Antiretroviral Management of Patients with Hepatitis B

Editor’s Note: According to interim results of the phase 3 ALLIANCE trial, the triplet regimen bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is superior to dolutegravir plus tenofovir disoproxil fumarate (DTG + F/TDF) in the initial treatment in adults coinfected with HIV and HBV.^[1]

This transcript has been edited for clarity.

When we consider the epidemiology, there was a study through the HOP, the HIV Outpatient study, of US clinics. The Hepatitis B surface antigen (HBsAg) positivity rate in this cohort of over 8000 persons, primarily men who have sex with men, was 8.4%.^[2] By CDC criteria, an endemicity rate greater than 8% would be considered an endemic country. In the United States, persons living with HIV reach the threshold of endemicity. Coinfection with hepatitis B in the HIV positive population is 10- to 20-fold higher than we would see in the general population. 

The US Military HIV Natural History Study was designed to evaluate patients living with HIV by hepatitis B status.^[3] Those with hepatitis B in a 10-year period had an 80% increased risk of progressing to a definition for AIDS, or even death. Certainly, we see that coinfected patients can have more severe complications not only from hepatitis B, but also from HIV. 

With hepatitis B, we see a lower conversion rate from E antigen to E antibody, and a slower conversion, or loss rate, of S antigen. Patients who are coinfected with hepatitis B are more at risk for complications in both domains if either the HIV or the hepatitis B is not well controlled. 

The screening for hepatitis B is composed of a panel for an S antigen, a core antibody, and an E antigen. If they're S antigen positive for greater than 6 months, that's considered chronic disease, and that's where we identify most of our patients. Most of our patients are asymptomatic, but positive for S antigen. 

The core antibody establishes exposure. That's the anchor. If they're core antibody positive, then they've been exposed to hepatitis B. Very rarely would that be a false-positive result. Again, the exposure is through shared modes of transmission, primarily blood-borne injection drug use or as a sexually transmitted disease, especially in men who have sex with men. 

There are occurrences of isolated core antibody among persons living with HIV that can be at a rate from 20% to 70%. Usually, that's because of immune dysregulation where persons are exposed and their surface antibody has not risen to the level of detection. Those persons may actually be in zero recovery, and not chronically infected. A smaller proportion of patients would have S antigen that would not be at the threshold for detection. 

If there's a concern among providers—if the LFTs are abnormal or elevated and cannot be explained by any other criteria and serology is negative, then hepatitis B DNA can be ordered. If that's positive, that's occult hepatitis B, which occurs in about 10% of patients.^[4] The risk factor for that, again, is probably poorly controlled HIV. 

How do we address therapy? Every patient with HIV should be started on antiretroviral therapy right away. Every patient with hepatitis B should be started on therapy, which includes two drugs that are both active against HIV and hepatitis B, specifically the tenofovir-based drugs, either TDF (tenofovir disoproxil fumarate) or tenofovir alafenamide, combined with lamivudine or emtricitabine. We should follow these patients with a HBV-DNA level every 6 months. They should have a two-log drop within the first 6 months. Then hopefully, they should be virologically suppressed within about a year. 

The viral loads for hepatitis B are orders of magnitude higher than HIV, so the virologic decay may be slower. In about 15% of cases, we see that the HIV is virologically suppressed, but the hepatitis B is still detectable.^[5] Where do we move to look at the reasons for virologic non-suppression in the hepatitis B side of the equation? We need exquisite adherence to both the tenofovir-based drugs and either lamivudine or emtricitabine. 

Adherence levels of less than 95% have been determined to be a risk factor for not achieving virological response for hepatitis B.^[6,7] Prior exposure to lamivudine will also translate to a slower response for hepatitis B virologic decay. Both S antigen positivity and a higher viral load level can indicate that there may be a slower response rate to the dual NUC (nucleoside/nucleotide) therapy for hepatitis B even though it’s controlling the HIV. Cohort studies, including the CNICS in the United States and other studies in Europe, have examined this.^[8] 

For those patients with a one-log increase or viral rebound from their nadir for hepatitis B, we should first check for hepatitis delta (HDV), which is a coinfection that is transmitted via the same mechanisms as hepatitis B.^[8] Hepatitis delta does not respond to oral antivirals, so it should be checked. If either that antigen or antibody is positive, then we should check hepatitis delta DNA. 

We can check for resistance. Of note, with tenofovir—a very potent agent—we do not see, phenotypically, resistance to tenofovir. We can get that resistance test and perhaps they might be resistant to the lamivudine or the emtricitabine. 

Those resistance rates, in the setting of non-adherence, can emerge quite quickly, even within a matter of weeks or months. After a period of years, most patients, if they're not adhering to their therapy, will be resistant to the lamivudine or emtricitabine. For those patients, we first need to make sure that we emphasize strict adherence to their antiretroviral therapy. We can also intensify hepatitis B therapy by adding entecavir. 

Entecavir is a very potent hepatitis B drug, but it also has anti-HIV activity. Entecavir should not be used alone for HIV; it should only be used in the setting of HIV virologic suppression so we don't promote any type of HIV resistance or the M184V resistance mutation in the setting of entecavir monotherapy. That's how we monitor our patients and how we look for a virologic response. 

When we look to see who should be screened for hepatocellular carcinoma, again, everybody should have noninvasive staging, either serologically or with FibroScan. Then, they should have a liver ultrasound at baseline. Those patients who need to be followed and screened on a 6-month basis with imaging (primarily ultrasound) are the same as in hepatitis B monoinfection. 

A higher rate of hepatocellular carcinoma is seen in: patients with cirrhosis, a family history of cirrhosis, active hepatitis B with elevated ALT and a viral load of over 100,000, Asian males aged greater than 40, Asian females aged greater than 50, African Americans, and Africans. 

Hepatocellular carcinoma can occur in the absence of cirrhosis. It's different than hepatitis C in that regard we do not need the stepwise progression to cirrhosis for hepatocellular carcinoma to develop in hepatitis B infection. Hepatocellular carcinoma can happen at any fibrosis state in hepatitis B infection. 

Finally, for patients who are living with HIV, and do not have hepatitis B, and are well controlled on their tenofovir-based regimens, tenofovir itself actually acts as prophylaxis. Those patients who are not actively infected with hepatitis B should be vaccinated for hepatitis B, and they should be reassured that if they're taking tenofovir, that should double their comfort level that they're protected against getting hepatitis B. 

All patients with HIV should be screened for hepatitis B and vaccinated if not immune. 

The virologic response rates for hepatitis B may be slower than for HIV. Exquisite adherence to tenofovir plus lamivudine or emtricitabine enhances hepatitis B virologic suppression over time. 

Finally, we should monitor HBV-DNA levels every 6 months. As HIV providers, we are sometimes not as on top of the game when it comes to looking closely at hepatitis B. We need to make sure that we have those labs in every 6 months—we need to do a better job. 

Importantly, with appropriate monitoring, we're able to keep track of hepatitis B and to avoid the inadvertent discontinuation of tenofovir that would put a person at risk for hepatitis B flares which can be quite severe. Liver failure, need for transplantation, or death can occur when tenofovir is discontinued from the regimen, most likely for HIV purposes. 

When tenofovir needs to be discontinued, we can then provide an alternative agent, entecavir, to control the hepatitis B and prevent those severe consequences.