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7 May 2018
Short, simple and well tolerated cures are now available for most patients with chronic hepatitis C. This webinar, the second and final instalment in the Seek to Treat series guides you through the new hepatitis C treatments, how to treat chronic hepatitis C in the GP setting and discusses how to follow up to ensure tolerability and efficacy of the prescribed treatment.
Dr Marie Healy
Dr Joseph Lawler
Sammi: Welcome to this evening’s twilight online Seek to Treat: Simplifying HCV Treatment in General Practice webinar. My name is Samantha and I am your host for this evening. Before we make a start, I would like to make a quick Acknowledgement of Country. We recognise the traditional custodians of the land and sea on which we live and work.
Before we get started, I would like to introduce our presenters for this evening. We are joined by Dr Joseph Lawler and Dr Marie Healy. Joseph 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 in Mount Sinai Hospital in 2014. He is now a Consultant Gastroenterologist and Hepatologist in Central Sydney and Western New South Wales LHD. 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 for 15 years. I will hand over to Marie now to take us through the learning outcomes for this evening.
Marie: Welcome everybody. We are hoping at the end of this activity that you will be able to discuss the new hepatitis C treatments, their high cure rate and their high tolerability, explain how to treat chronic hepatitis C in the GP setting with specialist support if required, and undertake follow up to ensure the tolerability and the efficacy of the prescribed treatment.
Joseph: And so this slide illustrates the history of hepatitis C treatment in Australia and summarises the annual number of individuals with chronic hepatitis C initiating hepatitis C treatment over the last 20 years. And you can see as we move from left to right, we move from through the different eras of treatment from standard interferon in the late 90’s through to interferon with ribavirin, pegylated interferon in the early 2000’s and into the red bars where we see the use of interferon-free or direct acting antiviral medications. So in total, over 61,000 Australians or 26% of Australians living with hepatitis C have been treated with DAAs. And prior to treatment, prior to 2015 when these medications were listed and available on a trial basis, the rate of interferon based therapy was averaging about 1% to 2% of all patients being treated. So this is a significant change. So the challenge now is to maintain these really high treatment rates that we see to the right of the graph since 2016 and achieve hepatitis C elimination in Australia by 2030. But really I want to stress that you as GPs have a really important role in addressing this challenge in hep C elimination. It should be noted that there are no liver disease stage restrictions for prescription of hepatitis C medications in Australia. And looking at the New South Wales data, in New South Wales from March 2016 when the new treatments were listed, through to September 2017, 20,000 people, nearly a quarter of the people living in New South Wales with hepatitis C have access to these treatments.
Marie: That is fantastic, Joe. So look, we will go on to why we should treat hepatitis C. Look, there are really two broad benefits for treating this chronic infection, decreased transmission and improved clinical outcomes for the individual. So we are sort of looking at the public health and the individual benefits of treatment. So for the individual, curing hepatitis C and that is what we mostly aim to do with these treatments, will reduce progression of the liver disease and increase liver-related and overall survival. For those with cirrhosis there are other benefits, including reducing the risk of complications such as clinical decompensation and variceal bleeding, liver cancer and the need for liver transplants. So all of those would really be a strain on the health system. Not all patients with cirrhosis will achieve all clinical outcomes or improvement, in particular those with decompensated cirrhosis so you have got an argument there to treat patients with mild liver disease before they develop cirrhosis. So that is about really an early intervention in chronic hepatitis C, you know, picking up cases and treating.
There is emerging evidence that curing hepatitis C can improve patient reported outcomes, such as quality of life, neurocognitive functions, fatigue and work productivity. Extra herpetic manifestations such as cryoglobulinemia, insulin resistance and cardiovascular disease also have potential for improvement with treatment. And treatment is easy these days. So the role out of direct acting antivirals has made treatment so much easier and well tolerated. Compared to the old interferon based therapies they have the following benefits: Easy administration because they are in oral form, much better tolerability with significantly fewer side effects, a shorter course of treatment 12 weeks in most cases is it not, Joe?
Joseph: Yes, that is right.
Marie: And less monitoring while on treatment and of course, higher rates of sustained virological response. That is cure at 12 weeks. Also, we now have great guidelines to follow such as the Australian Recommendations for the Management of Hepatitis C. The consensus statement you can see there. This all results really in an increasing number of candidates suitable for treatment and it means GPs have a greater role to play in curing hepatitis C.
So the next slide illustrates the increasing prescribing of these medications by GPs over 2016. So you can see that the proportion of individuals commenced on direct acting antivirals by GPs increased from 8% in March to 31% in December 2016. In New South Wales the increase was actually 54%. And this is great. And it is increasing because GPs are finding that treating hepatitis C is straightforward with high patient tolerability. The latest percentage of hepatitis C treatment initiations by GPs in New South Wales was as I said 54%. And that was in three months from July to September 2017. So that is great.
Look there are times to consult with or refer patients to a specialist, but really there are sort of four basic groups I guess in a nutshell; those people with cirrhosis, those with renal impairment, those with co-infection with hepatitis B or HIV or those with a past treatment of hepatitis C. And we are talking about people who have had direct acting antivirals –
Joseph: That is right.
