Sammi: Good evening everybody and welcome to this evening’s Hepatitis C Case Studies for General Practice Webinar. My name is Samantha and I am your host for this evening. Before we jump in I would just 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 and present.
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 the Clinical Fellowship in liver medicine and liver transplant medicine at The Mount Sinai Hospital in New York City in 2014. He is now a consultant gastroenterologist and hepatologist in Central Sydney and Western New South Wales LHD.
And Marie has been a GP in Redfern for more than 20 years with experience and interest in aged and chronic care and Aboriginal health. Marie has also been an RACGP examiner and QA examiner for 15 years. So, thank you Joe and Marie for joining us this evening.
Marie: Thank you. Hi everyone.
Joe: Thank you. Hello everyone. Again.
Sammi: Wonderful. So I will hand over to Marie now and she will take us through our learning outcomes for this evening and then jump into the presentation.
Marie: So, hi everyone. By the end of this activity, you should be able to firstly order and interpret tests necessary to diagnose hepatitis C and prepare patients for treatment, recognise risks, signs and symptoms of liver disease and other comorbidities that require management or referral to specialist care. And chose appropriate hepatitis C antiviral therapies according to virus genotype and potential for drug interactions. So we are going to try our best to cover those three learning outcomes.
Here are the three cases we will be following in the context of our learning outcomes. They reflect a range of presentations that we as GPs can expect to manage. With access to great therapies and clear guidelines, GPs can feel confident that they have the skills and resources to cure hepatitis C across many scenarios. So we have got Ahmed who is a 52-year-old male originally from Egypt, Joe a 63-year-old man with abnormal liver function tests and then Tu, a female 32 years old of Vietnamese background seeking treatment.
So we will progress to the first case who is Ahmed.
Joe: Ahmed. So yes, Ahmed is a 52-year-old engineer who was born in Egypt and he presents for the result of his hepatitis C antibody test after he had a medical check-up recently. Also of note, his father recently died of liver cancer in Egypt. He has a past medical history significant for hypertension, dyslipidaemia, reflux, depression and erectile dysfunction and his medications are listed there. There is no history of alcohol or smoking and his BMI was 23.5 with blood pressure of 134 on 76. And he was found to be anti-HCV antibody positive. His examination was otherwise normal and he has no signs of cirrhosis. So we have a gentleman here with a significant country of birth given the priority populations we have identified in the past are understanding that Egypt has quite a high prevalence of hepatitis C. We also have a history of his father having hepatocellular carcinoma which is a bit of an alarm bell and sort of expression of his risk of liver cancer. And we also know that he has exposure to hepatitis C.
So, as a GP Marie how would you proceed in this situation? And we can give everybody an opportunity to think about this before we go to the next slide.
Marie: Yes, well already I am thinking, we have got a middle aged man with a significant history. He is from a high-risk area. His father died of liver cancer and he has had exposure to hepatitis C obviously because of the hepatitis C antibody test. And I do not the presence of several comorbidities and medications, so I think we are going to need a systematic approach to assessing this man with a view to finding out where his liver is at and what we need to do about it. So, I guess one of the first things I would ask myself, is does he actually have current hepatitis C infection? So we need to check for hepatitis C RNA. In other words, need to check for viraemia. So here we have hep C RNA which tests for actually actual active infection. So if it is positive, a quantitative Hep C RNA and genotyping can be done. This is useful for prognostic reasons although essentially it remains a Medicare requirement as well.
Does he have significant co-infections? I would have to ask that because you know, if you have got hepatitis C have you got other infections? Yes, that is it. So, if he does not have them, it will help decide what vaccinations he needs. So checking for hepatitis B, hepatitis A and HIV. So active hepatitis B I understand requires specialist treatment so I would be sending him off to you, Joe. Otherwise I would offer vaccination if he has got low or absent immunity.
Hepatitis A is really common in childhood in this age group. If he comes back negative, offer vaccination. Obviously people do not carry hepatitis A. So HIV again. If coinfection is present, well that becomes a lot more complicated. So that requires specialist treatment and lots of work there. The baseline test that we do want in looking for comorbid is the blood count, liver function, urea, electrolytes, the INR. These are all – and the full blood count – these are all important in the assessment for you know, cirrhosis and comorbidities.
Also the alpha-fetoprotein because his father had liver cancer and add an abdominal ultrasound.
Joe: To check his, yes, that is right.
Marie: So here are his results. So they are quite interesting. He does actually have active hepatitis C. He has got positive hepatitis C RNA and he is genotype 4. It looks like he has got past resolved hepatitis B and A. You can see the negative antibodies and he has got the negative core antibody for hepatitis B and a positive surface antibody so that is a good result. The liver function tests I can see are normal but the full blood count… are not normal, I am sorry about that. They are not normal and I guess you would be thinking that might be because of his positive hepatitis C.
Joe: Yes, so the ALT and the AST are just a little bit up.
Marie: Yes, yes. But reassuringly, the full blood count and INR are normal. But he certainly does need further assessment for fibrosis and / or cirrhosis given those abnormal LFTs and the positivity of the hepatitis C infection.
