Hepatitis B Virus – Hepadnaviruses

by Sean Elliott, MD

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    00:01 The hepadnaviridae viruses.

    00:05 The hepatitis B viruses are small and enveloped with a circular, partially double-stranded DNA genome, and importantly, they encode their own reverse transcriptase.

    00:17 The viruses themselves are resistant to low pH, which is important as they're aspirated and enter the circulation via the stomach.

    00:26 They also are resistant to moderate heating, as well as detergents in terms of cleaning in the hospital or healthcare setting.

    00:34 And typically, as we'll see, the hepatitis B virus can cause both an acute and/or a chronic infection. It's quite versatile in its cause of disease.

    00:45 Transmission, as you are probably aware, is anything and everything, especially exposure to blood and body fluids.

    00:52 So a parenteral exposure, sexual exposure, babies born to mothers actively infected or even chronically infected, of course, are at risk.

    01:02 The incubation, then, of hepatitis B virus is months and sometimes even longer than that.

    01:08 So, let's walk our way through the replication of hepatitis B virus.

    01:13 Again, it's a little bit different because it carries its own reverse transcriptase.

    01:18 We'll start with the complete virus as it attaches to and embeds itself to its target hepatocyte.

    01:26 It then sheds its external envelope, injecting the capsid into the cytoplasm, and ultimately injects the core, the DNA material, into the nucleus of the hepatocyte.

    01:39 There, the viral genome is first transcribed into long, double-stranded RNA, and then back transcribed to DNA circles, which again, remember are not completely double-stranded.

    01:52 These then exit the nucleus and are packaged into new capsid material, which then gains further envelope material on its way out, and eventually lyses and extrudes itself from the hepatocyte.

    02:06 So it's, again, as we're seeing is a recurring theme in viruses, when the fully formed virus leaves the cell, in this case, the hepatocyte, is when lysis occurs and the affected cell creates an inflammatory reaction.

    02:23 Let's then look, serologically, at the course of infection because there are multiple different ways, different antigens expressed by hepatitis B that can help us understand at what stage in that life cycle we just saw, we're at in terms of infection.

    02:38 If we're able to detect the presence of the surface antigen, and the E antigen represented by hepatitis B, that means the virus is present. Doesn't mean necessarily that it's doing anything, but it's simply that it's present and starting to expose itself to the hepatocyte.

    02:59 When we start to see in the blood stream antigen to the E antigen, the serum HBeAg, and actual viral DNA being released, that means there's active processing going on and the virus is very transmissible.

    03:16 Once we then start to see immunoglobulin M like in a humoral or an antibody response to the core antigen for hepatitis B, that means that infection has occurred, but it's been quite recent that we haven't yet had time to create an immunoglobulin G response.

    03:33 Therefore, when we see IgG antibody to hepatitis core antigen, that means that previous infection has occurred, and this takes typically about 6 months to convert from an immunoglobulin M to an immunoglobulin G response.

    03:49 The hepatitis B surface antigen antibody or some people abbreviate this to be HBsAg antibody.

    03:58 This means that either the infection has occurred and it has resolved and that patient is lucky. They have lifelong immunity.

    04:06 Or that we have vaccinated the patient with hepatitis B surface antigen, the typical vaccine strategy, and they have made an appropriate and protective response.

    04:17 However, if there is persistent hepatitis B surface antigen in the setting of a known infection, this means that there's chronic infection.

    04:26 The body's immune system has been unable to convert to lifelong protective response with immunoglobulin G antibody.

    04:35 If we further look at presence or absence of antibody to the E antigen, as well as presence or absence of DNA from the virus that suggest either in the setting of chronic infection, that the patient is a healthy carrier if they're negative for both E antigen and DNA, or they are actively infectious as a carrier.

    04:57 And in this case, they have both E antigen and DNA to hepatitis B present in the bloodstream.

    05:06 To, again, refresh our memory of where these different components are that we test for, we'll look first at the core antigen. It's a major core antigen.

    05:15 And as you can see, it lies underneath the envelope shown in purple on this image, and instead, is the red ring-like structure that that represents a surrounding group of core antigen to protect the internal capsid.

    05:31 And this contains both genome and core enzymes.

    05:35 The surface antigen -- as the name would suggest, it's not too hard -- lives on the surface, and that would be present in that purple surrounding envelope material which you see present on the image.

    05:49 And then the E antigen. Now this is closely approximated in the space around the core antigen. And so, when one sees expression of the E antigen, that means that initial uncloaking or removal of the envelope has occurred, and this typically is detected in the bloodstream.

    06:08 So, pathogenesis. Hepatitis B virus enters.

    06:11 It's typically either injected through parenteral or through some other exposure to blood and body contents.

    06:18 It survives any acid challenge, and it creates a viremia. Travels through the bloodstream to the liver.

    06:25 If the patient has been previously immunized against Hepatitis B surface antigen, then no further action can occur. There's no ability for the virus to attach, and in fact, the immune system can detect this new virus and get rid of it.