Marie: And have failed treatment. So really, they are the people who you would broadly consider referring to a specialist. So you know, they are the four groups that I want you to bear in mind.
So look, we might go onto the PBS requirements. They are pretty simple, actually. We are dealing with adults, so the patient must be aged 18 or over. The treatment criteria is that it is done by an experienced doctor and we will talk about that a little bit later. The information provided for the application must be the patient’s hep. C genotype and their cirrhotic status and the medical records must document evidence of chronic hepatitis C and evidence of the hepatitis C virus genotype.
So, we will just go onto the PBS criteria. Experienced means that to start prescribing, GPs should have completed a formal education session such as this, and before prescribing independently, it is recommended that GPs consult with a specialist for at least 10 completed treatments through to cure. Look, this is a guideline, a recommendation. Some people might be extremely competent and start prescribing a little bit earlier than that, but that is the general guideline that is recommended people follow.
So Joe, we might go on to who should actually be considered for treatment.
Joe: Yes, look in Australia, all people that are living with chronic hepatitis C should be considered for treatment. The only exception would be those that have a limited life expectancy of less than 12 months due to non-liver and non-hepatitis C related comorbidities, such as a disseminated malignancy for example. And again, reminding you that there are no liver disease stage restrictions on PBS in terms of cirrhotic status.
Marie: Somebody with quite advanced cirrhosis should still be considered.
Joe: That is right, and remember that that is going to be considered in a specialist setting and most of the patients we are talking about here in Australia with hepatitis C do not fall into that. So most of the community do not have cirrhosis and can be treated in the context of general practice.
Marie: Now there was a question, should you wait six months for every patient to be diagnosed and treated, given that we are supposed to be treating with chronic hepatitis C?
Joe: Look, that is part of the PBS requirements, but I think rather than have just depending on two HCV RNA’s separated over six months to define chronic hepatitis C, you can use your clinical judgement including history, so looking at how long risk factors have been present, so if the risk factors have been present for the infection for 10 years, 20 years, and there has been persistently abnormal liver function tests, I think it is reasonable to diagnose chronic hepatitis C in that sense. But if someone is quite young and they have no evidence of cirrhosis and they have only just recently been at risk of the infection, then that might be a time when you would watch and wait for six months.
Marie: Because, if they have an acute infection, they can get over it, can’t they, yes.
Joe: Up to a quarter to a third of patients can clear the virus spontaneously and that is the rationale.
Marie: Yes, yes. Oh great, well we might go on to discuss the new hepatitis C treatments, their high cure rate and their high tolerability. So, this slide here – now do not be frightened – it shows the brand names for all interferon-free regimes currently listed on the PBS. These are the ones that are on the market, and they can all be used to treat different patients depending on their needs, but generally GPs will be using Epclusa, the one on the left and Joe, just tell me what that is a combination of, because I just cannot quite get my tongue around it.
Joe: So that is a combination of sofosbuvir and velpatasvir. It is two drugs in one pill, so it is a fixed dose combination that covers all genotypes, one through six. So that really simplifies treatment choices in community practice.
Marie: And it is one tablet daily for 12 weeks, so they get 28 and two repeats.
Joe: That is correct.
Marie: And so Joe, the next slide I think you could have a look at.
Joe: Yes, just a look because there is that overwhelming number of treatments available on the PBS and I just wanted to point out that in terms of clinical efficacy they are all pretty equivalent for the type of patients, the non-cirrhotic patients that are being treated in general practice. So the cure rate is greater than 95% with all the DAAs across the genotypes for non-cirrhotic patients. So I think we just keep pointing out the Epclusa regimen because it is an easy one to remember and it is pangenotypic and there are few restrictions in terms of renal failure for example, which we cover later in the talk.
Marie: Okay, great.
Joe: so, in terms of the treatment options, as we were just saying for all hepatitis C genotypes you can use a pangenotypic regimen that is effective across all those genotypes. And at the moment, the drug that is listed that falls into that class is the sofosbuvir and velpatasvir combination which goes under the brand name of Epclusa. But, there are more pangenotypic regimens likely to be listed this year. Okay? And remembering that the DAA cure rates for non-cirrhotic patients exceed 95%.
Marie: I know, it is great, isn’t it? So I guess, ah look we will discuss the potential side effects because they are pretty much minimal and you know, so they say really are tolerated well, aren’t they? So the box on the right there relates to treatment regimens containing ribavirin, so that is really what specialists are going to be dealing with mainly, isn’t it?
Marie: So on the left, the medications the GP can expect to prescribe are listed there and the top one is the one that we are going to be mainly using. Look, they have got high tolerability with the potential for mild and sort of non-specific side-effects and they can be used in all genotypes, but the top one Epclusa is going to be the most likely. So these sorts of symptoms, how often are you seeing those sorts of symptoms – headaches, fatigue, nausea?
Joe: The headache comes up fairly frequently but it can be managed with simple analgesics like paracetamol and anti-inflammatories. The fatigue I have not seen a lot of. Sometimes GI upset is mentioned, but if you encourage patients to take their medications with food you see that less. And nasopharyngitits is something that has been listed as a complication of the Epclusa treatment, but I have not yet seen it in patients.
Marie: And how, what proportion of people would stop treatment?
Joe: Less than 1%.
Marie: Less than 1%.