Joe: Yes so as you pointed out, the fibrosis and cirrhosis assessments are a really critical part in this pathway to treatment in general practice. So the degree of liver fibrosis is important as a prognostic factor for progression of disease or clinical outcomes. And assessing fibrosis informs us of treatment urgency. So if there is significant fibrosis or cirrhosis, the urgency to treat is now. It also indicates need for additional screening if you are concerned about cirrhosis. Those patients need to be assessed for liver cancer as we have discussed, oesophageal varices and other complications. It also determines in some cases the regimen you would choose to treat in terms of hepatitis C and the duration of treatment and it is certainly required by the PBS for prescribing. And also dictates the post-HCC clearance management in these people.
Marie: Yes. Yes, okay well look, we might continue with how we are going to assess the fibrosis and whether it is significant or present in this man. So obviously it involves consideration of several factors. The gold standard is liver biopsy, really a comprehensive approach is generally used as illustrated on this slide. It gives the clinician a good indication as to the stage of fibrosis and the presence or absence of cirrhosis. So I guess in your experience Joe, biopsies are left for cases where it is more complicated or you have not got a clear picture after this.
Marie: But this would give a pretty good indication in most cases.
Joe: Absolutely and we should stress that liver biopsy is definitely not required to treat hepatitis C and it has not been a requirement for more than 10 years.
Marie: Yes. Yes, so obviously taking a history, doing an examination, the non-invasive tests and the laboratory investigations are all part of that comprehensive assessment of fibrosis. We have covered that in previous webinars, but it is just good to go through it again.
So Joe this is the FibroScan that I have gone ahead and organised?
Joe: Yes. So this is transient elastography which gives us a non-invasive and painless indication of how stiff or hard the liver is and reflects on the level of fibrosis. So he has had a reading of 6.8 which is pretty good, but as you can see it is on the cuff there and it might suggest that he has early fibrosis or even – so there is no indication to refer this gentleman on to specialist care. It is perfectly reasonable to treat him in general practice and he does not need to be screened for those other complications of cirrhosis such as varices.
Marie: Yes, okay. But we have also done the APRI score, so we have used this non-invasive calculation on figures that we have already got there.
Joe: Yes, and this is a really important test to be aware of and it is available online for free and you can have it as an App on a smart phone. Because you do not need to have access to FibroScan in order to treat hepatitis C, but you do need to have some form of assessment. And you can utilise all of those, the history and the biochemical findings and the full blood count to make a decision, with the assistance of a tool like this. And it uses commonly ordered tests like AST and platelet count to give you a value, a ratio index. It can sort of make cirrhosis less likely or more likely. So a score of less than one is what we would see as acceptable and in Ahmed, this is consistent with his FibroScan assessment.
Marie: Okay. So also, we organised an ultrasound.
Joe: Yes. I think this is important in Ahmed’s case, particularly given the family history of liver cancer. But remember with hepatitis C you do need cirrhosis to be at risk of hepatoma. Given that family history, that screening was warranted. But remember you can also utilise the ultrasound findings to help you in your assessment for cirrhosis. So, this report is that the liver and spleen were completely normal. So no imaging evidence of cirrhosis and no imaging evidence of hepatoma.
Marie: Yes. Yes, and you often get a report that says you know, the spleen is not enlarged and there is normal portal flow and other things.
Joe: And they cannot see any varices, yes. All those things.
Marie: Yes. Yes, okay then. Alright, so we have summarised what we know about Ahmed then. So he is a man that had a screening test and was found to you know on the check up, was found to have been in contact with hepatitis C. He has got chronic hepatitis C infection and with no indication after comprehensive assessment of cirrhosis. His comorbidities are hypertension and dyslipidaemia, so that metabolic sort of stuff. Reflux, depression and erectile dysfunction. No co-infection that we have found. He is on several medications. He has had no previous treatment because this is a new diagnosis for this man. Cirrhosis screening is not indicated because he is, on comprehensive assessment he is found to have minimal or early fibrosis.
Joe: That is correct.
Marie: And so he can be treated by the GP. So let us see what we need to consider. So, what are his treatment options? We need to look at what we are going to do, and I think you know, obviously we are going to offer him direct-acting anti-virals so we need to consider his medications and other things. And other factors to consider are treatment history and adherence. So, is he interested in treatment and…
Joe: So yes, we have got a gentleman with no cirrhosis with genotype 4 infection and we will go back to the table that is available through the GESA website and this is all reproduced on a wall chart which provides a quick and easy access summary. So given this gentleman has genotype 4 infection, he could use the two pangenotypic or sorry, in general practice, you can use one of the two pangenotypic regimens available with the sofosbuvir and velpatasvir, or Epclusa. Or the glecaprevir and pibrentasvir, the Maviret. He also qualifies for Zepatier, the elbasvir and grazoprevir. So there are quite a few treatment choices there.
Marie: Yes. Yes and just for that second one, he can have eight weeks of treatment.
Joe: That is right.
Marie: There is no cirrhosis. So that looks pretty good too. Alright, great.
So look he is on a few medications and this tool is to help us to look at drug-drug interactions. So you can enter your medication into the tool. Enter all the other medications that he is on and review the interactions. So, all you have to do really is add the information and they come up with a table of the interact – what is safe.
