned about compliance, you can use blood tests and you can use the HCV RNA to try and fill in the gaps in the story to see if people are sticking to their course of therapy.

Marie: Yes. So look, monitoring on-treatment has not been arduous but we can see that monitoring has been simplified again. You know it is great for GPs that this has happened, and for patients, because we are increasingly seeing drug combinations that are of high efficacy and tolerability. Obviously, follow up is guided by other factors such as adherence issues as Joe said, comorbidities and patients should be aware that they should be reviewed if concerns arise in any rate. For many people treated in a primary setting however no formal treatment related assessment is required while on therapy. I think a follow up to check adherence and how they are going is the important thing. You do that when anybody is on a new medication at any rate.

Joe: That is part of the therapeutic relationship and facilitating treatment.

Marie: I think it is, yes. After treatment is finished an appointment should be arranged for three months post, or 12 weeks to test for a sustained viral response, or test of cure we are calling it, hepatitis C PCR and to re-check the liver function test.

Joe: And we know that people that are being treated in general practice are the non-cirrhotics. If at that point, that time, so 12 weeks after treatment completion the RNA is undetectable and the liver function tests are normal, then they can be essentially cured of their hepatitis C and discharged from hepatitis C for life, unless they have an ongoing risk factor. If you are concerned through persistence of viraemia on that test or if there are abnormalities on the liver function test, that can be a prompt to refer to specialist care.

Marie: So, also the recommendations for the management of people with HCV and renal impairment as Joe mentioned have been updated. So people with moderate to severe renal impairment should still be referred to specialist centres for consideration. Look it has got an eGFR less than 50. Generally the cut off is 30, but GPs should know how comfortable they feel around that 30 to 50 borderline mark. So if somebody is very, very stable you know and it is a safe drug to use in renal impairment, that is a judgement that the GP can make. The pangenotypic glecaprevir and pibrentasvir.

Joe: Pibrentasvir, that is the Maviret.

Marie: Are cleared by hepatic metabolism and they are now the preferred treatment regimen for people with severe renal impairment. So somebody with an estimated GFR of greater than 30 and a GP who is experienced, could still do that.

Joe: Could still treat that patient, yes. So there was an additional PBS listing this year and that was the Vosevi which is a combination of sofosbuvir which some of you might be familiar with as part of the older treatment, Harvoni and the newer regimen, Epclusa, plus velpatasvir which is found in Epclusa. The new drug there is protease inhibitor, voxilaprevir. Okay? And this is pangenotypic. It is a co-formulated once daily single pill 12 week regimen. Now it is just important for the community to be aware that it is available for people that fail first line DAA treatment. So this is drug that will not be used in general practice because by definition a patient that has failed DAA therapy should be referred on for specialist care, but it is just an important change.

Now something that has come up just in the last few weeks, on the 28^th August actually was a box warning from the FDA in the States. Now it is saying in patients with moderate to severe liver impairment, Child Pugh B or C, the use of protease inhibitor containing drugs, so Maviret, Vosevi and Zepatier can cause rare cases of worsening liver function or liver failure. Those types of patients are typically presented within the first four weeks of treatment and just note that these drugs, so the Maviret, the Vosevi and Zepatier are not appropriately used in this population so when you look at the prescribing guidelines and the consensus statement, they should not be used. And that is because of the hepatic metabolism of the protease inhibitor component. So it just highlights the importance of identifying cirrhosis before commencing on a course of treatment. And it highlights for specialists the need to assess the severity of liver disease. So these drugs can be used safely in compensated or Child Pugh A cirrhosis, but great caution needs to be used in anything beyond that and certain contraindications to decompensated liver disease.

Marie: So having that system for assessment with the FibroScan and your biochemical markers and your physical examination and the platelet counts, I think all of those we cannot just take for granted can we, because you know, that has happened.

Joe: So I do not want this to discourage people from prescribing hepatitis C treatments but just be aware that the recognition of cirrhosis and its assessment is really important.

Marie: Yes, definitely. So on that jolly note we will go to our next case study. Now, so Jake. Here we have Jake. He is 58, looking for a GP. He has had some time in custody and was found to have hepatitis C whilst in custody, genotype 3A. He is unemployed and he is still occasionally injecting stimulants. He rarely drinks alcohol. He identifies as Aboriginal. His past history is gastroesophageal reflux treated with esomeprazole and he is slim with a BMI of 20. And there are no signs of cirrhosis. So, what other assessments would be appropriate for Jake?

Joe: So, yes, we have been through those baseline assessments and screens for hepatitis B and he has got apparently a diagnosis of hepatitis C and a genotype so we know that we know that we need to be considering this gentleman further for treatment.

Marie: Yes.

Joe: We have talked about that requirement to assess for the presence or absence of cirrhosis. So there are a couple of tools that we use and here is one of them.

Marie: Yes, that is the APRI test, so we are looking at the AST level and its upper limit of normal divided by the platelet count to give us a score there, a ratio and so it appears quite low, much less than one the ratio.

