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AUGUST 2006
Main Article:
Managing Hepatitis B Virus Infection: An Interview with Chloe Thio, MD - Associate Professor of Medicine, Johns Hopkins Medical School
David Alain Wohl, MD
Associate Professor of Medicine
AIDS Clinical Trials Unit
The University of North Carolina - Chapel Hill
There have been a number of significant developments in the management of HBV in recent years, particularly new therapeutic agents that can be used by both the HIV co-infected and the HBV mono-infected patient. IDCR Co-Editor, David Wohl, MD, interviewed Chloe Thio, MD to get her perspective on the state of the art of the management of HBV. Dr. Thio is an infectious diseases physician at Johns Hopkins in Baltimore specializing in the management of patients with HIV and viral hepatitis co-infection. She conducts clinical investigations of HBV therapy and recently published an article in Clinical Infectious Diseases titled, "Treatment of Chronic Hepatitis B Infection in HIV-Infected Persons: Thinking Outside the Black Box." Dr. David Wohl (DW): The prevalence of hepatitis B virus (HBV) in prisons and jails in the US is several fold higher than the general population, and in many correctional facilities HBV screening is routinely conducted in inmates who are HIV-infected, therefore, I want to start by asking you about the management of HBV in the HIV-infected patient. What is your approach to managing HBV in HIV+ inmates who have active HBV but also have a high CD4 cell count and no indication for HIV therapy? Dr. Chloe Thio (CT): Before I would even consider HBV therapy in a newly diagnosed patient with active HBV infection, I would monitor them for six months to a year just to be sure this is a chronic infection and not acute HBV. Specifically, I would look to see if hepatitis B surface antigen (HBsAg) was lost or if the serologic pattern shifted from hepatitis B e antigen (HBeAg) positive to negative. This would help me determine if this was a person in the midst of a recent infection and possibly clearing their virus. Importantly, even if this is chronic HBV infection, a small proportion of people will clear the virus on their own - approximately 0.5% per year (1). So, I would monitor closely for a time, as I'd want to be sure I know the patient before starting therapy, especially since HBV therapy is not as effective as we would like. However, if the patient has evidence of end-stage liver disease I would consider therapy sooner. DW: What if in this case the HBsAg is found to persist during the first year? What would you do then? CT: First, I would check several serological tests including HBeAg, anti-HBe, and a HBV DNA level. I check the HBeAg status to know if the patient has HBeAg positive or negative chronic hepatitis B and to follow the HBeAg status with therapy. There are some people with positive HBsAg and normal liver transaminase levels who have undetectable or low HBV DNA levels (i.e. less than 104) and those people I would not treat (2). For those with higher HBV DNA levels I need to decide whether their HBV needs to be treated. In such cases I would consider getting a liver biopsy. The liver biopsy can be helpful in determining the need for HBV treatment - especially in a patient with low HBV DNA levels (3). So, for instance, in the case of a patient with a CD4 cell count of 450/mm3 who has a HBV DNA of 105 I would consider a liver biopsy to determine if treatment is needed now or can be deferred until HIV therapy is initiated later on. If the biopsy does not show significant liver disease, I might wait and do nothing except follow them every six months checking their ALT and their HBV DNA levels and look for development of liver problems such as cancer. Such patients will in the next few years probably need HIV therapy and at that time I can use drugs that have activity against both HIV and HBV. DW: You are saying that liver biopsies can help the provider decide if HBV therapy is indicated but in many correctional facilities liver biopsy is difficult to obtain. How essential is the liver biopsy? CT: The problem is that you cannot really rely on HBV DNA levels by themselves to tell you who needs HBV treatment. Therefore, the biopsy can be particularly helpful in determining whom not to treat. Certainly, if someone has an HBV DNA level of 109 and an ALT of 100, that person needs treatment and you really do not need the liver biopsy. But, if someone has an HBV viral load that is 105 and an ALT of 40 it is really hard to know how much liver damage is present, and a biopsy that shows minimal damage may dissuade you from treatment while the presence of more significant disease would support therapy. That said, outside corrections we often do get liver biopsies even in patients with clear cut indications for HBV therapy to have some idea as to what stage of the disease they have. But, without the luxury of the biopsy if there is a patient who by HBV DNA and transaminase levels plus clinical presentation you think needs HBV treatment, a biopsy is not essential. In cases where you are inclined not to treat, the biopsy becomes more imperative since you do not want to defer therapy of a patient with end-stage liver disease just because they have low levels of HBV DNA - which can happen. DW: It sounds like persistent HBsAg positivity and a HBVDNA level at least 105 copies/ml qualify a patient for therapy. What about ALT? CT: ALT is something that we do look at. The main reason is that studies have shown that for people with active HBV and normal ALT the response to treatment is very low. So, we tend not to treat them unless they have evidence of liver disease. This relatively low treatment response is likely because you need an immune response to the virus in addition to antivirals and those with elevated ALT have more of an immune response to HBV. DW: Any other criteria for treatment for HBV? CT: For those from Asian countries but also for people from here, a family history of liver cancer is important and would tip me toward treating earlier as HBV is oncogenic and with that history I am more aggressive in trying to treat. Otherwise, that is it. DW: For the patient we have been discussing who has HBV-HIV co-infection and high CD4+ cell counts and who does qualify for HBV therapy by persistent surface antigen positivity, HBV DNA levels and elevated ALT, what treatment would you recommend? Let's assume he does not want to or cannot have a liver biopsy. CT: Foremost, no patient in this country should be treated with lamivudine (Epivir, Epvir-HBV, 3TC) alone as the active HBV agent - HIV+ or HIV-. Resistance develops relatively quickly and can hamstring future therapy. In this case, it is unlikely anyone would try to treat this patient with lamivudine mono-therapy but, were he to need HIV treatment he could mistakenly be placed on an antiretroviral regimen in which lamivudine is the only active HBV drug. In the situation of a patient who does not require HIV treatment I might consider pegylated interferon-alpha (Pegasys, Peg-Intron) because it does not have any effects on developing HIV drug resistance (4). Here an HBV genotype might be helpful as recent studies suggest that genotype A - the most common in the US - and genotype D, respond best to this agent. So, if he were genotype A that would push me to pegylated interferon. If pegylated interferon cannot be administered you would need to use drugs that will not be active against HIV so as to not risk HIV drug resistance. So, in a patient without prior HIV therapy and therefore unlikely to have lamivudine resistance my first choice would be entecavir (Baraculude). It is more potent than the alternative, adefovir (Hepsesera) (3, 4). In addition, to date, there is less resistance with entecavir than with adefovir - but this can be because entecavir has not been studied as much as adefovir. But, entecavir is more potent so I think we will see less resistance over the long term. DW: We learned the hard way in HIV, and more recently hepatitis C virus (HCV), infection that mono-therapy is not as effective as combination therapy. Should we be treating HBV with more than one agent? CT: In the long term we may find that there might be a combination that is more potent than mono-therapy. As I said before, I would not use lamivudine alone as resistance develops rapidly. Now, with entecavir I feel fairly comfortable using this agent alone since there is practically 0% risk of resistance in the first year of treatment. You can monitor the patient's HBV DNA levels during that year and if it falls to undetectable then the risk of resistance is even closer to zero and you may be able to get away with mono-therapy. However, if the HBV level during the first year does not become undetectable, you might become concerned that this patient is at increased risk for resistance and consider adding a second drug. DW: So, you might add adefovir? CT: Right, I might but there are no data to support this. As more data emerge my algorithm might change. I think dual therapy will have its role but unlike HCV and HIV it may not be a 'one size fits all' solution. DW: And, how long are we talking about as far as HBV therapy? CT: With pegylated interferon treatment is for a year if you are HBeAg positive. If the patient is HBeAg negative then we really do not know how long to give pegylated interferon. There is a study that showed 24 months of standard interferon alfa 2b is better than less than 24 months (5). We do not know if this is also the case for pegylated interferon alpha. In general, I am less excited about using pegylated interferon in someone who is HBeAg negative as it tends to be longer term therapy and the response rates are not that great compared to those who are Hepatitis B e antigen positive - especially if they are genotype A. For the nucleoside and nucleotide analogues the duration of therapy differs based on the HBeAg status. In persons with HBeAg-negative chronic Hepatitis B, indefinite therapy is needed since rebound invariably occurs. In HBeAg-positive disease, therapy can be stopped a minimum of six months after anti-HBe seroconversion but patients need to be monitored for relapse since it does occur. DW: How do you monitor for treatment success once starting HBV therapy? CT: For the first year at least I like to monitor every three months by getting a HBV DNA level and liver enzymes. In a correctional setting if that is impractical, I think every six months is also fine but you get a better sense of how the patient is doing with more frequent monitoring. If the HBV DNA is not undetectable after a year of therapy, consultation with a hepatitis specialist is in order. DW: Our goal is undetectable? Not just a substantial reduction in viremia? CT: Undetectable is my goal. We actually do not know what level of virus you need to obtain to reduce