Joe: Yes, so in this slide we have on the left hand side got all of his co-prescribed medications and then as we move across to the right, there are the three available medications that we could prescribe for this gentleman and we can see that the elbasvir and the grazoprevir, the Zepatier combination gets the green light all the way down his co-medications. And just to point out, that does not necessarily mean that that is the only choice. On the website you can click on those orange squares and the yellow triangles and you will come up with prompts and there are strategies to get around those warnings. So for example with statins, often you can suspend treatment for the period of treatment. For Rabeprazole, often PPIs can be stopped and use non-pharmacological methods to deal with reflux. So yes, the easiest pathway here is to use Zepatier, but you could get around the issues with the other two options as well.
Marie: Yes, sure. Sure. Yes, so you have got options there, definitely. So, look these are the PBS population and treatment criteria in the general statement of drugs for the treatment of hepatitis C. So you can see that patients must be over 18, treated by a doctor experienced – you can treat and gain experience along the way as we have discussed in previous webinars. There is the information you must provide on your application. The genotype of hep C and their cirrhotic status. And in this case he is non-cirrhotic and you must document in your medical records evidence of chronic hepatitis C infection which we have, and evidence of genotype. So it is pretty straight forward and if you are gaining your experience there are special forms that you can use to submit to the specialist. It gives you a bit of a summary that you can keep in your file of your assessment and management plan for this patient, but you can also develop a good relationship with a hepatologist such as I might have with Joe so that I could contact him by phone, describe the case and I could be supervised by him too. So you can work up a relationship, a working relationship with a specialist too to gain your experience. So there is a couple of ways of doing it, but that is sort of a systematic way that people you know, can certainly use.
Joe: Yes, so he has been treated with 12 weeks of elbasvir and grazoprevir and in terms of monitoring, in September GESA revised their recommendations for on-treatment monitoring and they basically removed any requirement for on-treatment monitoring for non-cirrhotic patients being treated with DAAs.
Marie: Yes, because they used to say LFTs halfway between or something like four weeks after or something.
Joe: Yes, four and then nothing till the end. And then four weeks after. But now it has been really simplified. So now we only have to treat, to test people 12 weeks after the treatment completion. Okay? And that is really to assess cure. There is a caveat to all of that, that if you are concerned about compliance and things like that you can do liver function tests and monitor viral loads on treatment to check on compliance. But if the treatment is fairly straightforward, there is no mandated monitoring on-treatment. Because these medications come with so few side effects and they are effective.
Marie: So basically you are in treating this man, you are working him up, assessing him and you are really involved in that hepatitis C care and monitoring and treatment for six months. Because he will be treated for three months, and then after another three months, you will check for –
Joe: Check for a cure, yes.
Marie: Check for sustained viral response which is cure and his LFTs again.
Marie: Alright then, good. So, does he require ongoing liver cancer screening after he is cured of hepatitis C, Joe?
Joe: So no. Because we did our pre-treatment assessment and found him to have no evidence of cirrhosis. So because, as he does not have advanced fibrosis or cirrhosis, he does not need to be monitored for liver cancer onwards, nor be assessed for complications of cirrhosis.
Marie: So even though he has got that family history, we are maybe presuming that his father had cirrhosis and hepatitis C? Yes. Yes. Okay, then. Alright. So we might go onto the next case.
Now here is Joe. Now Joe was diagnosed with hepatitis C three years ago via preoperative screening. He is a 63-year-old Italian builder, emigrated to Australia aged 25. Married with three children, four grandchildren. And a couple of years ago, he was diagnosed when he was screened before coronary stenting. So, he was found to have hepatitis C antibody positive and mildly abnormal liver function tests which have been slowly declining over the years. There is no obvious risk factors for hepatitis C and he has had no previous hepatitis C treatment. So we have got a man who was diagnosed about three years ago just through pre-operative screening. So. Now here is his past history, so looking more at Joe in detail. Hypertension. He has got diabetes, ischemic heart disease. He had coronary stents as we know. He was worked up for those, dyslipidaemia, reflux, depression, chronic back pain from prolapsed discs, osteoarthritis, and osteoporosis. Look we see a lot of chronic disease in general practice. This should not scare us. We have got a lot of people on a lot of medications and with a lot of comorbidities. You can see his medications there, it is on that sort of metabolic pathway he has here with all of those medications. He does drink 200 – 240 grams of wine weekly and he smokes 10 cigarettes a day. So he has got significant comorbidities and a high medication burden and has the added risk of regular alcohol intake.
So, what are we going to do with Joe? Well. We will have a look at him, examine him and see what we think. His blood pressure there is a bit elevated as is his body mass index. It is in the obese range with central adiposity. So it does make the abdominal exam difficult but you cannot detect hepatosplenomegaly. There are no signs that you can detect of chronic liver disease and no signs of heart failure. So I guess that is a little bit reassuring.
Joe: So what would you do now? What other tests would you like?
Marie: Okay, well look. Again, I would like to know what the state of his liver and infection is and I would like to know what his renal function, blood count and his diabetes control and all of those things are. So I would like to know where his liver is at and where his general health is at. You know? So, here we have the results. And let us break this slide down. On the right we have got his serology results. And this does confirm chronic hepatitis C infection. Good, he is HIV negative and he has past resolved hepatitis A and B. So he does not need vaccinations and he does not have HIV as far as we know. He has got a negative test. But he does have a chronic hepatitis C. We have got genotype 3a.
Now on the left are his biomarkers that do indicate a few issues. So his diabetes control is not too bad. His cholesterol is not ideal. The alpha-fetoproteins are normal. But Joe could you comment on his blood count and biochemistry there?