Joe: Less than 1%. Very different to the interferon era.
Marie: Alright, great. So we might go on to explain how to treat chronic hepatitis C in the GP setting, of course with specialist support if required. So, we have got, we are going to talk about the essential steps. Basically, let us walk through the major steps in treating an adult with chronic hepatitis C. So, firstly determine the genotype. Now, you need this for PBS prescribing, and the viral load, quantitative is requested for genotype 1 because sometimes a shorter course of treatment can apply. Also, you should get baseline blood count and biochemistry. We did mention renal function before, and check other serology to determine comorbidities and assess the need for vaccination. Secondly, assess for cirrhosis and refer if present. Also, refer those with renal impairment, infection or if they have had past treatment with DAAs. Next, select the regimen. Remember there is that pangenotypic regimen. Then check for drug interactions. The list of prohibitive drugs is relatively short and we will go on later to show you how you can access information easily on checking for drug-drug interactions. Then you monitor on treatment, and hooray check for cure at 12 weeks. And then follow up as required.
So the next slide will further explain some of these points. Joe, would you be able to sort of go through?
Joe: So look again, and this goes through the PBS requirements and the essential information that you need to prescribe these medications. So, as we have said before, you will need to identify current chronic hepatitis C infection with the presence of the HCV RNA in the blood, and quantification can be useful in genotype 1 infections. If it is low, it can qualify for half only with truncated duration of eight weeks treatment, and of course genotyping is a PBS requirement. Whilst it does not impact upon your treatment choice with the pangenotypic regimens, it is a PBS criteria. You also want to determine the impact the hepatitis C has had on your patient. And basically, assessing whether your patient has cirrhosis, or whether they do not have cirrhosis. And that has implications for the context in which they are treated and also their care post-cure. So, it can influence the treatment duration and regimen and whether ribavirins are added. And it also identifies people who need to be screened for the complications of cirrhosis, like hepatocellular carcinoma or even hypertension and gastroesophageal varices. Now, it is important to identify whether somebody is treatment naïve, people who have not been treated, or treatment experienced. And if they have had treatment before, sort of work out why they have failed or whether they have been reinfected. And as we have said, if they have failed direct acting antiviral therapy, they need to be assessed and treated within the context of specialist care.
Marie: Somebody had a question about hepatitis B reactivation, and what should GPs know about this in terms of treating people with hepatitis C?
Joe: Look, there has been some evidence of hepatitis B reactivation in patients, mainly that are surface antigen positive. So, when you are screening your patients before treating with the direct acting antivirals, if you identify a surface antigen positive patient, they should be referred through to a specialist clinic. So there are different ways to approach that problem, some people may need treatment of hepatitis B simultaneously, or if they are low risk, just monitored through treatment looking for a hepatitis B flare.
Marie: And say somebody is found not to be immune to hepatitis B, should you delay treatment?
Joe: Not at all, not at all. I think, I mean it is a really important point, if you have identified somebody that is susceptible to the infection and they already have a chronic viral hepatitis, you want to get on and protect them, so do not delay initiating the course of vaccination for hepatitis B, and you can safely vaccinate and treat the hepatitis C.
Marie: Great, okay, so no interaction there.
Marie: Good. Okay, so here we have got a reminder about pre-treatment assessment, really going back to basics. So, take a good history, examine the patient, get them up on the couch and arrange appropriate tests to assess for likelihood of cirrhosis and other comorbidities. So, the history should document risk factors for the progression of liver disease, such as HIV, hepatitis B, diabetes, obesity, fatty liver. Also ask about alcohol use and medications. Take a good medication history because you want to assess for hepatotoxic drugs and potential interactions with the hepatitis C treatment. Past treatment for hepatitis C should also be noted if it has occurred and refer those people. The base line bloods and non-invasive tests to assess fibrosis are really part of this assessment, and include renal function, full blood count, coags and liver function tests. Renal impairment and coinfection should prompt specialist referral as previously mentioned.
There is no real single way to diagnose cirrhosis, and liver biopsy is not frequently performed. So, the next couple of slides should address this issue. An ultrasound is preferred over CT scan if you are going on to other imaging. An ultrasound is preferred as the first line test above CT scan. Say, if the Fibroscan is unavailable or if there is a need to further assess for cirrhosis or liver lesions. If the ultrasound is supportive of cirrhosis, additional confirmation is not really needed. A liver biopsy is sometimes needed, but how often do you find, Joe?
Joe: Pretty rare. It used to be a requirement to access hepatitis C treatment, but not for many years and it is certainly not part of the treatment algorithm now, but sometimes you will have rare patients that it is really difficult to establish whether they have cirrhosis or not.
Marie: So the first four boxes on this slide are the way that you know, is generally the last two are really sort of in special circumstances, aren’t they?
Marie: Alright, then.
Joe: So this slide just illustrates or reinforces the need to establish a diagnosis of cirrhosis in patients before they are being treated, because it has implications for future prognosis. It determines the urgency for treatment to prevent complications and progression of cirrhosis from compensated to decompensated disease. In some cases it can determine the treatment regimen and duration and the addition of ribavirin for example in a specialist setting. And as we said before, the diagnosis of cirrhosis does prompt further investigation of complications of cirrhosis like liver cancer and portal hypertension.
