[Robert Brown]

Hello everyone, I’m Dr. Robert Brown. My colleagues in this presentation are Dr. Kim Brown and Dr. Carrie Frenette.

[Kim Brown]

Thank you, Bob. It’s great to be here today.

[Carrie Frenette]

Yes, thank you. We are excited about sharing this timely information with you!

[Robert Brown]

Great! Let’s get started.

[Robert Brown]

We are here today to discuss the latest expert guidance regarding the management of chronic hepatitis B. This is a non-CME educational video which is sponsored by Gilead Sciences.

Today we are going to talk about the rationale for earlier treatment of chronic hepatitis B. We will review the evolution of hepatitis B guidelines and recommendations, including the most recent AASLD/IDSA guideline updates. That will be followed by an overview of antiviral treatment, and we will conclude with additional resources.

We will start off with Dr. Kim Brown reviewing the rationale for earlier treatment of chronic hepatitis B.

[Kim Brown]

Thank you, Bob.

[Kim Brown]

As we've come to know, hepatitis B virus does increase the risk of hepatocellular cancer. Hepatitis B virus is classified as a group one carcinogen, and this means that the hepatitis B virus can cause cancer in humans. This would be similar to other group one carcinogens, such as cigarettes and asbestos, which can cause cancer in humans.

People with chronic hepatitis B have a high risk of hepatocellular cancer, with a 25- to 37-fold increased risk of liver cancer compared to non-infected people.

So, it becomes important to understand the risk that patients with chronic hepatitis B have with respect to cancer progression.

[Kim Brown]

The mechanisms that influence the risk of developing hepatocellular cancer can be both direct as well as indirect. And what's important to understand is that these may occur at early stages of tumor development and during any phase of hepatitis B infection.

Hepatitis B virus can lead to chronic hepatitis, which is chronic inflammation of the liver. And there are several mechanisms that contribute, over time, to the development of liver cancer. These include direct mechanisms, such as integration of hepatitis B DNA into the host genome, which occurs virtually at the time of infection, and also chromosomal instability.

There are also indirect mechanisms as liver damage occurs and the inflammation continues and fibrosis progresses. This process accelerates the development of liver cancer. Considering both the direct and indirect mechanisms, although hepatocellular cancer is typically thought of as arising in patients who have cirrhosis, about 20% of hepatitis B-associated hepatocellular cancer develops in the absence of cirrhosis, in large part because of some of these direct mechanisms.

[Kim Brown]

It is important to note that hepatocellular cancer can occur at any phase of hepatitis B infection, at the beginning, at the middle and at the end.

Integrations of hepatitis B DNA into the hepatocyte genome are detectable at all phases of chronic hepatitis B, and are initiated within hours of infection.

The risk of hepatocellular cancer is generally proportional to the level of HBV DNA. But again, when you look at all of the phases of hepatitis B, e-antigen positive chronic infection, e-antigen positive chronic hepatitis, e-antigen negative chronic infection, e-antigen negative chronic hepatitis, and then the surface antigen negative phase, there is an increased risk of developing hepatocellular cancer at any of these phases.

[Kim Brown]

The level of ALT has often been considered as part of the decision-making process when thinking about who should receive antiviral treatment. Shown here is a meta-analysis of 19 clinical studies. There were more than 2700 patients who were treatment-naïve with chronic hepatitis B and normal ALT.

These data were derived from liver biopsies, and what you can see on the right is that 35% of patients who had normal ALT had significant inflammation and another 30% had significant fibrosis.

So, this is critically important when thinking about the guidelines and using ALT to see who should be treated, because again, about a third of these patients who had normal ALT, in fact, had abnormal liver biopsies when investigated.

[Kim Brown]

This is a general schema showing the guidance from the European Association for the Study of the Liver. The general idea has been to separate patients into those who should be treated and those who shouldn't be treated.

On the left, you can see patients who have low HBV DNA and normal ALT, and the guidance recommendation is to monitor them closely, but in some cases now it’s appropriate to consider treatment.

On the right, you can see that patients who are recommended for treatment were those who had elevated HBV DNA and elevated ALT and again, these patients were regarded as treatment candidates.

But for the most part, there is a significant percentage of patients who sit in the middle. These patients are described as being in the indeterminate or gray zone where it is recommended to monitor the patient over time to see which category they would eventually fall into. A 2015 study from the Hepatitis B Research Network cohort analyzed data from 1390 participants with chronic hepatitis B and found that 38% were in the indeterminate or gray zone when treatment was not clearly recommended. Most of these patients, when re-evaluated, are still in that zone. So, it’s important to rethink what happens to these patients, especially in light of their risk for hepatocellular cancer.