Joe: And one is that level that we use to sort of reassure us that there is no evidence of cirrhosis. And this is a really great tool because not everyone has access to FibroScan. You can download this calculator from the internet and a multitude of free Aps and it is using commonly ordered tests like the component of the liver function test and the platelet count to contribute to your assessment of cirrhosis. So you know, it is not a perfect test but it is a very good test and it can be put together with your clinical assessment, your history, your examination, your imaging to help work out whether you have cirrhosis.

Marie: And we would of course include his renal function and his haematology, well his platelet counts there and we do his renal function as well.

Joe: Absolutely.

Marie: So, Joe take us through that FibroScan result.

Joe: Okay. So Jake has had a FibroScan. Fortunately he had access. The result there up the top you can see is 6.2 kPa, or kilopascals which is the units that this test is measured in. So looking at the graphic below there, you can see the arrow and the green section. The limitation of that green section is 7 kPa. So you can see he falls into that safe range of the non-cirrhotic, F0 to F1. So he has no or even very mild fibrosis. So I would be really reassured you know to treat this guy safely in the community with a low APRI and that low FibroScan result.

Marie: Well I might ask you some questions. Do you think Jake can be treated in the primary care setting?

Joe: Yes, absolutely. I think you know we have established that he has got hepatitis C. We know he is non-cirrhotic. We know that he does not have renal failure. He is injecting drug use but he seems to be going pretty well so I think ongoing injecting drug use is not a contraindication to treatment, okay? It is certainly something you need to consider and it can be a relative contraindication because you know, we all know how chaotic, patients who use stimulants can be very difficult to manage and if you cannot be guaranteed compliance or there is a question mark over their ability to comply with treatment, that might be something to sort out before you consider treatment. But ongoing injecting drug use is certainly not a contraindication for treatment.

Marie: So what are the treatment options available for Jake and for what duration?

Joe: So we have Jake who has got genotype 3 infection. He has never been treated before so he has never been exposed to the DAAs. His viral load is 2.3 million international units per mil and he does not have cirrhosis. So his options are pretty good and I think we are pretty happy to treat him in the community setting.

Marie: Okay, so in my own mind I would like to summarise what I known about that I have been through the assessment, okay? So he has got chronic hepatitis C.

Joe: He has got risk factors for infection going right back.

Marie: Yes, that is right. We have done the genotype and the viral load. There is no evidence of cirrhosis so there is no other liver comorbidity that we know of. His other comorbidities are gastroesophageal reflux and the amphetamine use. There is no coinfection that we know of. He is on esomeprazole, a proton pump inhibitor. He has had no previous treatment that we know of and so I think I would use this information to guide therapy and follow up.

Joe: So I would refer back always to the HCV consensus statement and look at your wall chart and have a look at the treatment options available. So there are two options for him and you can see there he has got genotype 3 so the top two rows would be the sofosbuvir and velpatasvir which is Epclusa or the newer Maviret, so glecaprevir and pibrentasvir would be suitable. I think looking at this gentleman and you know, this is the type of patient that you really want to treat with a truncated course of treatment, so we have an eight-week regimen available for this gentleman. So it is going to be less stressful to look after him because we have a shorter duration of care and I think he would appreciate the shorter duration of care as well. So, you know you consider both the top two options. I would lean towards the second option in this case given the possibility of treating his for four weeks shorter duration. And it depends on what you are comfortable with and what the patient wants as well. But regardless, whatever treatment you choose you are going to need to check on drug-drug interactions because that might sort of dictate your treatment choice as well. So, we all know or hopefully we all know about the Liverpool drug-drug interaction tool. So it is a free online tool.

Marie: It is very user friendly.

Joe: It is very user friendly. It is very straight forward. So all you have to do is enter your treatment choices, your hep C treatment choices and any other medication that is being co-prescribed and you will come with a kind of traffic light waring, so red for contraindication to co-administration, amber for potential interactions, yellow for very weak risk although risk and green for go no barriers. So it is a very, very useful test. So with this gentleman we have chosen the glecaprevir and pibrentasvir and we have seen that esomeprazole or the PPI has come up with a potential weak interaction. So this medication has been marketed as safe to use with esomeprazole but I think it always warrants a review. Okay? So, please utilise the Liverpool drug-drug interaction website. It is a really critical part of treating these people.

Marie: But he might not have much reflux. You might be able to actually say to him, why don’t you try not taking it and see how you go, too? You know, that is always a thing, isn’t it?

Joe: Yes, these ones are pretty commonly prescribed and people often get on them and they never get off them. So you can always review the need for a proton pump inhibitor. You can consider stopping it or you could consider switching to a weaker medication like a histamine receptor antagonist such as famotidine.

Marie: You would have to go back and look at the interactions again to see what interacts with that, but alright, yes.

Joe: And that would be if you are using the Epclusa regimen, but you should feel pretty confident in co-prescribing that PPI with Maviret.

