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Care for Patients With Hepatitis D Virus Infection: Expert Guidance for Primary Care Clinicians

  • Authors: Fabien Zoulim, MD, PhD; Juan Mendive, MD, PhD
  • CME / CE Released: 11/1/2022
  • Valid for credit through: 11/1/2023
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  • Credits Available

    Physicians - maximum of 0.50 AMA PRA Category 1 Credit(s)™

    Nurses - 0.50 ANCC Contact Hour(s) (0 contact hours are in the area of pharmacology)

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Target Audience and Goal Statement

This activity is intended for primary care physicians, nurse practitioners, and gastroenterologists.

The goal of this activity is for the learner to be better able to discuss the pathophysiology and disease burden of HDV worldwide, utilize current guidelines to recognize individuals at risk for developing hepatitis D virus (HDV) infection, and provide support for patients after their diagnosis.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Pathophysiology of HDV infection
    • Disease burden of HDV
    • Screening recommendations for HDV


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  • Fabien Zoulim, MD, PhD

    Professor of Medicine
    Hospices Civils de Lyon
    INSERM Unit 1052
    Lyon University
    Lyon, France


    Fabien Zoulim, MD, PhD, has the following relevant financial relationships: 
    Consultant or advisor for: AiCuris; Aligos; Antios Therapeutics; Assembly Biosciences, Inc.; Bluejay Therapeutics
    Speaker or member of speakers bureau for: Gilead
    Research funding from: Assembly Biosciences, Inc.; Beam Therapeutics; Johnson & Johnson; Viravaxx

  • Juan Mendive, MD, PhD

    Family Physician
    La Mina Primary Care Academic Centre Catalan Health Institute
    University of Barcelona
    Barcelona, Spain


    Juan Mendive, MD, PhD, has the following relevant financial relationships: 
    Consultant or advisor for: Reckitt
    Other: Participant in educational activity for Kyowa Kirin


  • Gillian Griffith, BA (Mod), MA

    Medical Education Director, WebMD Global, LLC


    Gillian Griffith, BA (Mod), MA, has no relevant financial relationships.

Compliance Reviewer/Nurse Planner

  • Stephanie Corder, ND, RN, CHCP

    Associate Director, Accreditation and Compliance


    Stephanie Corder, ND, RN, CHCP, has no relevant financial relationships.

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Developed through a partnership between Medscape and The European Society for Primary Care Gastroenterology.

In support of improving patient care, Medscape, LLC is jointly accredited with commendation by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

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Care for Patients With Hepatitis D Virus Infection: Expert Guidance for Primary Care Clinicians

Authors: Fabien Zoulim, MD, PhD; Juan Mendive, MD, PhDFaculty and Disclosures

CME / CE Released: 11/1/2022

Valid for credit through: 11/1/2023


Activity Transcript

Fabien Zoulim, MD, PhD: Hello, I'm Fabien Zoulim. I'm Professor of Medicine at the Hospices Civils de Lyon, and INSERM Unit 1052 in Lyon University in France. I would like to welcome you to this program entitled “Care for Patients with Hepatitis D Virus Infection: Expert Guidance for Primary Care Clinicians”. Joining me today is Juan Mendive, who an academic family physician at La Mina Primary Care Academic Center, Catalan Health Institute, University of Barcelona, in Spain. Welcome, Juan, to this event.

In this program, we will be discussing the pathophysiology, disease burden, and epidemiology of hepatitis D, and the risk factors for infection. We will also discuss who should be screened for hepatitis delta, and how to screen patients in primary care. We will use patient case scenarios to highlight this part. We'll also discuss specialist management approaches and new treatments, and finally, and importantly, the coordination of care of HDV patients, including the role of primary care physicians and nurses and nurse practitioners after specialist referral.