Joe: Yes, look on the full blood count I think the thing that stands out is that low platelet count. So we should really be seeing that to be comfortable that there is no cirrhosis greater than 150. His platelet count is coming in there at 129. So that could represent portal hypertension, splenomegaly and sequestration of the platelets, consumption of the platelets in the spleen. So, look his creatinine is okay and certainly his eGR is acceptable. But looking at the liver function test, his albumin is borderline at 36. So it is a little on the lower side but still normal and you can see that he has got a significant hepatitis. And that AST to ALT ratio is, you know it is not the 2:1 that we see with alcoholic liver disease and cirrhosis, but they are significantly elevated. I guess of concern too in this setting is the elevated GGT and that does make you think hard about alcoholic liver disease as well as fatty liver disease and he is definitely at risk of both of those.
Marie: Isn’t he, yes.
Joe: And on the basis of his history.
Marie: Yes, definitely. He has got the obese abdomen. He has got the diabetes. He has got the metabolic stuff and yes.
Joe: 240 grams of alcohol, yes, a week.
Marie: And then the hepatitis C. Whacko, hey. Yes, yes. So the factors contributing to his abnormal LFTs.
Joe: That is what we discussed, yes. I think we have confirmed that he does indeed have chronic hepatitis C and we are also asking questions about whether he has non-alcoholic fatty liver disease, as well as alcoholic fatty liver disease. So, yes I mean there has been some suggestion of cirrhosis on the basis of the blood tests that we have seen so. So I think we need to kind of look into that as well.
Marie: Ok, so we should go ahead and think about how we are going to assess his liver. Okay, so again well it is back to basics. It is really a good physical examination. We have taken a history, we know what the risk factors are. We are looking for ascites, peripheral oedema, muscle wasting, spider naevi, palmer erythema, jaundice and hepatic encephalopathy. I hope it is not that. It is quite late. But you know, other things, you know, we have been through that as medical students too and you know you can feel the parotids and does he have gynaecomastia, other things like that. So the AST/ALT ratio greater than 2 is suggesting…
Joe: It can suggest alcoholic hepatitis or cirrhosis. Yes. Certainly something I would think about.
Marie: We mentioned the lower platelet count.
Marie: So, and then large spleen due to portal hypertension. Now, an APRI.
Joe: Yes, so moving onto those non-invasive assessments to help build that picture of cirrhosis, whether that is present or not.
Marie: Yes, so you are looking, does he have an APRI greater than 2, FibroScan greater than 9.5 and on an ultrasound.
Joe: Yes and also I think being clear about the cut offs here and the recommendations. So the APRI of greater than or equal to 1 is when we start to think about cirrhosis. Less than 1 I would be very happy that it is not present. The higher we make that number, the more likely cirrhosis is. But what we are looking for in general practice is an APRI of less than 1 to feel safe that there is no cirrhosis. And in the FibroScan we are really using that cut off of 12 and a half for cirrhosis.
Joe: And ultimately the question we are asking in general practice is, is cirrhosis present or absent?
Joe: And the ultrasound as we said can help with finding splenomegaly, dilated portal vein and you know, nodular liver surface and things like that in a picture of cirrhosis.
Marie: Okay. Well, bearing those things in mind, let us have a look at his APRI score.
Joe: Yes, so look the APRI score again given the information we have got is not a surprise. And this comes in at well over 2. So that is a pretty clear indication, or very suggestive of cirrhosis. So, you know in a meta-analysis of 40 studies, investigators showed that an APRI of greater than 1 had a sensitivity of 76% and a specificity of 72%. And those ratios increased as we go above 2. So, I think we have got enough information there to suggest cirrhosis, but we can utilise other tools.
Marie: But there is more.
Joe: Yes, there is.
Marie: Okay, so we got him a FibroScan, too.
Joe: Yes. So 15.9 kPa. Yes. I think that is a pretty safe bet that this gentleman has cirrhosis and the FibroScan is a really good tool for telling you whether a liver is normal or whether that liver is cirrhotic. So if you are getting readings of much less than 7, or you know, the high 6’s, that is very reassuring, and once you are getting over that 12.5 kPa mark it is very suggestive of cirrhosis.
Marie: Okay, and just to make sure…
Joe: So do that ultrasound and we have got a large liver, so 17 cm span, a bulky spleen. So no clear cut cirrhosis, but there are suggestions there that he might have cirrhosis. But the portal vein was normal, so not dilated and pleasingly there is no liver lesion there, so we have excluded hepatocellular carcinoma.
Marie: Yes. Okay, so we can summarise what we know about Joe the Italian builder who was found to have hepatitis C in his workup for coronary stenting. So, he looks like, we have decided that he has cirrhosis. There is enough evidence to suggest that he has at least got early cirrhosis. So, and he has got other liver co-morbidities, so fatty liver and the alcohol use, and other medical risks. But no co-infection. He is on several medications. He has had no previous hepatitis C treatment but cirrhosis screening and specialist care is definitely indicated. So the treatment options for him, he should be referred to a specialist and that does not mean that I just go, okay great. He has got a lot of other comorbidities and it will be important that I see him regularly too to keep his diabetes under control and other things and assist with you know, adherence and referrals and things, but.
