G&H Why was a new hepatitis B virus management guideline recently created?
MN There have been many advances in terms of our understanding of the natural history of hepatitis B virus (HBV) and also cumulative knowledge over the past two-plus decades that the antiviral medications currently used for first line are effective and safe. Additionally, we are looking toward a future with HBV cure. There is more motivation for providers to diagnose patients infected with HBV and control the disease, hopefully not just to prevent future complications but also to eliminate the infection with an HBV cure that will hopefully be coming soon.
It is important to note that this guideline, which was released online at the end of 2025 and published in April 2026 in Hepatology by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA), differs from a guidance. A guidance gives more leeway for expert recommendations and is less stringent on the requirement of data. In contrast, a recommendation cannot be made in a guideline without sufficient supporting data, as determined by a methodology team assigned to the guideline committee. In other words, a guideline makes recommendations, whereas a guidance makes suggestions. There are pros and cons with each. In my opinion, it is better to be able to make a strong recommendation than just a suggestion. However, a guideline is also quite restrictive. The major shortcoming of the 2025 guideline is the lack of sufficient data on certain issues to make a recommendation and the inability to even make suggestions that make sense clinically from circumstantial data.
G&H What does this guideline recommend for preventing vertical and horizontal transmission?
MN Vertical transmission, from mother to child, is probably the main route of transmission that creates a reservoir of chronic infection globally as well as in the United States. Standard practice is to give a birth dose vaccine and then complete the rest of the vaccine series in the first 6 months of the infant’s life as well as give hepatitis B immune globulin (HBIG) because active vaccination takes time to develop; HBIG covers the first several weeks while babies are developing their own immunities. However, the breakthrough rate with this standard practice can be anywhere from less than 1% up to 20%, depending on maternal HBV DNA level at the time of birth. The recommendation in the 2025 guideline is the same as in the 2008 guidance, as well as practically all other HBV guidelines in the world, that 200,000 IU/mL should be the cutoff for maternal antiviral therapy. The only change in terms of vertical transmission is the addition of tenofovir alafenamide (TAF) as an option, along with the long-established option of tenofovir disoproxil fumarate (TDF). There is no known advantage between TAF and TDF. However, the real-world pregnancy data available for TAF, especially regarding safety, are minuscule compared with TDF. In my practice, I still use TDF in this setting. Providers should have an informed discussion with their patients regarding these details.
As for horizontal transmission, this is the first time that the AASLD/IDSA HBV management guideline addresses this issue. Previously, there had been no recommendations for treating someone simply to prevent that person from transmitting HBV infection to the household or other close contacts. This guideline recommends that treatment be considered in people who are at high risk for transmitting the infection to others, whether in a workplace setting, in their interpersonal relationship, or in the household. There are very little data for this recommendation, but given the safety of the medications available currently as well as the risk of transmission, the committee felt that it was reasonable to make treatment at least an option for interested patients in this setting.
G&H How does the guideline recommend managing patients in the immune-tolerant phase?
MN Historically, the recommendation was generally not to treat immune-tolerant patients. More recently, the recommendation has become to consider treating immune-tolerant patients who are older. In general, most agree with this recommendation, but defining which patients are older is a little controversial and the cutoff usually ranges from 30 to 45 years because the data are limited and studies have used varying age cutoffs. The 2025 guideline recommends treatment of patients with immune-tolerant HBV infection and no cirrhosis if their fibrosis is stage 2 or higher or the patient is 40 years or older. This is not new, but the guideline also includes a clause to consider discussion of treatment with patients younger than 40 years. This has pros and cons. It is good to offer the option of treatment to younger patients. This can be helpful because some payers use guidelines to approve or deny coverage. On the other hand, this clause can leave matters a little confusing for patients and providers. However, with the current lack of data, it is difficult to be definitive about an exact age cutoff.
G&H What is recommended for individuals in the hepatitis B e antigen–negative indeterminate phase?