Having said that, I will start with the pathophysiology of HDV. First of all, what is hepatitis delta virus (HDV)? HDV is a defective RNA virus that requires hepatitis B surface antigen (HBsAg). It is the hepatitis B virus (HBV) envelope for virion assembly, release, and transmission. Thus, it can only infect patients at the same time as HBV or after a patient has acquired HBV, so either a co-infection or a super-infection of HBV infection. You see here a figure and cartoon of the hepatitis delta virus. You can see the HBsAg, so the envelope of the virus that comes from HBV. The HBV envelope is required for HDV infection.

Inside the virus, you have the HDV RNA. This is the smallest of all animal viruses. It is a highly paired rod-like RNA structure. It has no specific enzyme, no polymerase or protease, but it has a ribozyme activity to cleave RNA. HDV uses host factors and enzymes for replication

Now, Juan, can you tell us about the burden of the disease?

Juan Mendive, MD, PhD: Thank you, Fabien. It's a pleasure for me to participate in this training program. Yes, actually, the disease has a very big burden and there are different studies where are trying to measure the burden of this. Prevalence is increasing worldwide in countries such as Mongolia, and the Republic of Moldova, and some countries in central or Western Africa, are supposed to have a very high prevalence of the disease at the moment. This is some data that are related to an epidemiological study from WHO, a recently published paper, but other different publications have estimated a very high burden.

In general, we can say that HDV infection is common among people positive for HBsAg worldwide, and that the estimated prevalence of this HDV infection is around 4.5% worldwide. Actually, the problem is even bigger if we measure positive infections in pathology clinics, where sometimes prevalence measurements are 16% higher. And prevalence is higher if we measure it among intravenous drug users or people who also have HIV infection. Some say as well that HDV causes an estimated 80% of cirrhosis and 20% of hepatocarcinoma associated with hepatitis B. These data are big and very relevant worldwide.

So as far as consequences of HDV infection are concerned, we have to say that this infection leads to rapid progression of liver diseases, and increased risk of cirrhosis, decompensated cirrhosis, liver transplant, hepatocellular carcinoma and mortality compared to monoinfection with hepatitis B.

Another important aspect to consider is the speed of disease progression. And to explain that, it would be relevant to say that hepatitis D infection can be acute or chronic. Hepatitis D infection can occur simultaneously with hepatitis B, infection. This is a co-infection and it is different from another kind of infection that we call super-infection, which happens in patients who have chronic hepatitis B. As far as co-infections are concerned, they are similar to hepatitis B acute infection, but usually it has a more rapid progression, and usually also a worse clinical outcome. Acute co-infections also lead to significant severe outcomes in acute hepatitis, and is present if the patient remains chronically infected. These co-infections are normally cleared in most patients. Only 5% of acute patients remain chronic. A very different aspect is of those with super-infections. They have a more severe disease course, with an increased risk of acute liver failure compared to acute hepatitis D co-infections, as we explained before. With these super-infections, the problem is that they are often mistaken and under-diagnosed in chronic hepatitis B patients, and this occurs in 5% of hepatitis D co-infections and most of the super-infection patients, up to 90% of them.

Dr Zoulim: Okay, so thank you, Juan. Now, let's spend a couple of minutes on the epidemiology endemicity and risk factors for hepatitis delta, because this will be very important for the screening of these patients. Can you elaborate a little bit more on this, Juan?

Dr Mendive: Well, yes, thank you Fabien. Yes, I already presented some data about the burden of the disease, and we also have data estimating the global prevalence. About 5% of patients that are already infected by hepatitis B, and the endemicity of this infection is actually a pandemic. It's all around the globe, although some of the countries have a higher prevalence, like Eastern and Southern Europe, the Mediterranean region, Middle East, Western and Central Africa, East Asia, and also the Amazon Basin in South America. As I already said, some countries have a very high prevalence of the infection. In the end, the global burden is really relevant, and we know about risk factors as well. We know that people suffering from chronic hepatitis B who have the highest HDV prevalence. That is a key issue for having HDV. And people who injecting drugs, men who have sex with other men, infants born to mothers with HIV, and sexual partners and household contacts of people who have HDV. Sex with someone who has hepatitis B or D, and also having hepatitis C or HIV may also be a risk factor for getting HDV. Healthcare workers may be also in a risk of the infection, so these are quite relevant aspects to consider