Joe: So yes, we will see what happened to Joe. So he was referred to specialist care given the finding of cirrhosis for ongoing management based on that assessment by the GP. He was diagnosed with compensated cirrhosis, so Child-Pugh A. So it is your standard early cirrhosis. And HCC screening obtained prior to treatment showed that there was no evidence of hepatocellular carcinoma. That is a really important thing.
Marie: That was the alpha fetoprotein and the ultrasound.
Joe: That is right. So he was treated with 12 weeks of Maviret which is the glecaprevir and pibrentasvir. There is a bit of a typo there, sorry. And he had the 12 week course, so just a reminder we discussed in the previous case that the gentleman was eligible for an eight week course given his absence of cirrhosis but definitely in the setting of cirrhosis, 12 weeks of Maviret is indicated. He underwent a gastroscopy and this demonstrated grade 1 oesophageal varices which did not require any banding. So he has been scheduled for a surveillance gastroscopy at 12 months to see if there is any progression there. He had his statin treatments suspended while he was on the Maviret and this statin was re-commenced upon HCV treatment completion, given that concern about the drug-drug interactions that we can see with statins and Maviret. He had no issues on treatment, sailed through and was cured.
Marie: Isn’t that amazing.
Joe: And it was confirmed 12 weeks following treatment completion.
Marie: Yes that is great, isn’t it, that you know you can get that. So, now my role in sharing the care with you, Joe. So he has had sustained viral response, a cure, but I would be coordinating his six monthly specialist reviews, so his screening with the ultrasound and the AFP. I facilitate the repeat gastroscopies. He would obviously need assistance to stop drinking.
Joe: That is a really important one. Because we can get rid of the hep C but there are other liver diseases that could lead to cirrhosis progressing and developing decompensated cirrhosis.
Marie: Yes. So diet, activity, all of those things. We are going to see if we can get rid of some of that abdominal obesity and his diabetes control. Aiming for a weight loss of at least 10% and then improving you know, all his other medical risks would be really important. So this is a bit of a specialist slide.
Joe: And this is one of the critical points of that pre-treatment assessment because it does dictate how we manage these people after SVR. So patients with advanced fibrosis, without sorry, without advanced fibrosis, you follow up them the same as if they were never infected with hepatitis C.
Marie: Yes, because you have cured the infection. They do not have fibrosis so yes, unless there is a risk you just treat them as yes, anybody else.
Joe: So it is a durable cure. But in patients with cirrhosis, you cannot forget about them because they need ongoing surveillance for liver cancer. But liver cancer risk has dropped, but it has not gone down to zero. And so that six monthly abdominal ultrasound serum AFP is really important. And then the endoscopic screening and surveillance for oesophageal and gastric varices in patients with cirrhosis is really important and should be facilitated through specialist care. And I think the other thing to remember about follow up is that you know, hep C eradication is durable, but people can be re-infected and if there are risks for reinfection, we should be assessing our patients with at least annual HCV RNAs to assess for re-infection. And we also need to look at other liver diseases in patients with persistently abnormal liver function tests after achieving SVR. So yes, you cannot quite hang your hat if you eradicate the hep C and the LFTs are still abnormal.
Marie: Yes, exactly.
Joe: Look for other comorbidities.
Marie: Okay, right. Okay, yes, there it is.
Joe: So, the recommendations for HCC surveillance after cure, you know, we did not make these up. So patients, the international guidelines suggest that patients with advanced fibrosis, so F3 or F4 fibrosis, as per the American Infectious Diseases Guidelines, that patients need to have six monthly ultrasounds and serum AFP. With those that have you know, unclear cirrhotic status with comorbidities like diabetes, alcohol abuse and fatty liver, any patients of older age, you can think about enrolling them in this program as well.
Marie: Right, yes. Yes okay fair enough. Okay, so I look that is clear. He was a cirrhotic man, you know so you are sharing care there with a specialist.
Now we will go on to our third case, who is Tu. Now, this lady is 32 years old, of Vietnamese background and she was discharged from hospital seven weeks ago where she was admitted for septicaemia associated with injecting heroin. She was commenced on methadone during the admission and is now dosing at a public clinic and admits that she has injected on two occasions since discharge. Now she was diagnosed with hepatitis C while in jail several years ago and had 48 weeks of pegylated Interferon and ribavirin for genotype 6. And she achieved a cure after that treatment. She has a history of schizophrenia and has had several psychiatric admissions. The most recent one was for psychosis five months ago when she was commenced on paliperidone depot. She has been homeless and living in shelters when she can. While she was an inpatient with sepsis, she was diagnosed with hepatitis C re-infection. It sounds very complicated. There are several challenging issues that already stand out. She is still injecting drugs and has a recurrence of hepatitis C. She has had past treatment for hepatitis C but not with direct-acting anti-virals, so I will keep that in the back of my mind. There are social housing and mental health issues and she is 32 and of child-bearing age. I can see a GP management plan coming on. So, there is a lot to think about there. So let us continue on with this story.
Now, she has a case worker. That is useful. That might be a drug and alcohol or mental health case worker. She feels that she is stable and should be considered has brought you in because she thinks that Tu should be considered for hepatitis C treatment. The schizophrenia is currently well controlled. She is attending the methadone clinic daily and has only missed one day over the past month. She has just found accommodation in a shared house near the methadone unit and she has made re-contact with parents and her younger sister and she wants to have the new treatment as her friend was cured from hepatitis C and the new tablet. So, Joe should she be considered for treatment? There is a lot to think about.