Marie: Yes, sure.
Joe: And just reinforcing that you know, with the diagnosis of cirrhosis, life-long surveillance is required with six monthly abdominal ultrasounds and serum AST for early diagnosis.
Marie: So we will go onto fibrosis assessment and the APRI score. So, the APRI score can assist with assessing the degree of fibrosis, especially if a Fibroscan say is not available. It can assist in excluding the presence of cirrhosis. So an APRI is calculated using the patient’s ALT level and platelet count and the labs upper limit of normal of the AST. So the lower the APRI score, say less than 0.5, the greater the negative predictor value, and therefore the ability to rule out cirrhosis. So a low score –
Joe: Is a reassuring result that can direct you to treat within general practice.
Marie: Okay, so then the higher the score, greater than 1.5 let’s say, the greater the positive predictor and the ability to rule in cirrhosis. Now, mid-range values therefore are less helpful, as they do not accurately differentiate intermediate fibrosis from mild or severe fibrosis. So the APRI alone is likely not sufficiently sensitive to rule out significant disease if it is in that mid-range.
Joe: But we do use that cut off of less than one as a reassuring sign.
Marie: Yes. So somebody asked, if the APRI is less than one, is a Fibroscan still needed?
Joe: Look, it depends. If you have the Fibroscan available, you can utilise that in terms of completing your assessment. You can also use your clinical acumen in terms of history and your estimation of the risk of cirrhosis, so if there has been a long duration of infection, if there has been life-long alcohol use that can increase your index of suspicion. You can also utilise those other modalities that we talked about, such as abdominal imaging, looking for imaging evidence of cirrhosis, or if you are really uncertain proceeding to liver biopsy, and if that is the case, sending on to a specialist clinic.
Marie: Well, you can also have fluctuating levels can’t you of platelet numbers and also you know,
Joe: And also with fluctuation of the liver enzymes, that is correct, yes.
Marie: Yes, so a Fibroscan is a good thing, isn’t it?
Joe: That is right.
Marie: So why don’t we go onto Fibroscan?
Joe: Yes, so a lot of people will now be familiar with what Fibroscan is, the availability has increased around the state. Just for those who are unaware, the Fibroscan is a painless ultrasound test. It just takes a few minutes to perform by the bedside and an ultrasonic wave is transmitted through the liver and reflected back to the probe, and calculations are made on the velocity of that wave and the stiffer the liver, the faster that wave will travel through. The stiffer the liver, the greater degree of fibrosis and cirrhosis. So it is a very useful test when the score is very low and you have a very soft and subtle liver, and the score is less than seven. It is very good when the scores are very high at ruling in cirrhosis, again like the APRI there is that grey zone in the middle that it is not great at differentiating between intermediate and moderate fibrosis, but very good at determining if somebody has a normal liver or a cirrhotic liver.
Marie: So, there is a question here, if the APRI or Fibroscan suggests fibrosis, what is the role of sonography there?
Joe: Well, as we said, if you use sonography as well you can find cirrhotic changes in the liver, so you might find a small nodular liver, you might find a dilated portal vein and other evidence of portal hypertension that can build a case of a diagnosis of cirrhosis.
Marie: So, we will talk about selecting the appropriate treatment regimen. And these are the main considerations for determining that regimen. So, define the HCV infections, so make sure you know the genotype and the viral load. Assess for cirrhosis, renal failure co-infection or past treatment and refer if present. Assess for other comorbidities and assess medication use, noting the risk of drug interactions, and provide the patient with adequate information to make decisions on treatment. So, treatment of hepatitis C can be guided through current PBS listed treatments and management recommendations. So you have got great guides here. You can get information on hepatitis C treatment in Australia from the General Statement for Drugs for the Treatment of Hepatitis C. And this is always up to date, so it lists the patient eligibility conditions and prescribing restrictions and the treatment matrices available for PBS prescription. Another resource is the Australian Recommendations for the Management of Hepatitis C virus infection, a consensus statement. But that can be delayed in terms of the updates. So, Joe, this looks fairly complicated. Would you simplify this slide for us?
Joe: That is right. And again, this slide illustrates all of the treatment options that are available on the PBS that you can prescribe. The top row highlighted in the grey is that sofosbuvir and velpatasvir fixed dose combination called Epclusa. So I just want to stress that that is the go-to drug for treatment in general practice for the non-cirrhotic population without renal failure. But there are a couple of things that might preclude you from using that treatment regimen, and drug-drug interactions is one of those reasons that might not allow you to use that medication in your patients, and also comorbidities and we have mentioned renal failure a few times and we cannot use sofosbuvir based therapies with people with a GFR of less than 30. So again, busy slide but it is just illustrating the breadth of the treatment options but highlighting that sofosbuvir and velpatasvir can be used across genotypes in many patients.
Marie: Okay, so I am going to ring up and get an authority. Oh, I am nearly there, aren’t I? Okay, so I have chosen the appropriate regimen, I think I will go with Epclusa, you know, and I will obtain a PBS authority to prescribe. I will generally require a 12 week course, so 28 and two repeats. And when I ring the number, I will be asked the number of weeks of treatment, so that is 12. Do they meet the general statement? Yes. The genotype? Well, pick one because I am going to use the pangenotypic regimen, and cirrhosis or non-cirrhosis? I am going to treat the person with no cirrhosis. So, that is pretty straight forward isn’t it?