Dr Zoulim: Yes. Thank you, Juan. And here is a slide that summarizes many of the studies that have been done on the prevalence of hepatitis delta virus worldwide, and several studies show that the range of prevalence of hepatitis delta among HBS carriers varies from 12 million to 48 million people. Here, you see one of the latest studies, which was based on a systematic review of more than 600 studies, many of them [from Asia, and it shows that almost 48 million people worldwide live with hepatitis delta virus. This is a major burden that is very often underestimated.

Now, an important topic is screening for HDV infection. We've seen the epidemiology, and now, Juan, I would like to discuss who should be screened for hepatitis delta virus?

Dr Mendive: Okay, thank you, Fabien. This is a very relevant question. Actually, the high risk groups would be the ones to consider. Obviously, those who have chronic hepatitis B should be prioritized for screening, because some of them are not properly assessed for hepatitis D infection. Other risk groups will be men who have sex on men, people who are using intravenous drugs, the intravenous drug users. People who come from very high prevalence, endemic countries, may also be considered for screening for HDV infection. People infected with hepatitis C or HIV should also be considered screening, as well as those with signs of hepatic damage, such as elevated ALT or AST. Sometimes we should be considering as well potentially people who may be suffering from a hepatitis B infection. People with a low HBV DNA that who have a co-infection or a super-infection with hepatitis D that has not been properly addressed or screened. HDV infection in the household, as well, and maybe there would be other possibilities to screen.

We always have to consider those patients who have been treated for another condition, for instance, for having another kind of hepatitis and who still don’t have good liver outcomes. We should also have the possibility of screening them for hepatitis D

Dr Zoulim: Thank you, Juan, for these important clinical considerations. Now I will review the guidelines from the International Society for Liver Disease regarding HDV screening. You see that the AASLD, for instance, recommends screening in HBsAg positive patients with risk factors for HDV, or from high prevalence countries. They also recommend HDV screening in patients with low or undetectable HBV DNA associated with high ALT. The APASL recommends screening in patients with chronic HBV and chronic liver disease, while the EASL is even more aggressive on screening, because they recommend screening all patients infected with HBV at least once in their lifetime.

So now the question is how to test. So we have to test HBsAg antigen positive people, and the guidelines recommend testing all HBsAg antigen positive carriers or only risk groups, depending on the guidelines. And the test would be done with anti-HDV antibody first and ,if positive, the patients will be tested for HDV RNA.

Now, to exemplify this important clinical aspect, I would like to discuss a couple of patient cases for primary care, to highlight the importance of screening for HDV. Juan, can you present us these 2 cases?

Dr Mendive: Thank you, Fabien. Yes, the idea is to present a couple of cases that are actually something that can be seen in our daily practice. The first scenario is a male patient, he's Peter, 24 years old, known to be a hepatitis B carrier and regularly had sex with other men in the past. He has been with the same partner for several years. He comes to the practice for a follow-up blood test, and he explains that he has a new partner and actually is a bit worried about eventually contracting new sexually transmitted diseases. He's worried about how to manage this new situation and asks for advice from us. In this situation, a blood test is performed, and because of his hepatitis B situation and this new partner situation as well, we included testing for HIV. This is a very common scenario that can happen in primary care or in another clinic, and we have used it here to make highlight something that can be seen in a daily practice. I'm not sure if you want to add something here, Fabien, in that case.

Dr Zoulim: Yes, sure. I think it's an important situation here, and really everyone should remember that in chronic HBV carriers, who are at high risk because of sexual practice, we should not forget HDV, because we usually think of HIV and syphilis and other sexually transmitted diseases. But very often HDV is forgotten in an HBV carrier. I think it was a very important point, and sometimes we have a bad surprise, that hepatitis delta can be found in these patients. Now let's talk about a second case which is a little bit different, but very common as well.