MN Encompassing approximately 40% of the hepatitis B population, this is a very large group of patients who do not fit into the 4 main groups of hepatitis B phases. Therefore, this is a large and important group that should be considered carefully. Essentially, indeterminate patients are those with high HBV DNA levels but their alanine aminotransferase (ALT) level does not quite meet the threshold of higher than 2 times the upper limit of normal (the treatment criteria for active HBV infection according to the AASLD/IDSA guidelines) or those who have elevated ALT but HBV DNA below the cutoff (20,000 IU/mL for hepatitis B e antigen [HBeAg]-positive patients and 2000 IU/mL for HBeAg-negative patients). However, many providers, myself included, probably consider patients with any ALT elevation (and in some cases even normal ALT) and HBV DNA above 2000 IU/mL to have active HBV infection regardless of HBeAg status. It is also worth noting that this updated AASLD/IDSA guideline still requires classification by HBeAg status, unlike other updated international guidelines, which generally use the same HBV DNA and ALT criteria for HBeAg-positive or -negative status. In a nutshell, HBeAg-positive indeterminate patients should be treated like immune-tolerant patients and should receive antivirals if they also have stage 2 fibrosis, are 30 years or older, or have family history of cirrhosis or liver cancers. For HBeAg-negative patients with HBV DNA less than 2000 IU/mL, the guideline continues to recommend no treatment even if ALT is elevated. This may be difficult for some providers and patients because if their HBV DNA is, for example, only 1500 IU/mL and their ALT is elevated to more than 2 times the upper limit of normal, does that mean the patient does not have active HBV infection? It can be argued that for this patient, in the absence of another cause of ALT elevation, the low-level HBV viremia may be enough to cause problems, and treatment may be beneficial. Although the current recommendation is no treatment in such a case, it is important to remember that this is only a guideline; it is ultimately the provider who makes the decision they feel is best after evaluating the patient carefully and discussing with the patient the pros and cons of treatment vs no treatment. If the patient has HBV DNA over 2000 IU/mL and ALT less than 2 times the upper limit of normal, the guideline recommends considering treatment and taking into account other potential risk factors, such as male sex, age over 40 years, and family history of liver cancer. I would also consider other risk factors this guideline does not include. Some guidelines include immunosuppressive medications, which can accelerate the development of cancer and fibrosis in general, and metabolic disease such as fatty liver and diabetes. The 2024 World Health Organization’s guidelines take into account concurrent liver diseases, family history, and other factors that contribute to long-term adverse outcomes, such as other comorbidities like diabetes and immunosuppression, which are known to increase the risk of liver cancer.
G&H Does the guideline recommend discontinuing nucleos(t)ide analogue therapy until hepatitis B surface antigen loss?
MN There have been emerging data on discontinuation of nucleos(t)ide analogue therapies in patients before hepatitis B surface antigen (HBsAg) loss. A large body of literature suggests that there is a small but finite risk of severe flares, liver decompensation, and even death after withdrawing nucleos(t)ide analogue therapy before HBsAg clearance in patients with chronic HBV infection. There is also literature suggesting that stopping nucleos(t)ide analogue therapy may boost the HBsAg clearance rate. Given the fairly limited data as well as the lack of real-world data to support safety of the withdrawal strategy, the current guideline generally recommends no discontinuation unless HBsAg clears first and only in patients who have no prior liver decompensation. In a patient with severe cirrhosis and hepatic decompensation, the recommendation is to continue therapy even after HBsAg clearance because HBV infection can still reactivate, which can place these patients at high risk for serious liver complications.
G&H When is liver cancer surveillance recommended in the new guideline?
MN Liver cancer surveillance is an important issue and should be considered whether the patient meets treatment criteria or not. Previously, liver cancer surveillance was not specifically addressed for HBV patients coinfected with hepatitis delta virus (HDV), HIV, or hepatitis C virus (HCV), nor was it addressed in patients who clear HBsAg or achieve HBV functional cure. HBV/HDV coinfection is well-recognized as a high risk for liver cancer, so the recommendation is to survey all of these coinfected patients regardless of disease stage, age, sex, and birthplace. Additionally, the current guideline recommends surveying patients coinfected with HIV who are men aged 18 years or older or women aged 40 years or older. This recommendation is made with the assumption that HIV-infected patients in the United States are now all on HIV-suppressive therapy so their HIV is well-controlled. As for patients with HCV coinfection, the assumption is that they should be treated for HCV first. Once they are cured, their liver cancer surveillance should be similar to that for patients with chronic HBV monoinfection. The data to support (or not) any of these recommendations are quite minimal. One may ask whether an HBV/HIV-coinfected patient who is female and 35 years old should be surveyed? The guideline uses a cutoff of 40 years, but, in my opinion, this should be discussed with the patient. Some providers may feel inclined to offer surveillance for younger patients as well.
As for patients after HBV functional cure, there have been many reports in the literature of a potential increased risk of liver cancer in these patients and generally in those who clear HBsAg at a latter age. The specific age is controversial—is it 40, 45, or 50 years? The guideline recommends continuing surveillance after functional cure for all patients with cirrhosis, which I think is reasonable because cirrhosis of any etiology is an established risk for liver cancer. Surveillance is also recommended for patients with family history of liver cancer in men older than 40 years and women older than 50 years at the time of HBsAg loss. This cutoff is not based on the best data, but I think the 40-year cutoff for men is reasonable. However, the 50-year cutoff for women is less clear; how is that different from 45 years, for example? In my practice, I discuss with the patient that this cutoff was not established based on a lot of data and offer surveillance for women who clear HBsAg after 40 years of age if the patient is interested. I also fully disclose to the patient the fact that data to support any of these age cutoffs are sparse. It is just known that most reported cases of liver cancer occurring after HBsAg clearance occur in patients older than 40 years.