More recent guidelines and algorithms recognize the value of being proactive with these patients due to their risk for hepatocellular cancer, as described in the next chapter of this video.

[Kim Brown]

Now, Bob Brown will take us through the evolution of hepatitis B guidelines and recommendations, including the latest guidelines.

[Robert Brown]

Thank you, Kim.

HBV DNA >2000 IU/mL is associated with increased risks of developing cirrhosis, end-stage liver disease, and HCC. Ideally, HBV DNA levels may be reduced to undetectable levels during antiviral therapy. On the other hand, natural fluctuations in ALT and limited sensitivity and specificity in reflecting hepatic necroinflammation limit the value of ALT in predicting disease progression. For these reasons, guidelines have evolved to emphasize HBV DNA cutoffs more than ALT in the treatment recommendations, and the cutoffs for HBV DNA over time have been reduced.

You can see this in the evolution of the guidelines from both the AASLD as well as additional guidelines, including the Simplified Approach Hepatitis B Algorithm, or SABA, which we'll review later, EASL guidelines, and now even the Chinese guidelines. At the same time, as the HBV DNA cutoff has declined, the ALT cutoff has declined, including even a normal ALT if risk factors are present.

[Robert Brown]

And here you can see this in a tabular format where, certainly for HBeAg-negative, 2000 has been the cutoff for HBV DNA based on whether there is an elevated ALT, the presence of fibrosis, or other risk factors or age.

For those who are HBeAg-positive, most of them will have an HBV DNA above 20,000 and you can see that in the Chinese guidelines, virtually any detected HBV DNA is recommended for treatment if there is either fibrosis or an ALT that's abnormal.

[Robert Brown]

Now I will review the 2025 AASLD/IDSA guidelines.

On the bottom of the slide are those with the more advanced disease. Patients with cirrhosis should be treated regardless of the level of HBV DNA or ALT.

[Robert Brown]

Next, here you can see that HBeAg-positive patients who have an ALT ≥2x ULN should be treated. The guidelines defined immune-tolerant as HBeAg-positive with HBV DNA >10 million IU/mL with normal ALT. Immune-tolerant patients were previously recommended for monitoring. In the updated guidelines there is a recommendation for consideration for treatment through shared decision-making between the clinician and the patient as to the clinical evidence and consideration of treatment.

[Robert Brown]

HBeAg-negative patients have always been recommended for treatment if they have an abnormal ALT and an HBV DNA above 2000, but now you can see that in those with HBV DNA above 2000 with normal or slightly above normal ALT, you can consider shared decision-making, as well as those with HBV DNA under 2000 who have abnormal ALT.

[Robert Brown]

In addition to patients who are treated under this algorithm, there are certain high-risk scenarios where all patients should be considered for treatment. These are high-risk scenarios where transmission of HBV may pose a risk to others, including persons engaged in unprotected sex or with multiple partners, persons who inject drugs, persons living with susceptible household members, and healthcare workers performing exposure-prone procedures.

[Robert Brown]

Given the complexity of the other treatment guidelines and the need for treatment to expand beyond experts in academic centers, a group of expert clinicians came together to develop a practical algorithm. This is called the Simplified Approach Hepatitis B Algorithm or SABA. This was published in 2022.

Once again, they agree with the AASLD guidelines that anyone with cirrhosis should be treated regardless of the level of HBV DNA or ALT.

[Robert Brown]

To simplify the regimen, they draw the cutoff based on age, because age is a major risk factor for both disease progression and liver cancer risk.

Those who are over 30 years old and have any HBV DNA over 2000 would be treated regardless of ALT.

[Robert Brown]

For patients under age 30, those with an abnormal ALT would be treated with an HBV DNA over 2000.

Once again, like many experts, they recommended a lower level of ALT. In SABA, it's 30 for men and 19 for women. In the AASLD guidelines, it's 35 for men and 25 for women.

[Robert Brown]

Now, I will hand it over to Kim Brown to review VEMLIDY as a first-line treatment option for chronic hepatitis B.

[Kim Brown]

Thank you, Bob.

[Kim Brown]

Now, I would like to discuss the use of VEMLIDY.

VEMLIDY is indicated for the treatment of chronic hepatitis B infection in adults with compensated liver disease.

VEMLIDY carries a Boxed Warning for posttreatment severe acute exacerbation of hepatitis B.

Discontinuation of anti-hepatitis B therapy, including VEMLIDY, may result in severe acute exacerbations of hepatitis B. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VEMLIDY. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

Please stay tuned at the end of this video. Dr. Carrie Frenette will review additional Important Safety Information for VEMLIDY.