Dr Mendive: Thank you, Fabien, and thank you also for your comments, very useful ones. The second scenario is about Maria. She's 38 and works as a volunteer for a non-governmental organization. She has just recently come back from Mongolia where she was living for 2 years in a rural area. She's worried about having contracted sexually transmitted diseases and asks for a blood test. Then for us, because she traveled to a country with high prevalence -- as we just said, this is one of the highest prevalence countries -- when we asked for blood tests, including testing for the possibility of sexually transmitted diseases, in that situation the issue is to also ask for a hepatitis D virus test. This is also something I would like you to comment on, Fabien. How do you see it?

Dr Zoulim: I think it's a very important point to discuss. We have also cases, for instance, of patients who are known to be chronic carriers, who are going back to see their family who live in high endemic areas. It can be Mongolia, it can be in Africa or elsewhere ,and sometimes we've seen patients, when they came back, having ALT elevation although they were previously inactive carriers of HBV. In that scenario, we should really also test them for hepatitis delta, because they may have acquired the delta infection when they were back visiting their family, and especially in highly endemic countries where they could have been infected through the household, and so on. The issue of identifying high risk factors, such as traveling to a high endemic country is a very important one, so we shouldn't forget this point as well. Now, let's present some key messages for screening in primary care. Juan, if you can discuss this point a little , that would be very informative.

Dr Mendive: Thank you, Fabien. I would like to say that primary care is an environment with huge opportunities for screening hepatitis D. Some of the key messages I would like to provide from my vision as primary care doctor is that primary care has a lot of opportunities to avoid stigma of populations who may be suffering from the infection, but may be also stigmatized from different reasons, for their risk factors or risky behaviors. Primary care can also have a very active role in avoiding missed opportunities. Whenever we have something to do, we shouldn't avoid it. That means that if we have someone who is a person at risk, we should try to take this opportunity to screen, because otherwise we're going to miss the opportunity. The good news in primary care is that we may have further opportunities, or people may come in a longitudinal way sometimes, depending on the health system, but the continuity of care is also one of the characteristics of primary care that can provide these follow-up possibilities. And also for other professionals in primary care, as nurses. We do have these possibilities of management and also to provide that holistic approach, so these are our characteristics that I think are good. It can provide a lot of opportunities for screening and management of this infection.

Dr Zoulim: Yes, those are very important points. So now I'll briefly discuss the treatments available for HDV. Currently, we have PEGylated interferon alfa, which is available. And as you all know, it has a broad antiviral activity. It is not formally approved for hepatitis delta treatment, but it is recommended by all international liver societies. Unfortunately, it has a low treatment response rate and it is associated with side effects. Beside PEGylated interferon alfa, we have newly approved therapies, especially bulevirtide, which is a novel viral entry inhibitor. It received European Union conditional approval in July 2020. And there are even newer therapies that are in clinical trial development. They include interferon lambda, the prenylation inhibitor lonafarnib, and nucleic acid polymers.

Let's look at the results of PEGylated interferon alfa in hepatitis data. Here you see a slide that summarizes all the recent clinical trials with PEGylated interferon alfa in this indication. And globally, the end of treatment response is around 33% of the patients. And when we look at the end of follow-up response, which is usually between 24 weeks or 48 weeks post-treatment cessation, the rate of response is around 29%.

There are studies that have looked at the response rate with a longer follow-up, and they're seeing that a late relapse can occur in almost 50% of patients who had achieved a follow-up response, indicating that overall the long term response rate is quite low. These studies also show that the HBS loss rate in the long term is a maximum of 10%, meaning that the curing HBV and HDV with PEGylated interferon is achieved in only a minority of patients.

Now, besides PEGylated interferon, we have a bulevirtide that has just been approved by the EU as I just told you in a conditional manner. It is an entry inhibitor that blocks the interaction between HDV and the cellular receptor for viral entry, NTCP. And we have seen recent results of clinical trials presented at different congresses, and they showed that bulevirtide at 2 mg per day induces a combined response at week 48 in 45% of the patients versus 2% in patients with delayed treatment. And there was no additional benefit with the use of a higher dose, 10 mg, as you can see here. So now the 2mg dose is used in phase 3 clinical trials and it is used in the conditional approval setting. This provides new hope for patients with chronic hepatitis delta.