Joe: There is a lot to think about, but she is addressing a lot of those issues that would make us concerned and absolutely I think she should be considered for treatment.
Marie: She certainly sounds motivated to do it and it looks like she has got some support there, so… now she still admits to having injected a couple of times since she was started on methadone. Is that a barrier to treatment?
Joe: No, absolutely not. I think, thinking about the injecting drug use as a relative contraindication, it is certainly not an absolute contraindication. Sometimes, people that are still actively injecting can have very chaotic lifestyles and you would be concerned about compliance issues, but otherwise, it is not a contraindication.
Marie: No. So we should be offering treatment to all people with chronic hepatitis C. We need to reduce its incidence in the community, and her comorbidities are actually not so uncommon. We see people with combined mental health and drug abuse issues and social risks and things like that can come along with those. The risk of re-infection and of missing doses are important to consider, but you can enlist the help of case workers and other supports. So, it is important that safe injecting education is given, that there is that drug and alcohol support, and making sure that there is good adherence to ensure the best treatment success in somebody like this. So, we know that her mental health stability has improved. We know that she is getting the regular methadone dosing. She has only missed it once in the last month and she is getting her depot injections. There is you know, consider if she is attending for the methadone, that she could have the treatment dispensed with that. So there is all those sorts of things to consider. So, no she should not be denied treatment. Okay.
Joe: And there is good evidence behind that as well. So you know, active injecting drug use is not a contraindication. Because evidence has shown from studies on the needle and syringe programs in Australia, that you know hepatitis C antibody prevalence is declining and in the last 12 months, hep C treatment uptake has increased from 1%-3% up to 2015 and increased to 22% in 2016. And again, to 36% in 2017. And treating this population is really critical to our national goals of eradicating hepatitis C in Australia. And sort of reducing the viremia in this community and transmission. So, studies, or meta-analysis of 38 studies including over 3,500 participants treated for hepatitis C with direct acting anti-virals with a history of recent injecting, or non-injecting drug use, or on opioid substitution treatment, demonstrated compliance or successful completion rates exceeding 97% which is impressive, and overall SVR cure rates of around 90%. So very, very close to what we would expect. You know a value of about 95% in a non-injecting OST…
Marie: Yes, so we are saying there is level 1 evidence that there is no reason not to treat.
Joe: Absolutely not.
Marie: Excellent. Okay. So, we need to assess her to prior to treatment. So what sort of assessment?
Joe: Yes, what does she need?
Marie: Yes, alright. Well, you know I think we go back to what we know, you know, about we need to work out what her viral load is, we need to work out what…
Joe: The co-infection status is, she has got risk factors for other blood borne viruses so you know, this is something we have really got to be clear about that.
Marie: I would love to know that she is not pregnant. But, what are her liver function tests. So all of those things. So it is your serology, again we have got the stuff on the right there, the serology and on the left we have got what those biomedical sort of biochemical parameters and things that we need to look at. So, what have we got here? So, we examine her. She has good blood pressure and a good BMI. Her blood count and platelet count and everything look good don’t they. She has got good renal function. Now her liver function tests are a bit out, aren’t they there?
Joe: Yes, the ALT is up a bit. The AST and GGT slightly. But otherwise we are looking okay.
Marie: The AFP is normal. Okay, so hepatitis B core antibody positive. So she has had previous hepatitis B.
Joe: And cleared.
Marie: And cleared it. And she is surface antibody positive, too. Yes, and she is antigen negative so that is good. HIV serology is negative and she has had past hepatitis A and she is immune. And she is not pregnant. Okay, so the case worker has provided us with the hep C RNA and the genotype which is 3A.
Joe: From the hospital admission.
Marie: Okay, excellent. Okay, so we have got all of that information, so now look, we know she has got abnormal liver function tests and we know that she has got hepatitis C again, so we need to work out the status of her liver.
Joe: That is right.
Marie: So here we go.
Joe: So we have got access to FibroScan. Absolutely. And we have got a reading of 6.2 kPa. So very reassuring.
Marie: In the green zone.
Joe: Yes, in the green zone. That she has no or very, very early fibrosis. So definitely no cirrhosis. So happy with that result.
Marie: Yes, yes, good. And we know we are going to use our calculator for the APRI.
Joe: Yes, so we have got a score there of 0.526.
Marie: Less than 1.
Joe: Less than 1. So very reassuring that there is no cirrhosis.
Marie: Okay, so we have examined her. We have checked the bloods and we have done the fibrosis assessment, so what we now know about Tu. Okay, so she was reinfected in 2017 during that septicaemia, you know, they found out when she had septicaemia that she had a reinfection. She has got type 3 A. She has got early or minimal fibrosis. There is no liver comorbidity that we know of, no coinfection. She has got the other comorbidities though of schizophrenia and some ongoing intravenous drug use. The medications are paliperidone and methadone, and she has had previous non-direct acting anti-viral treatment and she does not need cirrhosis screening. So the negative pregnancy test is just reassuring. But I note she is not on contraception, so we might have a look at that later.
Joe: And look I just want to raise, a question has come through asking if the APRI is normal, do we need to go on and do a FibroScan? And it is a good point. You definitely do not need a FibroScan. We just wanted to use the FibroScan and APRI to reinforce the message about fibrosis assessment. So we understand that FibroScan is difficult to obtain in some areas and you can combine with your history and examination, your assessment with imaging and the APRI, that is sufficient to determine whether someone maybe has cirrhosis. So yes, utilise the tools that you have available but you do not have to have a FibroScan.
