Sam Lam, PharmD, on Hepatitis B Reactivation

The US Centers for Disease Control and Prevention estimated that more than 21,000 people contracted acute hepatitis B (HBV) in 2018.  Many more—approximately 862,000—are thought to have chronic hepatitis B. While HBV is preventable thanks to a vaccine, and treatable with antiviral medications, it cannot be fully eradicated. Even after successful treatment for HBV, patients may experience reactivation of the virus, particularly if they are exposed to immune-suppressing treatment for other diseases ranging from cancer to rheumatoid arthritis to inflammatory bowel disease.

We recently sat down with Sam Lam, PharmD, hepatology clinical pharmacist at Beth Israel Deaconess Medical Center in Boston, for an overview of hepatitis B reactivation, its prevention, and its treatment.

RALN: What exactly is hepatitis B reactivation and what causes it?

Dr Lam: The natural cause of hepatitis B virus infection is really an interplay between viral replication and the host immune response. Hepatitis B continues to persist in all of our patients with infection, even those with evidence of serological recovery, also known as the loss of surface antigen protein. And this is because the HBV genome is repaired to form a covalently closed circular DNA or cccDNA in the hepatocyte nucleus. And when we talk about HBV reactivation, it is really a reflection of the loss of HBV immune control in patients who either have chronic hepatitis B or those who have had a previous exposure to the hepatitis B virus. This usually happens when a patient is receiving immunosuppressive therapy for another concomitant medical condition.

RALN: So if a patient has had hepatitis B and has gone through the treatment, the hepatitis B is still present in the body?

Dr Lam: Yes. We can never eradicate the virus because it's integrated into the hepatocyte's genome. Even patients who has been treated for the hepatitis B infection, unless they have lost surface antigen, they always have the virus. And for patients who have either only had a previous exposure but not a positive surface antigen, we call that resolved infection, but they are still at risk for hepatitis B reactivation if they were to be immunosuppressed.

RALN: Is the immunosuppression is the key here? If someone with a past history of hepatitis B then needed immunosuppressive therapy for rheumatoid arthritis, that could then cause the reactivation of the hepatitis B virus?

Sam Lam: Certainly, yes.

RALN: How does this usually present? What kind of clinical manifestations would a gastroenterologist see in a patient who is going through this?

Sam Lam: The most important point is we would see a new detectable HBV DNA level or an increase in the patient's HBV DNA level, whereas they may previously have an undetectable HBV DNA level or very low levels, suppressed by their own personal immune system. Some experts would look into specific numbers such as an increase in 1 to 2 logs in the patient's HBV DNA level and that will increase to 10- to 100-fold in the DNA number or even what we would call seroreversion, where patients may be surface antigen-negative and because they undergo certain immunosuppressants, they now become surface antigen-positive, meaning that the patient now has chronic hepatitis B infection.

Manifestation really differs from patient to patient. Some would remain asymptomatic and just have an increase in their HBV DNA level. Other patients could become symptomatic, they could also have a flare, which means that if we do blood work, it would be coupled with increase in their serum aminotransferase or liver enzymes.

RALN: Why would you go and look for the surface antigen in a patient who's asymptomatic? Or are these patients checked periodically to see if the HBV is reactivated?

Dr Lam: A patient who is at risk for HBV reactivation prior to initiation of their immunosuppressive therapy— whether it be chemotherapy or rheumatological therapy on certain biologics—should be checked by their provider for their full hepatitis B serologies to see if this is a patient who could be at risk and then take the necessary measures.

RALN: So any patient who has a history of HBV who is going to, as you say, go through chemotherapy, immunotherapy or take a biologic drug, should be tested?

Dr Lam: They should.

RALN: Is this widely known among the gastroenterologists treating patients who have had hepatitis B?

Dr Lam: Absolutely, yes. There's list of notable medications that are known to cause hepatitis B reactivation and really for any patients who undergo these type of medications. Their specialists and providers should check the patient for their full hepatitis B serologies to see if the patient has infections to the HBV virus or if they've had resolved infection, meaning that they only have that core antibody.

RALN: What would some of those drugs be?

Dr Lam: Some of the notable agents that could cause and are known to cause HBV reactivation include some of the more potent immunosuppressive medications, such as monoclonal anti-CD20 antibodies and medications such as rituximab, anti-CD52 agents. We have tumor necrosis factor inhibitors, such as infliximab, etanercept, adalimumab, and even high-dose glucocorticoids. Medications such as antirejection transplant medications, antimetabolites, or even hepatitis C direct-acting antiviral medications have a warning regarding the risk of hepatitis B reactivation.

When we think about immunosuppressive therapies that are associated with HBV reactivation, usually we think about chemotherapeutic agents and also biologics that are used to treat autoimmune disorders such as Crohn's disease. And in fact, rates of HBV reactivation have been reported to be as high as 70% among patients who are surface antigen-positive and receiving standard chemotherapeutic care. Specifically, the risk is higher with the use of regimens that include anti-CD20 monoclonal antibodies, again, such as rituximab. A case series has demonstrated reactivation of HBV in patients with Crohn's who undergo infliximab treatment, another TNF inhibitor medication.

RALN: Are some of these drugs more problematic than others, even among the anti-TNF class? You mentioned rituximab, which is known to be a B cell suppressant.