Marie: Okay, so now we have got the patient on treatment. Now they do say that you recommend 100% adherence, yes, so look it is important I guess, adherence is important to ensure the success of the treatment and to reduce development of resistance. You aim for 100%, but occasional missed doses may not affect the treatment outcome. Any idea how many missed doses are important Joe?
Joe: Look, I think we have always got to stress to our patients that you know, 100% compliance is desirable for treatment success and avoidance of viral resistance, but there is evidence coming through with post-marketing data, that several doses can be missed, but we do not want to tell our patients that.
Marie: No, we will keep that to ourselves.
Joe: That is right, we want to make sure we maximise the number of doses and there are many strategies that you can use to optimise that.
Marie: Okay, so some of the strategies are highlight the benefits of the treatment to the patient. Explain why they are being prescribed the medications, what can be done to achieve a cure and what happens if doses are missed. So what does happen if a dose is missed?
Joe: Look, if you remember within 18 hours, you can take the pill that day but never double dose.
Marie: Okay, so if, do you extend the duration of treatment somebody has asked if there have been missed doses?
Joe: No, I think you would just continue the treatment until all pills are taken.
Marie: Okay, yes, alright.
Joe: So that could be beyond your estimated treatment duration, then just keep going until all pills are gone.
Marie: And on the right, there is just a box there to remind us about different ways that you can improve adherence by using dose boxes and reminders and supervised dosing and there is also the NPS MedicineWise App. Look up the NPS and you can find resources for improving medication adherence.
So, drug-drug interactions, Joe. Gee, that looks a bit complicated too.
Joe: Look, it does not need to be complicated.
Marie: Okay, good.
Joe: I think if everyone utilises this website which is listed at the bottom of this slide, it is the Liverpool University UK, www.hep-druginteractions.org. And very simple, easy to use. You punch in the regimen that you would like to use and the medications that the patient has been co-prescribed and you will come up with a traffic light system, so you know, green is go no worries, no interactions. Amber is use with caution and red is incompatible, cannot use or co-prescribe the medications. In terms of the medications that cannot be co-prescribed across the board is carbamazepine and some of the other anticonvulsants. So sometimes you might need to either find an alternative or talk to your neurologist and find alternative anticonvulsants.
Marie: And sack the herbalist by the looks of things.
Joe: Often you can do without St John’s wort.
Marie: Yes, yes, okay.
Joe: With the amber alerts, if you click on that amber box, you do come up with some advice on what to monitor and strategies to deal with potential interactions. So yes utilise this website.
Marie: Easy to use.
Marie: Yes, okay. So let us look at the type of scenarios you might get caught up with here as a GP. So, GPs can commence treatment with specialist approval until you are experienced, we said about 10 completed treatments through to cure. You can prescribe independently once you are experienced. You can refer chronic, complex patients to specialists, that is people with renal impairment, coinfection, people who have failed previous treatment and those with cirrhosis, and you can share care with specialists or clinics depending on your level of experience and confidence. So you might be part of a team supporting a patient with lifestyle advice, monitoring and preventative health measures such as immunisation updates. So you can really be involved across the spectrum anyway.
So gaining specialist approval if you are not experienced in hepatitis C, it is assisted by some forms that you can use. So look, it can be as informal as finding a specialist who is quite happy to work with you in making it via the phone, or, but you can actually use special forms here to seek approval from a specialist and the form sort of acts as sort of a checklist too, doesn’t it?
Joe: That is right. Yes, a bit of a reminder of things you need to consider when treating hepatitis C.
Marie: Yes, yes. So that looks good. That is the remote consultation form and there may be localised proforma in your area. So it can be downloaded there from GESA. But there is another form isn’t there that we go on to the next slide.
Joe: Yes, so the Kirby Institute and ASHM are looking at real world data, or collecting real world data on the uptake of these medications in Australia and you can utilise the study to get your specialist approval. By completing this online form which you can see illustrated on this slide which is accessible through the www.reach-c.ashm.org.au you are consenting for patients de-identified data to be entered and collected for that REACH-C study. There are requirements to enter your SVR data, so the 12 week post-treatment data on treatment success. It can be a good resource for people who do not have easy access to specialist consultation, and particularly those in the regions.
Marie: And are you finding people are using these remote consultation forms and things like that?
Joe: Yes sometimes, but I mean there is not, they do not have to be used. A consultation can be a corridor to discussion. It can be an email to a specialist that you know.
Marie: I guess if you have got a good working relationship between a GP.
Joe: Absolutely. Yes, the PBS does not define what that consultation means.
Marie: No, okay, alright. That is great. So, undertaking follow up. To ensure the drugs are tolerated, that they are working. So, we will go over the overall on-treatment monitoring for the direct antivirals is less intensive than what was required for interferon-based therapy. Each practice or GP can develop a system to enable it to be done routinely. Remember to assess for treatment adherence at each visit. So, as you can see, after one month of therapy, check the LFTs and ask the patient about adherence and check for drug interactions and tolerability. So they are the basic steps that are required. There are some specific monitoring steps for certain regimens, so people treated with elbasvir plus grazoprevir should have liver function tests at week eight to screen for hepatotoxicity. So they can be done as an alternative to the week four LFTs can they, if they are on that particular medication, Joe?