Marie: Okay, thank you.
Sammi: Regards to FibroScans Joe, there was a question that had come through earlier asking if GPs can request FibroScans?
Joe: Absolutely. We are seeing them in many different states so you can have liver clinics offering that service. There is a stand alone FibroScan clinic. And many imaging centres around the state now are offering FibroScan as part of their assessments as well.
Marie: Yes, I know at RPA they do them for people who are being worked up for hepatitis C and GPs can refer. They are just part of the assessment.
Joe: And in the community in radiology places you know, you will often find unsolicited FibroScans as well.
Marie: Yes. Yes, okay. So, here we have this.
Joe: So just, we wanted to go through two prior infection results because a few genotypes have bounced around this history and we did confirm that she had a genotype 6 infection in 2001 and cleared that with a 48 week slog of pegylated Interferon and ribavirin, and she was definitely cleared of that infection with blood tests at six months which is how you assessed cure at that time.
Joe: Given that she has been diagnosed with hepatitis C in 2017, it is very suspicious that it is a reinfection with another genotype, rather than recurrence or failed treatment, because we are looking at those two different genotypes. So just interpret those results as this is a new de novo infection.
Marie: Yes, we are just starting again, aren’t we?
Joe: Yes, that is right.
Marie: Yes, yes. Okay so we are going to consider her treatment options.
Joe: Yes. So we again we turn to the GESA consensus statement wall chart. She has got, she is eligible for those pangenotypic.
Marie: Now she is type 3a, so she is the first two.
Joe: Yes, so we have got the Epclusa and the Maviret that are available there. Given that she is non-cirrhotic, we could use the eight-week regimen of the Maviret or the 12-week version of Epclusa. She does not qualify for the elbasvir and the grazoprevir or the Harvoni given her genotype.
Marie: Well, if I was looking at that, I guess you know, I know I would have to look at the drug-drug interactions and I would be looking at that, but I would be thinking, gee you know it would be great if I could get her through the eight weeks. Fewer adherence problems, so yes how do we encourage it? You have got to think about this.
Joe: And particularly in this setting, in this patient.
Marie: So yes, yes, we will look at some of the things. So okay, so it looks like she is motivated. She wants to try this treatment, so luckily the medication is tolerable and she looks like she is getting some social support. The schizophrenia appears to be, we are told is under good control. She has got a case worker there. So she is getting those supports. We want a regime that is not too complex and these are just a daily dose. You know, so that is really good. That could be done with the methadone if we could work out something like that.
Joe: So the Epclusa is one pill a day, so it is a fixed dose combination pill and the Maviret is three pills at the same time.
Marie: Daily. Yes, yes. Continuity and the systems of care and access to care and frequency of follow up office visits and blood tests. Well that is really good now. The new guidelines.
Joe: The monitoring is much more straight forward.
Marie: Yes. Okay, so.
Joe: Just wondering if we can ask one of the questions that have come through. And it is a really good point. They are asking about her treatment experience, with the pegylated Interferon and ribavirin. So given that she is not DAA experience, so she has not been treated with the new medication, so we are not thinking about DAA resistance in this setting, it is appropriate to proceed with treatment in general practice.
Marie: Yes, yes.
Joe: So it is DAA experienced patients that we need to worry about. We did not have anything to treat them with in Australia until the 1st April, so just a few days ago when Vosevi was put on the PBS which will not be able to be used in general practice because it for, purely for a population that is at risk of DAA resistance.
Marie: Oh, right, okay. Yes, yes. So we can treat her in general practice because she is still DAA treatment free. Yes, yes. Yes, yes. So here are some other ways that we can look at, these are adherence strategies that we can use. Social and peer supports. And she has got family back in her life now, so that is great. Establishment of a routine. Or remember she is having the methadone program, if we can link her in with that. Directly observe therapy. Again, you know at the methadone clinic or the pharmacy. Good communication with the treating doctor, discussion of adherence. Barriers and potential solutions. Look if somebody is motivated, that is a great start, isn’t it, talking about those things and we are obviously aiming for 100% adherence if we can get it, and you know, certainly her history does not tell us that we should not aim for that anyway, I think. She has got support and she has been attending the methadone clinic, so I would be hopeful that we would make a good fist of that. There are some great references at the Department of Veteran’s Affairs and on the hepatitis websites that you can look at in the end to look at those adherence strategies.
So, treatment planning for Tu. We would need to counsel her that as far as we know, 100% adherence is going to give her the best chance of a cure. And she wants a cure. She is excited about the prospect, it sounds like. We enlist the support of the mental health worker. Now we would have to address contraceptive practices and whether that would be by injecting long-acting contraception or a pill, that would be a discussion that we would need to consider also with her direct-acting anti-viral and might influence our treatment choice, yes. And looking at combining it with daily methadone.
Joe: And yes, that combination of the daily dosing with methadone is a really great way to facilitate compliance. And takes a lot of the stress of managing the medications from patients that have so many things on their plates.
Marie: So look, we should look at the drug and drug interaction.