the risk of resistance mutations or stop the progression of liver disease but for now we should shoot for undetectable. DW: Let's talk for a moment about the HIV-infected patient who has a history of lamivudine exposure. How is the management of this patient different? CT: With prior exposure to lamivudine, you have to suspect there is lamivudine resistance. There are resistance tests for HBV that can be performed by central laboratories but if there is a history of prolonged lamivudine treatment that may be all you need. If you are not ready to treat their HIV, then the options you have are adefovir or entecavir. I wouldn't use pegylated interferon since there is a recent study showing that HIV-uninfected people with lamivudine resistance respond less well to this agent (6). Or, you can consider the combination of adefovir and entecavir. Adefovir has been shown to be effective in lamivudine-resistant HBV. Entecavir is also effective but the lamivudine resistance mutations are part of those that are required to lead to entecavir resistance. In the first year of treatment, about 7% of persons with lamivudine resistance develop entecavir resistance (4). DW: If you were going to start HIV therapy what would you choose? CT: I use tenofovir (Viread) along with lamivudine or emtricitabine (Emtriva, FTC) - Truvada (Tenofovir+FTC fixed dose combination) is easy to use. Obviously, in a patient with lamivudine-resistant HBV, emtricitiabine would not be an active drug but we have learned from the HBV mono-infected that in lamivudine-resistant patients treated with adefovir, co-administration of lamivudine delayed adefovir resistance. So, I would use lamivudine or emtricitabine here even though there are no data looking at this phenomenon with tenofovir - but I am extrapolating from the adefovir experience. DW: What about HBV treatment for the HIV-uninfected patient? CT: What therapy I use depends on whether someone is HBeAg positive or not. If someone is HBeAg positive there is much more resistance data for entecavir than for tenofovir so if I am only going to use one, I would choose entecavir over tenofovir. Their potency is probably equivalent and my guess is that there will be little tenofovir resistance in the first year but it has not yet been studied in mono-infected patients so I tend not to use tenfovir alone and instead use Truvada - even in the mono-infected patients. Being HBeAg negative changes things and these are almost two different diseases. People with negative HBeAg require long-term therapy. Those who are HbeAg positive you are able to monitor for conversion to anti-HBe positive and then, when that happens, stop therapy six months after seroconversion occurs. In HbeAg negative patients if you stop therapy they almost always rebound. So, in the HbeAg negative situation I virtually never use mono-therapy since I know they are going to be on the drug a long time. DW: I am going to shift gears and ask you to clarify an issue that is getting increasingly confusing. How should we screen people with HIV-infection for HBV infection? A recent study by Raj Gandhi and colleagues from Harvard Medical School suggests that isolated Hepatitis B core antibody (anti-Hbc) may be falsely positive in a large proportion of HIV-infected people (7). In this particular study patients with anti-Hbc detected on HBV serologic testing but no other serologic evidence of HBV infection had a very muted response to HBV vaccination suggesting the absence of an anamnestic response that would be expected if there was prior HBV exposure. CT: This is an issue where we really do not know the answer. In terms of screening to vaccinate for HBV I would only order the HbsAg and anti-Hbs and not the anti-Hbc. That way you are never stuck with the situation of the isolated anti-Hbc. If both the surface antigen and antibody were negative, I would vaccinate. This is one approach. In cases where there is isolated core antibody detected, I would obtain an HBV DNA. If that reveals no virus detected I would check it again in six months along with their serologies. If the result were the same I would vaccinate them for HBV. DW: Do you ever check for HbeAg or anti-Hbe? CT: The paper by Raj Gandhi found that people who had anti-Hbe present were less likely to have their anti-Hbc be a false positive result (7). If you are worried about the core antibody being a false positive you could check the anti-Hbe but it would not change my management, as I would still vaccinate them to try to elicit surface antibody. DW: While we are on the topic of HBV vaccine, what dose do you use? The data on response to HBV vaccination among HIV-infected patients indicates a generally low response rate. Dialysis patients often receive a higher dose (40 ug) of the vaccine compared to the standard dose (20 ug) to overcome a similar suboptimal response rate. CT: I initially start out with the standard dose vaccine and then if they do not respond, I administer the renal dose of the vaccine. DW: Then you must be checking for hepatitis B surface antibody (anti-HBs) response in everyone you vaccinate? CT: Correct. As you said, vaccine rates are low and you want to know if they respond appropriately. If they don't, despite a higher dose vaccine, then you want to know just for the purpose of counseling the patient. DW: Thanks for taking time out to do this. CT: Thank you. References:
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