Marie: Yes.

Joe: But always, you know if you can rationalise people’s medications that should be encouraged.

Marie: Yes, definitely, yes.

Joe: But I also should make a point too. If you were to choose Epclusa in this gentleman, the other option to use in place of esomeprazole would be omeprazole at a dose of 20 mg dosed four hours from the Epclusa. That is another possible way.

Marie: Yes. Now there is a question here about us assessing Jake. What imaging should we start with in assessing for fibrosis?

Joe: Look, imaging is not always needed, but if you have question marks over the presence or absence of cirrhosis, utilise everything you have got. Okay? An abdominal ultrasound, you know there is no radiation involved, it is a simple test. It is not painful. It can give you lots of information, so you are looking at the echotexture of the liver which will be reported. You are looking for macronodular cirrhosis like a bumpy liver edge. You are looking for portal vein dilation that might indicate cirrhosis and you are looking for splenomegaly. You know, varices and all those sorts of things. So you can put that into your assessment.

Marie: But if you have got a low score on the FibroScan, and a low ratio on the APRI score.

Joe: And a history of a young person who only has risk factors you know going back a few months. Or a few months ago, going back a few years and your pre-test probability of cirrhosis is low, you know, have confidence in your judgement.

Marie: Yes, yes.

Joe: So in Jake the GP has chosen the Maviret option for eight weeks. Okay?

Marie: Excellent, yes, yes. And so what testing does he need at the end of treatment? At the end.

Joe: At the end of treatment? So at the end of treatment, we need nothing. Okay? And that is a change from the old guidelines where you were doing test on-treatment and at end of treatment, that has disappeared that requirement. So yes, that is good news.

Marie: Yes. So, does he need any further testing then?

Joe: Absolutely. And we highlighted this before in our discussion that the SVR assessment or the cure assessment, that is due at 12 weeks after completion which includes at the minimum an HCV PCR and liver function test and then if your HCV PCR is negative or the virus is not detected, that is considered a cure. And if the liver function test has normalised with treatment, then there is no need to monitor for hepatitis C unless there are ongoing risk factors and there is no need to refer on to consider other liver diagnoses.

Marie: Okay, well that brings us to the next slide, now that you have brought that up. So we find that he has a sustained viral response, so he has got a cure from treatment and his liver function tests have normalised. So does he need any further follow up for hepatitis C?

Joe: So, no. He has had an SVR so he has had a cure. He has not got cirrhosis and his liver function tests are normal. So he is cured and he can be discharged from your care. But remember, he has said that he still injects occasionally so he has got ongoing risk factors for infection, and we all know that we do not have immunity to hepatitis C, you can get it again. So the recommendations are that if people have ongoing risk factors, like injecting drug use, you should check HCV RNA every six to 12 months to assess for reinfection and remember that the antibody might stay positive for the rest of his life. So doing an anti-HCV antibody test has no role in monitoring for re-infection. You need a PCR, okay?

Marie: Yes, yes.

Joe: So I think you have also got to remember to do a bit of education here and remind Jake that he can get hep C again and that he would be at risk if he has got high risk injecting practices, sharing needles and paraphernalia. And you know, use that opportunity to refer him to drug health services and rehabilitation.

Marie: I have got a question about 5% failures. How do you manage? Well, that is under the specialist.

Joe: Yes, yes that is right. And then we have got this new drug Vosevi which picks up a lot of those people so that is very effective. But if you are diagnosing a reinfection, it just highlights that history that you are taking and really delving into the treatment history. If they have got a history of DAA exposure and they are still RNA positive, get them off to a specialist.

Marie: Yes, yes. Well look, that brings us to the end of that webinar. And thanks for the questions during the webinar, too. There is one more. What alternatives to consider in patients with liver compromise with hepatitis B or A? Now look that again is a coinfection and that is seeing a specialist. So you would refer them.

Now there are hepatitis C online learning resources for you to look up. There is the ASHM eLearning webpage listed there. The NPS MedicineWise and the mdBriefCase and there is also hepatitis C web resources from GESA, ASHM and ASID. And we are hoping that the learning outcomes have been achieved and that you feel that you will be able to discuss the justifications for identifying priority populations when assessing and managing HCV infection and we went through those in quite a lot of detail. Demonstrate a sensitive and non-stigmatising approach to the diagnosis, assessment and management of HCV infection and we did that with the role play. Examine the new HCV treatments to patients, including the differences from the previous pangenotypic regimen and we discussed some of the new guidelines there, and explain the simplified recommendations for on-treatment monitoring to patients which is basically most of them need no on-treatment monitoring other than engaging in a great therapeutic relationship. So we wish you all luck in our attempt to cure hepatitis C in Australia.

Joe: And thanks so much for taking the time to listen to us tonight.

Sammi: That is great. Thanks so much Joe and Marie for joining us this evening and also thank you to everybody online. We do hope you enjoyed the session and we hope you enjoy the rest of your evening.