[Kim Brown]

When you look at all of the many guidelines that are out there for treatment of hepatitis B, VEMLIDY is recommended as a first-line hepatitis B therapy for appropriate patients with chronic hepatitis B. This is true for the AASLD/IDSA guidelines, the EASL guidelines, the simplified algorithm from SABA, the Chinese guidelines, which have become even less restrictive in terms of who should be treated. And then finally, the Asian American Treatment Algorithm.

All guidelines that are currently out there do recommend VEMLIDY as a first-line therapy for appropriate patients with chronic hepatitis B.

[Kim Brown]

And now, I would like to introduce Dr. Carrie Frenette who will provide more information on resources for VEMLIDY. Dr. Frenette.

[Carrie Frenette]

Thank you, Dr. Brown.

Gilead has support resources for patients with chronic hepatitis B. With the VEMLIDY Co-Pay Program, eligible patients with commercial insurance may pay as low as a $0 co-pay for out-of-pocket costs for VEMLIDY, up to $6000 per year with no monthly limit.

Support Path can help patients to understand their coverage and identify financial support options. To learn more, visit mysupportpath.com, and for multilingual assistance, call 1-855-769-7284, Monday through Friday, between 9 am and 8 pm Eastern Standard Time. These are subject to change and restrictions apply. See the full terms and conditions at mysupportpath.com/providers.

[Carrie Frenette]

Now, let’s review some additional Important Safety Information for VEMLIDY.

[Carrie Frenette]

Warnings and Precautions

Risk of Development of HIV-1 Resistance in HBV/HIV-1 Coinfected Patients: Due to this risk, VEMLIDY alone should not be used for the treatment of HIV-1 infection. Safety and efficacy of VEMLIDY has not been established in HBV/HIV-1 coinfected patients. HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with VEMLIDY, and, if positive, an appropriate antiretroviral combination regimen that is recommended for HBV/HIV-1 coinfected patients should be used.

New Onset or Worsening Renal Impairment: Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with TAF-containing products. Patients with impaired renal function and/or taking nephrotoxic agents (including NSAIDs) are at increased risk of renal-related adverse reactions. Discontinue VEMLIDY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Monitor renal function in all patients – See Dosage and Administration.

Lactic Acidosis and Severe Hepatomegaly with Steatosis: Fatal cases have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (TDF). Discontinue VEMLIDY if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity develop, including hepatomegaly and steatosis in the absence of marked transaminase elevations.

[Carrie Frenette]

Adverse Reactions

The most common adverse reactions (incidence ≥5%; all grades) in clinical studies through week 144 were headache, upper respiratory tract infection, abdominal pain, cough, back pain, arthralgia, fatigue, nausea, diarrhea, dyspepsia, and pyrexia.

Drug Interactions

Coadministration of VEMLIDY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir and the risk of adverse reactions.

Coadministration of VEMLIDY is not recommended with the following: oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, or St. John’s wort. Such coadministration is expected to decrease the concentrations of tenofovir alafenamide, reducing the therapeutic effects of VEMLIDY. Drugs that strongly affect P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) activity may lead to changes in VEMLIDY absorption.

Consult the full prescribing information for VEMLIDY for more information on potentially significant drug interactions, including clinical comments.

Dosage and Administration

Testing Prior to Initiation: should include HIV infection.

Prior to or When Initiating, and During Treatment: On a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.

The dosage in adults is 1 tablet taken once daily with food.

Renal Impairment: It’s not recommended in patients with end stage renal disease (ESRD; estimated creatinine clearance <15 mL/min) who are not receiving chronic hemodialysis; in patients on chronic hemodialysis, on hemodialysis days, administer VEMLIDY after completion of hemodialysis treatment.

Hepatic Impairment: Not recommended in patients with decompensated (Child-Pugh B or C) hepatic impairment.

Pregnancy and Lactation

Pregnancy: A pregnancy registry has been established for VEMLIDY. Available clinical trial data show no significant difference in the overall risk of birth defects for VEMLIDY compared with the background rate of major birth defects in the U.S. reference population.

Lactation: TAF and tenofovir can pass into breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VEMLIDY and any potential adverse effects on the breastfed infant from VEMLIDY or from the underlying maternal condition.

[Robert Brown]

Thank you for joining us today for this discussion about the 2025 AASLD/IDSA guidelines and how earlier treatment may be an option for your appropriate adult patients with chronic hepatitis B.

[Kim Brown]

Thank you, Bob. And yes, thank you for joining us, we hope that today’s video will aid you in the management of your patients with chronic hepatitis B.

[Carrie Frenette]

Thanks so much for joining us!