Joe: Yes, that is correct.
Marie: Yes, they can, alright. Then, routine on-treatment Hep CV RNA testing is not mandated but may be considered where there is a clinical concern about non-adherence to treatment, especially in people with cirrhosis. Do you do that much?
Joe: Yes, yes it can be. I mean, if your liver function tests are not improving when you are assuming someone is on treatment, it can help you answer that question.
Marie: Right. Okay, so but for GPs, it is generally at week you have had your base line tests and at week four you would check the LFTs and check their adherence and check for drug to drug interactions and any adverse events. And then at the end of treatment, check their liver function tests and then 12 weeks post treatment –
Marie: - their liver function tests and their HCV RNA and you are looking for a cure. You do not want any RNA hep C RNA to be detected.
Joe: Yes, that is the definition of cure. So absent or undetectable HCV RNA 12 weeks after the treatment completion, that is a cure.
Marie: So, sorry can we just go back there. So at week four, four weeks after you start treatment, LFTs. At the end of treatment, LFTs. And then 12 weeks after that, look for sustained viral response. So it is a 24 week follow up basically.
Joe: That is correct, yes.
Marie: Okay, yes, yes, okay. Thank you. So 24 week follow up to confirm cure. So, the sustained viral response at 12 weeks post treatment completion, is a cure. So there is undetectable HCV RNA. This does not need to be repeated if there are no ongoing risks. If the risk of reinfection is high, you can repeat testing yearly. Note that the HCV antibody test will remain positive after cure and it should not really be repeated. So warn patients that this happens and you know, because if they get the test done by another doctor they might think they have got hepatitis C again, but that is the antibody and it will remain positive in most circumstances. Treatment failure is where there is still detectable HCV RNA 12 weeks post treatment completion. So, at 24 weeks after the beginning of it all, that they should not have it. That is going to be a small percentage of patients.
Joe: That is correct. Yes.
Marie: Okay, so post treatment follow up. Now this is in people with no cirrhosis, so these are the people that GPs are generally going to be treating. You are looking for a sustained viral response at 12 weeks. Now, if they have got normal liver function tests they do not need any regular follow up unless there is an ongoing risk of reinfection. If they have got abnormal liver function tests, I think refer them to a specialist?
Joe: Yes, because you need to think about other liver diagnoses that might be co-existing.
Marie: Yes. Now if there is no sustained viral response at 12 weeks we can refer them off.
Marie: Yes, okay, yes, alright. Thank you.
Joe: And so in terms of the cirrhotic population, we just thought we would throw this in for interest. So the SVR-12 the cure is assessed at the same time points, so 12 weeks following treatment completion and these patients cannot be discharged back into the community, they need to be monitored because they have been diagnosed with cirrhosis. And we have said before, looking at hepatocellular carcinoma with six monthly liver ultrasounds and serum alpha-fetoprotein, screening for oesophageal varices with upper gastrointestinal tract endoscopies, so gastroscopy to assess there. Looking for osteoporosis complicating cirrhosis with two-yearly DEXA scans. And looking at vitamin D levels. And then looking for evidence of decompensation, so progression of the cirrhosis from compensated to decompensated with ascites and encephalopathy, variceal bleeding, peripheral oedema. And just the point down the bottom, monitoring the severity of the decompensation with scores such as the MELD score or Child-Pugh score and considering interventions such as transplant if need be.
So we just also wanted, we have mentioned before that there are some new pangenotypic regimens coming through the pipelines which are not listed on the PBS at the moment, but both have been TGA approved. So it is just to point out, so there will be a combination, a fixed dose medication of sofosbuvir and pibrentasvir that will be able to be used in renal failure and then there is a re-treatment option, a fixed dose combination pill that is sofosbuvir and velpatasovir, which they are the two drugs in Epclusa, there will be voxilaprevir added to that.
Marie: An extra-long word added in there.
Joe: That is correct. So, yes, so they will be for re-treatment of DAA failures.
Marie: Yes, gee it is moving along really, isn’t it?
Joe: At apace.
Marie: So, let us just summarise those essential steps in treating hepatitis C, because look it is easy. You are going to cure these people, and you know, so get into it. So remember, treatment is straight forward and well-tolerated and most patients are suitable for GP care unless they have basically got cirrhosis, renal impairment, coinfection or past treatment. The monitoring has been simplified and information is readily accessible for checking drug interactions. So, test them for hepatitis C, the genotype and their viral load, do your baseline tests, exclude cirrhosis, establish prior treatment experience, select your regimen, check for drug interactions, monitor them on treatment with LFTs at four weeks then LFTs at the end, and then 12 weeks after treatments, check for sustained viral response – at 24 weeks that is, so 12 weeks after treatment has finished, and then follow up according to the recommended guidelines.
So, in order to really consolidate what we have been talking about and learning tonight, we will do this case discussion and we are just going to talk about Jake, who is a fairly typical patient that you could expect to come across. So he is 58, unemployed. He has used amphetamines since 1985 and still injecting occasionally, minimal alcohol use. You have tested him for his genotype and it is G3A. He has got a past history of reflux and he is treated with esomeprazole 40 mg a day. He is a thin build with a BMI of 20, no signs of cirrhosis. So, Joe what other assessments do you think we would need?