    06:43 However, assuming the patient is unimmunized, then we have attachment of the hepatitis B virus as we talked about before, to the hepatocyte, and it replicates causing low-level inflammation, but no liver damage.

    06:59 During this incubation period, however, we can have a very strong, cell-mediated immune response from the human's immune system.

    07:08 And if there is a strong response, meaning it's attacking those inflamed or lytic hepatocytes, that acute disease, acute hepatitis will develop, occurring in about a quarter of patients who are infected with hepatitis B.

    07:24 And this is highly likely to cause complete resolution and development of a strong and protective immune response.

    07:32 The patient will survive that quite well.

    07:34 If, as is more common, the patient has a mild immune initial response, this is unfortunate because it means that they are highly likely to have a chronic infection.

    07:46 And if so, that means that they can develop further disease, further cirrhotic disease going on.

    07:53 Looking even more specifically at what happens with the infected hepatocytes, the hepatitis B surface antigen is a very active or very highly able antigen to trigger an immune response.

    08:09 And it frequently creates a type III hypersensitivity reaction, which can cause or contribute to that active hepatitis.

    08:17 If, however, in the setting of chronic infection, there is a reactivation and/or there is a co-infection with hepatitis D or delta, then the patient is at high risk to develop permanent liver damage accompanying with cirrhosis, which occurs in 10%.

    08:37 The patients, then, who have over 30 years of that chronic, low-level infection, the ones who had a mild immunologic response to the initial acute infection are at high risk to develop, ultimately, a hepatocellular carcinoma.

    08:52 So, in this case, although it may be unpleasant, it's far better to have the acute, fulminant hepatitis, get it over with and get a seroprotective response, than to be cursed with a mild initial reaction, mild or no hepatitis, but then a chronic infection.

    09:09 So, how do we prevent the disease and then how do we eventually test for it? Well, prevention starts with looking at the most common source; a transplant or a blood transfusion-related -- a transfusion -- excuse me, transmission of the virus.

    09:26 And this is countered by doing ELISA, enzyme-linked immuno assay of blood from donors to screen out those who are hepatitis B positive.

    09:35 Vaccinations also exist and vaccinations include a non-functioning hepatitis B surface antigen subunit.

    09:45 This vaccine is administered to all newborns, typically, in the first 2 weeks of life, and again at 2 other points in a primary care series, depending on what country one lives in.

    09:57 Health care workers, if not previously vaccinated as newborns themselves, also deserve immunization.

    10:04 And then of course, those patients who are at risk. So, transplant coming up, patients require multiple transfusions.

    10:12 The diagnosis we've talked about looking serologically for the different antigens that we've talked about, and looking at an IgM and/or an IgG response.

    10:23 Those patients then determine to have active infection at risk for progression, deserve treatment, and that's typically shown when they have evidence of liver dysfunction; a doubling in the liver enzymes, AST and ALT, some degree of jaundice, some degree of liver dysfunction, like being coagulopathic, etc.

    10:45 If we then decide to treat, currently, the primary treatment includes reverse transcriptase inhibitors uch as we use in treating human immunodeficiency, HIV, virus.

    10:57 And these include these viruses -- our anti-viral agents here: lamivudine, entecavir, emtricitabine, and adefovir.

    11:06 The dipivoxil and famciclovir are different antivirals, which also has some putative or proposed activity in the setting of hepatitis B treatment.

    11:16 But discovery continues, as we speak, to see about how effective they actually are.

    11:22 So, hepatitis B virus is absolutely something which occupies the attention of those of us in hospital-acquired infection prevention careers, but also, for those who work with high risk patients who are at risk for acquiring the virus through sexual practices, transfusion, parenteral, etc.

    11:41 It's a complicated virus, but it's quite instructive in understanding how a viral growth pattern can inform its testing strategy.

    About the Lecture

    The lecture Hepatitis B Virus – Hepadnaviruses by Sean Elliott, MD is from the course Viruses.

    Included Quiz Questions

    1. ...circular, partially double-stranded DNA.
    2. ...circular, partially double-stranded RNA.
    3. ...linear, partially double-stranded DNA.
    4. ...linear, partially double-stranded RNA.
    5. ...linear, partially single-stranded RNA.
    1. Reverse transcriptase
    2. RNA polymerase
    3. DNA hydroxylase
    4. RNA hydroxylase
    5. RNA reductase
    1. HBsAg antibody
    2. HBeAg antibody
    3. HBcAg IgM antibody
    4. HBcAg IgG antibody
    5. HBV DNA
    1. Healthy carrier
    2. Infective carrier
    3. Vaccinated against hepatitis B
    4. Recently infected
    5. Previous infection in the past year
    1. Type III
    2. Type I
    3. Type II
    4. Type IV
    5. Type V

    Author of lecture Hepatitis B Virus – Hepadnaviruses

     Sean Elliott, MD

    Sean Elliott, MD

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