As for HBV-monoinfected patients, which make up the largest group, the guideline committee did not conduct a new literature search or their own analysis. The guideline released in November 2025 adopted the liver cancer surveillance recommendations for HBV patients from the guidance released in 2023. The recommendation made by the 2023 guidance is to survey men older than 40 years from endemic countries and women older than 50 years from endemic countries as well as people from Africa at an earlier age and those with a family history of liver cancer or a PAGE-B score of 10 or higher. The PAGE-B score was developed in Europeans receiving nucleos(t)ide analogue therapy and is only one of many liver cancer score options, some of which have been shown to perform better than this score. If a patient is not being treated, a different scale should be used such as the REACH-B score, which was developed by the REVEAL group many years ago for untreated patients. The REAL-B score was developed in treated HBV patients and is one of the few scores that take into account diabetes, which is now an increasing problem. There are many resources online for different scores that can be used, and I would encourage providers to become familiar with one that they feel most comfortable with and use it for their patients.
The age cutoffs adopted by the hepatocellular carcinoma AASLD 2023 guidance that were then followed by the AASLD/IDSA 2025 guideline were often cited because of the lack of data showing benefits of surveillance in men younger than 40 years and women younger than 50 years. However, if there is a lack of data showing something, that does not mean it does not exist; one needs to consider the risk and benefit of the intervention in such a situation. Because of the lower risk of liver cancer in younger patients and the generally small sample size of younger patients in various cohort studies of HBV, most analyses were underpowered to accurately estimate liver cancer risk for the younger population, which is often interpreted as negligible risk. Emerging data suggest that women younger than 50 years could have a liver cancer risk of 0.2% per year, which meets the threshold for cost-effective surveillance. This guideline provides a good framework to base our practice on, but whether we should recommend or dismiss a particular patient from surveillance should depend on deeper discussion of the patient’s overall risk and the suboptimal data that some of these recommendations are based on.
G&H What does the guideline not address? What further research and guidelines are needed in the future?
MN Previous guidances and other guidelines around the world agree that patients with severe liver disease such as cirrhosis should be treated with antivirals, regardless of ALT or HBV DNA levels. However, this guideline did not address another group of patients with severe liver disease—those with liver cancer. Fortunately, the European Association for the Study of the Liver guideline recommends treatment for liver cancer patients without further requirement of any particular threshold of fibrosis, HBV DNA, or ALT, and that has been my practice for many years. Even though this 2025 guideline does not address this, liver cancer is considered an even more severe form of liver disease and cirrhosis, so I think providers should consider HBV treatment in liver cancer patients. There is a large body of literature showing significantly improved long-term survival of patients with HBV-associated liver cancer with antiviral treatment, and HBV antivirals are much less expensive and much better tolerated than almost all liver cancer treatments. There are still a lot of gaps where patients and providers could use more guidance in regard to indeterminate patients. The 2025 guideline added to the previous guidance and emphasizes shared decision-making with the patient, but providers who are not seeing several HBV patients each day or each week may appreciate more specific guidance than just suggestions to consider. Additionally, the current
recommendations, in my opinion, are still too complicated. HBV linkage to care is very poor; lots of data have shown that only approximately 20% of HBV patients in the United States have been diagnosed, and only a fraction of these patients have been treated. Even among cirrhosis and liver cancer patients, only 30% to 50% have received antivirals. One of the major reasons, I believe, is that the complexities of the guidelines have made them confusing and do not make it easier for providers to use them or to treat more patients. I hope future guidelines can simplify matters further to make them more accessible for a broader community of providers. I also think future guidelines should dig deeper and reconsider the recommendations for liver cancer surveillance.
Disclosures
Dr Nguyen has received research funding via Stanford University from Pfizer, AstraZeneca, GSK, Delfi, Inogen, Exact Sciences, Curve Biosciences, Gilead, Helio Genomics, the National Institutes of Health, Roche, and Aligos; and has done consulting and/or served on the advisory board for GSK.
Suggested Reading
Ali FS, Nguyen MH, Hernaez R, et al. AGA clinical practice guideline on the prevention and treatment of hepatitis B virus reactivation in at-risk individuals. Gastroenterology. 2025;168(2):267-284.
European Association for the Study of the Liver. EASL clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2025;83(2):502-583.
Ghany MG, Pan CQ, Lok AS, et al. AASLD IDSA practice guideline on treatment of chronic hepatitis B. Hepatology. 2026;83(4):974-997.
Huang R, Do AT, Toyoda H, et al. Distribution, characteristics, and natural history of diverse types of indeterminate chronic hepatitis B: a REAL-B study. Aliment Pharmacol Ther. 2025;62(3):349-358.
Huang R, Trinh HN, Yasuda S, et al. Differential HCC risk among HBV indeterminate types at baseline and by phase transition. Gut. 2025;74(11):1873-1882.
Pan CQ, Saadi S, Ghany MG, et al. Technical systematic review supporting the 2025 AASLD practice guideline on management of chronic hepatitis B. Hepatology. 2026;83(4):998-1019.
World Health Organization. Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection. https://www.who.int/publications/i/item/9789240090903. Published March 29, 2024. Accessed June 15, 2026.