Now, in the final part of our discussion, I think we should focus on the role of primary care physicians and nurses and nurse practitioners in supporting patients with hepatitis delta after they've been referred to specialists. Juan, I would like you to tell us about the pathways of care in these patients.

Dr Mendive: Thank you very much, Fabien. I think this is a key issue to consider, because once we've screened the patient, when we have hopefully diagnosed the infection, we should actually try to do the best for this patient, and that means to do the best in terms of treatment and retaining the patient in the system. The pathway of care can be very diverse in different health systems, and this is very diverse worldwide. But all health systems should try to guarantee this retention of patients in the system, and that will imply that these patients actually remain in the unit, in the liver unit or a specialized unit where they can have the best treatment options.

So for issues related to screening, as we said before, it would be very relevant also to consider the vulnerable populations, migrants. These people should have the right to access care and to be retained when necessary for appropriate treatment. All things related to language problems, all these things related to vulnerable people, should be actually contemplated properly in systems regarding to this appropriate treatment and retention.

Keeping people in the care system after diagnosis will actually imply a proper and adequate coordination between primary care and coordinated care, so this is more than just referral. That needs a proper coordination, and we should prioritize hepatitis D infection for people in really difficult circumstances. People who have difficulties in accessing the system should even be prioritized for treatment. We will try to emphasize the importance of providing appropriate counseling and doing it in a motivational environment for people in order to make them aware of the importance of their own treatment.

All the decisions should take into consideration the patient’s vision and values, and the treatment decision processes should also take into account the patient’s views on that. This is relevant for always guaranteeing patient satisfaction. All the shared care decisions process, always with the vision for a holistic approach, including the evaluation of emotional impact. A lot of times this is forgotten and it's very relevant to these vulnerable people that we often see in primary care.

Global and social perspectives to address are very important. Facilitate access to empower communities and to raise awareness among the population and health professionals, not only related to the treatment of these infections, for instance, or management of therapeutic plans, but even earlier, we should try to emphasize the importance of health promotion and prevention strategies and behavioral change, when needed.

To explain a bit of this, I would like to show a comprehensive approach to the different factors contributing to the burden, not only for the viral hepatitis, but also, for instance, HIV/AIDS and other sexually transmitted diseases. It is a multi-factorial problem that provides stigma and restrictive outcomes that imply a maintenance of discrimination, poverty, and disability in vulnerable populations that will lead to chronic risk of infection. This has been pointed out by WHO in a recent document in July of this year. In order to address these problems, we should try to make a holistic approach for the different perspectives in societal intervention. That will provide help to these populations, working in coordination with not only our health sector but also the social and community sectors. That is a key factor in guaranteeing access into health systems, and also maintaining that accessibility to the system for these people.

Dr Zoulim: Thank you, Juan. These are such important factors and considerations that we need to address when we are dealing with patients with hepatitis delta, and I think we've covered quite a lot today.

So now to conclude, here are the take-home messages of this program. So HDV is a frequently occurring disease in HBV carriers. And as you've seen, it is very often underestimated and overlooked. It accelerates the progression of hepatitis B, and it creates bottlenecks for access to care. As we've seen, vulnerable populations are high-risk groups, so these are very important points to consider for the management of these patients. And this is especially important because new treatments for hepatitis delta are becoming available and we've seen the promising results with bulevirtide. However, accompanying this there is a need for patient counseling programs. And the last very important key message is that all HBV carriers should be tested for HDV at least once in their lifetime

I would like really to thank Juan for a great discussion. Thank you for watching this program, and please continue to answer the questions that follow and complete the evaluation.

Dr Mendive: Thank you.

This transcript has been edited for clarity. It has not been copyedited.

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