Joe: Look, in think we need some other investigations to look for renal failure, look at his renal function tests, full blood count and INR, looking for evidence of liver disease. We do need to establish whether he has cirrhosis or not, so I am thinking about utilising what non-invasive tools we have, like the APRI and Fibroscan. That is the next step, I would think.
Marie: So we will presume we have done the full examination of him, and clinically we do not think there is any cirrhosis but we will do the APRI score. So the basic bloods will include biochemistry including renal function and LFTs as you said, and haematology. Here the APRI score has been calculated for us, and it appears quite low, much less than one, so Joe how would you interpret that?
Joe: Look, it is pretty reassuring. It is quite a low score and I think that we could be reassured that this gentleman does not have cirrhosis.
Marie: Yes, okay.
Joe: But you know, we might want to confirm that with further investigations.
Marie: Alright, okay, well, alright, well luckily our local hospital has a Fibroscan service available and here we have his results. He seems just by the cut off there at seven, so he has got mild cirrhosis, doesn’t he, mild fibrosis I am sorry.
Joe: No, no I mean that is a pretty low score, so we use less than seven as no significant fibrosis, so a score of 6.2 kilopascals I would consider normal.
Marie: So mild or absent fibrosis is likely and the low APRI score, we are saying that we do not really think that fibrosis is an issue here.
Marie: Alright. So it would appear here, that he is at low risk for liver disease progression.
Joe: If we get rid of his hep C.
Marie: And that is what we have to do, isn’t it?
Marie: Okay. So what we need to know about Jake, okay so the date of infection, well he started using around 1985, so.
Joe: We use that first risk factor as the marker.
Marie: Yes, okay, good. Okay, we know his genotype and the viral load is
Joe: 2.3 million.
Marie: Does that mean anything?
Joe: Not in this context.
Marie: No. Okay, because we are going to cure him anyway. No evidence of cirrhosis.
Marie: So low level or absent fibrosis. Liver comorbidities? No. He is not overweight, he does not have diabetes.
Joe: He does not drink a lot of alcohol.
Marie: He does not drink a lot of alcohol. But he does have other comorbidities, gastroesophageal reflux. He is on esomeprazole and amphetamine use. No signs of coinfection. No previous treatment for hepatitis C. So what is the plan? Okay. So can Jake be treated in the primary care setting?
Joe: Yes. We have got a gentleman who has got chronic hepatitis C. He has got no evidence of cirrhosis. Some people might be concerned about his ongoing amphetamine use, but it is not an absolute contraindication to treatment. In fact, if he is turning up to seek help, he is attending a general practice and if you can engage him and he does not have a chaotic lifestyle that can sometimes go with ongoing amphetamine use, you know, it is very reasonable to treat him, in fact it is desirable because we can reduce the risk of transmission with him, yes within an injecting drug population.
Marie: so when is it a barrier to treatment? Ongoing injecting drug use?
Joe: Well, as I said, when injecting drug users’ lifestyle is chaotic and they may not remember to take pills, they might not have their blood tests done, that makes it very difficult to treat those patients. So you know, ongoing injecting drug use is not a contraindication, but it is a precaution. It is something to consider in your assessment.
Marie: Okay. So what are the treatment options available to Jake and what duration?
Joe: Well, if you go back to your previous slide you can see that there are a few treatment options open to him and we have got a gentleman with genotype three who has not been treated before, has no evidence of cirrhosis, so we could look at that tabulated form of the treatment options for all hepatitis C, so of course he can qualify for the pangenotypic regimen, the sofosbuvir and velpatasvir, with a treatment duration of 12 weeks. But he also qualifies for the sofosbuvir and daclatasvir regimen, so still sofosbuvir based. We would not need ribavirins in this setting because he does not have cirrhosis. Again, it is a 12 week duration, but it is two pills to take as opposed to one. So the only difference between those, I mean they are equal in efficacy but slightly simpler treatment regimen, only one pill to remember to take rather than two.
Marie: Okay, alright.
Joe: Oh and look, I should have mentioned too, we do need to think about drug-drug interactions and we have already assessed that he does not have renal failure so he can use these sofosbuvir based regimens, but there might be something that pops up.
Marie: Yes, he is on this esomeprazole, so.
Joe: Yes, so I think, you do not have to remember all the drug interactions off the top of your head and I always stress the importance of using this website and assessing the drug-drug interactions. So, if we look at esomeprazole.
Marie: This is how it comes up Joe.
Joe: Exactly, so just going back, you put in the treatment options that you have. You can see dactlatasvir, sofosbuvir and then sofosbuvir velpatasvir combination. So esomeprazole is compatible with the dactlatasvir and sofosbuvir combination. But you get an amber alert for the Epclusa tablet. And here it comes. And so when you click on that amber alert, it will give you the risks and the things to look out for. So it is not the end of the road. Often people are on proton pump inhibitors and they can actually stop them. Then reflux may not be a problem requiring ongoing treatment. So that is the first strategy to use. But you can actually, and as prompted by this website, you can use a low dose of omeprazole, Losec separated from the DAA dose, although the efficacy of that is by four hours. So there are other strategies.