Joe: The drug-drug interaction. So let us pull out the Liverpool website. So we have punched in her current medications, the methadone and paliperidone and her two treatment choices, the Maviret and the Epclusa. Now you can see there is a little warning sign there of potential interaction with paliperidone and that is certainly not a medication that we would want to mess around with, given that it serves so well in stabilising her mental health problems. And then also thinking about her contraceptive options. She would not be able to be treated with an oral contraceptive with Maviret. So, yes, I think sofosbuvir and velpatasvir would be a treatment choice.
So we have chosen Epclusa and what sort of monitoring would we require for Tu?
Marie: Alright, well we know that we do not have to check her liver function tests during the course of treatment, but it will be important to support and keep a clinical eye on her and check on symptoms, adherence to medication, asking about injecting and sexual activity. So that in terms of the actual hepatitis C monitoring, we can wait three months or 12 months after – or three months or 12 weeks after she has finished treatment and we just check her liver function tests and we check for a sustained viral response. So we check the hepatitis C PCR.
Joe: Yes. So at that three months post-treatment completion follow up, these are her findings. So Tu had reported that she had minimal side effects on treatment. She had a bit of fatigue and headache at the initiation of treatment and those symptoms wore off with time. And that is what we see commonly. You know, rarely do we see side effects, but this is a similar story to what you might expect to encounter.
Marie: Yes, so she injected amphetamine and missed one dose. So does this have an impact on treatment success? What you are seeing here?
Joe: Look, missing one day is not going to be a huge deal. And there has been a question that has come through online about missed doses and obviously we try and maximise compliance wherever we can and stress 100% compliance, but we do not need to be too concerned about dropping off a few days here and there. I just instruct patients never to double dose, and this is to continue until completion. So if they are finishing a day later or a couple of days later, that is what you would recommend.
The injection of amphetamine, I think with this injecting behaviour, we are using this opportunity to discuss injecting practises and make sure we are reducing her risk of re-infection. But you know, that is no other concern there.
Joe: So in terms of people who inject drugs or are on opioid substitution programs compared to those that are not, we know from the evidence that treatment adherence rates are similar. We know that SVR are similar and we also know through good data that reinfection rates are low. So you know, I just do not want people to be too concerned or frightened about addressing treatment in this population.
Marie: Yes, yes.
Joe: It is that duration of infection that drives transmission amongst people who inject drugs and you know, we know that those people with chronic hepatitis C are infectious until that virus has gone from their blood. So to reduce viral transmission we want to reduce the number of contacts and reduce the probability of transmission of that contact. Recommending the use of safe injecting equipment and regular testing within the drug using networks. And we want to reduce the duration that our patient is infectious to others, and this is the only way that we are going to be able to eliminate hepatitis C.
Marie: So getting more GPs out there testing.
Joe: Absolutely, that is critical.
Marie: And then treating. Yes.
Joe: That is critical.
Marie: Yes, yes. So, in summary we are encouraging GPs to test all patients with risk factors. Test for the hepatitis C virus to confirm current infection and then follow through with your gnome type and your baseline tests, including testing for other comorbidities, and co-infections. You can treat people with chronic hepatitis C but refer those with cirrhosis, renal failure or co-infection with hepatitis B or HIV to a specialist. There is a great tool for evaluating, for direct drug interactions, so that will help you select an appropriate treatment regime and it is important to assess adherence and to encourage adherence right through the treatment. Get approval from a specialist to prescribe for at least 10 times or until you are really confident and experienced in hepatitis C treatment and check they have treatment for 8 to 12 weeks depending, and then 12 weeks after that you check for hepatitis C RNA and then liver function tests. So you are checking for, has their liver improved, depending on their comorbidities, has it gone back to normal and have they got a sustained viral response or a cure. Tailor the follow up according to the treatment outcome, the liver disease stage and reinfection risk. So patients with cirrhosis need ongoing, lifetime surveillance for liver cancer and re-treatment should be offered to people who become reinfected.
In summary, treatment for most patients is straightforward. It is becoming more straightforward all the time. Refer to the Australian Guidelines for the Management of Hepatitis C Virus Infection: a consensus statement 2018 for current treatment regimens. It is an easy read and it is very clear. There is a handy two page treatment checklist on the GESA website, on the GESA site and on your table. If in doubt consult with your local specialist and consider further training. Enjoy the miracle of curing hepatitis C in your practice.
So, we hope that the learning outcomes have been met, so to order and interpret tests necessary to diagnose hepatitis C and prepare patients for treatment. To recognise the risks, signs and symptoms of liver disease and other comorbidities that require management or referral to specialist care and to choose appropriate hepatitis C anti-viral therapies according to virus genotype and the potential for drug-drug interactions.
I will go back to that so we can think about it. So that is the end of the webinar. I hope it is all clear.
Sammi: That is great. Thank you Joe and Marie very much. We are up to time. There is just one question that we got very early on in the Ahmed case that I just wanted to flag. Someone has asked with self-imported DAAs for Medicare eligible patients, are these medicines okay?
Joe: Look, it is a difficult question you ask, because you do not know and I do not think it is really relevant in Australia because access is open. All you need is a diagnosis for hep and you qualify for PBS listed medications. So I would just encourage people to use PBS prescribed medications.
Sammi: Perfect. Well that does bring us to the end of the session, so thank you again to Joe and Marie and for everybody who has joined us on line, we hope you enjoyed the session and we hope you enjoy the rest of your evening.