Dr Lam: Absolutely. Certainly. We can really categorize the level of risk that the patient has in terms of them being prone to HBV reactivation and the class of drugs, the specific agents, as well as the patient's underlying HBV serology or status. We could really accurately categorize them in terms of how much at risk a certain patient is at so the providers could accurately determine whether we should just monitor the patients or put them on prophylactic treatment.

RALN: And what would that prophylactic treatment be?

Dr Lam: I think the first thing we need to do is to assess a patient's risk. And again, the risk of HBV reactivation among patients receiving immunosuppressive therapy is really dependent upon the surface antigen status of the patients. Generally speaking, patients who are surface antigen-positive, meaning that they have chronic hepatitis B, those who may be e-antigen positive, or have a high baseline HBV DNA level, these are the patients that are at the highest risk. In contrast, patients who are surface antigen-negative with only a HB core positive, meaning that they have had previous exposure but now havea resolved infection, these patients are at a much lower risk for HBV reactivation. But this group of patients is especially important for providers to monitor if they ever undergo immunosuppressants or chemotherapy, because they are often not having as frequent follow-ups with providers and many of them are not already on HBV antivirals.

Once we decide that a patient does require prophylactic therapy against HBV reactivation, we have very safe, effective nucleotides. We normally recommend either entecavir or tenofovir, which also comes in 2 different formulations, the TDF and the TAF. These are usually preferred over formulations of HBV antivirals, such as lamivudine, due to the risk of developing drug resistance. And usually we would like to stop the patient on these antivirals if we deem necessary, prior to initiation of the immunosuppressants. The duration of treatment typically is for at least 6 to 12 months after the withdrawal of the chemotherapy or immunosuppressants, but this is when really the specialist or the providers' experience and clinical expertise comes into play as to how long to maintain the patient on HBV antivirals.

RALN: And these antivirals are effective in your experience in helping to prevent reactivation?

Dr Lam: Very effective. Very effective, with really minimal, minimal side effects. For example, if a patient with chronic hepatitis B who is naive to treatment or if they've had previous exposure to HBV, were to start on chemotherapy, we will start them on entecavir or tenofovir prior to their chemotherapeutic agent and maintain them on that medication throughout their treatment. And it is shown to be very effective in preventing HBV reactivation.

RALN:  If a patient does in fact experience reactivation, how do you then treat that patient?

Dr Lam: Antiviral treatment is warranted for all patients who end up developing HBV reactivation. And even if the patient is asymptomatic, the goal here is really to prevent a flare of the disease, to prevent any further liver damage, to calm down their liver, to prevent the progression of liver disease and liver damage. Severe hepatitis and even hepatic failure can develop in up to 25% to 50% of the patients with HBV reactivation. In fact, treatment for HBV reactivation is the same as treatment for someone with chronic hepatitis B, actually the same treatment as prophylactic therapy as well. Again, we would recommend either entecavir or tenofovir to be administered in these patients. And again, we will avoid lamivudine, due to resistance.

Unlike hepatitis C, where we are able to achieve a sustained biologic response with antivirals, when we talk about hepatitis B, we do have very effective nucleotides suppressing the HBV virus but due to the nature and complexity of the HBV DNA and its integration, we are not able to completely eradicate the virus. In this case, after a patient experiences HBV reactivation, we would treat them as the same way as a patient who has chronic hepatitis B and in this case, the patient may have to stay on HBV antiviral lifelong.

RALN: Is there any contraindication in treating for HBV while a patient is going through chemotherapy? These drugs don't conflict or counteract each other?

Dr Lam: The drugs usually do not conflict with each other, drug-drug interactions as well as side effects profiles are very minimal with entecavir and tenofovir. But then we would depend on a clinician's expertise as well as clinical pharmacists that are in that clinic to run a drug-drug interaction check to determine whether entecavir or tenofovir or even the newer formulation of tenofovir, Vemlidy, is the best option for the patients. There usually are no contraindications when a patient is undergoing chemotherapy or taking certain immunosuppressants.

RALN:  Is there anything else you would like to add that would be helpful for the practicing gastroenterologists to know about HBV reactivation?

Dr Lam: Prior to initiating any sort of immunosuppressants, whether it be chemotherapeutic agents, TNF inhibitors, or even high-dose glucocorticoids, if you know the patient is going to be on it for an extended period of time, it is very important to check the full HBV serology panel and that typically includes the surface antigen, which would tell the provider whether the patient has chronic hepatitis B infection or not. It would include the core antibodies, which would tell the provider whether the patient has had a previous exposure to HBV.

And if either of these is positive, then we need to consider whether the patient needs to be on HBV reactivation prophylactic therapy. A lot of times the providers would choose to just monitor the patient if their risk is very low. And included in the HBV serology panel is also the surface antibodies. This will tell the provider whether the patient is immune to the hepatitis B virus or not. If they do not have immunity, we can and should provide the patient the vaccination so that they develop the necessary titers to protect themselves against the HBV virus.

RALN: And I take it that in all these cases, when a physician who plans to put a patient with a history of HBV on any kind of immunosuppressant, it's a good time to call in the hepatologist for a consult to help map out the appropriate treatment.

Dr Lam:  Correct. I would do the same as well. I think for low-risk patients, reaching out to a hepatologist or an infectious disease specialist is very appropriate. For the high-risk patient, referral to a hepatologist may be better.