Marie: So, ranitidine would also be an option.
Joe: Famotidine low dose.
Marie: Yes, okay. Yes, okay.
Joe: That is right, so in this situation we have got the gentleman who is on esomeprazole. You review the indication for the proton pump inhibitor.
Marie: We do not do that often enough.
Joe: That is true. And consider stopping it if you like. Or switching to an H2-receptor antagonist, like famotidine or ranitidine, if you are wanting to use the Epclusa. And you can use omeprazole at a 20 mg dose four hours separate from the Epclusa dose.
Marie: Would anyone, in somebody like this, would you maybe do, you know, maybe check them for helicobacter and maybe treat before you did the?
Joe: Yes, it depends on the clinical context.
Marie: Yes, sure. Okay, so in this instance, we will say Jake has had treatment with the Epclusa for 12 weeks. So, let us talk about the testing that needs to be done at the end of treatment. So, at 12 weeks.
Joe: At 12 weeks we need to look at his liver function tests and hopefully they are normal.
Marie: Okay, and so does he need any further testing beyond that?
Joe: We have got to remember that completing the 12 weeks of treatment is not the end. We do need more testing in another 12 weeks, so 12 weeks post treatment completion. So looking for the hepatitis C RNA in the blood and also the liver function tests.
Marie: Yes, okay. Well, here he goes. He has had a sustained viral response, so he has been followed up at 24 weeks and his liver function tests are normal. So does he need any further follow up for HCV?
Joe: Look, we have confirmed that he is non-cirrhotic so from that perspective, he does not need ongoing follow up, but remember that he does have ongoing injecting drug use behaviour, so he is the sort of patient that we would need to look out for reinfection. Okay, and remembering the hepatitis C antibody may remain positive for the rest of his life, so checking the HCV RNA one or two times a year to see if he has been reinfected.
Marie: Yes, yes. So that is one of those special cases.
Marie: So, look here is some really good resources, because look keep them, put these up as your favourites because we have given you a lot of information tonight but there is a lot of support for prescribers and the community out there. So, ASHM has eLearning up there you can see, and NPS MedincineWise has eLearning and as I said previously, they have got ideas on adherence strategies as well. MD Briefcase eLearning as well. And there are specific hepatitis C resources through GESA, ASHM and ASID. So those resources are up there too.
Now do not forget that the patients need a lot of support. Some people will be more interested than others, but try and link them in with Hepatitis New South Wales. There is also a hepatitis information line. And you know, it is important that they can access information and support services in the community. Then there is GP and practitioner support. There is a directory of local doctors prescribing HCV and dispensing pharmacies. And there is information and resources for GPs as you can see with these two sites here.
Joe: So I think in terms of wrapping up the talk and summarising what we have been through today, you know, we want to stress that you know, T is for test, screen everybody that is at risk for hepatitis C and remember that hepatitis C can be cured in most patients. And confirming hepatitis C means that patients have the hepatitis C antibody and the RNA present in the blood. So consider treatment of all people, including people that inject drugs.
Marie: So we have got to assess them for liver fibrosis and other comorbidities, so make sure you do a really good assessment leading up to treatment and refer patients off if they have cirrhosis, renal failure, and coinfection or have had previous treatments. So you can share the care with the specialists but you do need specialist input and advice and management for those special categories.
Joe: Remember to evaluate for drug-drug interactions and utilise that online resource, the hep-druginteractions.org and that is going to help you select your appropriate regimen. And remember to assess adherence throughout the course of treatment.
Marie: So, when you start prescribing get approval from a specialist to prescribe. You can use the remote consultation request form that we discussed. And that is for you to build up experience in hepatitis C treatment. And they can get the scripts dispensed from a community pharmacy. So you just need to go through the authority line as we said.
Joe: And our aim is to treat all people with chronic hepatitis C. We monitor them on treatment and remember to check their SVR 12 weeks after treatment completion. You can tailor you post treatment follow up according to the treatment outcome, the liver disease stage and reinfection risk. And remember that patients with cirrhosis need ongoing lifetime surveillance for liver cancer and should be managed in a specialist setting. And retreatment can be offered to people who become reinfected so do not give up then.
Marie: Well look we hope that has been really helpful. So look, this presentation was developed by a cohort of great organisations, so ASHM, the Australian
Joe: Society for HIV Medicine.
Marie: Yes, yes good Joe. And the next one, Joe.
Joe: The Australian Liver Association as part of the Gastroenterological Society of Australia and the Australian Society of Infectious Disease. We know the RACGP and also the wonderful Kirby Institute.
Marie: Yes, okay. So we will go through now the learning outcomes. I think we should have managed them. We are hoping that you should be able to discuss the new hepatitis C treatments, their high cure rate and high tolerability, explain how to treat chronic hepatitis C in the GP setting with specialist report if and as required, and undertake follow up to ensure the tolerability and efficacy of the prescribed treatment.
Sammi: Great. That brings us to the end of this evening’s session everybody. I would like to thank Joe and Marie again for joining us and I hope you all enjoy the rest of your evening.
Joe: Good night everyone.
Marie: Good night.