Functional Cure of Hepatitis B Infections Among Patients Coinfected With HIV

Disclosure: The authors have nothing to disclose.

Abstract

Objectives

In patients with hepatitis B, functional cure is defined by loss of hepatitis B surface antigen. Some studies have suggested that up to 10% of patients coinfected with HIV and hepatitis B virus (HBV) achieve functional cure. The primary objective of this study was to determine the incidence of functional cure among patients coinfected with HIV/HBV who were taking a tenofovir-based antiretroviral therapy (ART) regimen.

Study Design

This was a single-center, prospective, institutional review board–approved, interventional study conducted at the Cone Health Regional Center for Infectious Diseases clinic in Greensboro, North Carolina, from August 1, 2024, to February 28, 2025.

Methods

Patients were included if they were 18 years or older, had confirmed HIV and HBV diagnoses, and were currently receiving care at the local infectious diseases clinic. The primary outcome was the incidence of functional cure of hepatitis B.

Results

A total of 37 patients were included in this study. Two of the 37 (5.4%) achieved functional cure of HBV after being treated with long-term ART (95% CI, 0.7%-18.2%). Ultimately, labs were collected in only 74% of appointments due to logistical constraints. No patients who achieved functional cure of HBV were eligible for HBV revaccination due to the production of hepatitis B antibodies at the time of cure. One patient with functional cure of HBV developed a hepatitis B antibody level of 10, indicating full immunity.

Conclusions

The incidence of functional cure among patients coinfected with HIV and HBV was lower than previously reported rates in the literature. Further local studies are needed to evaluate the most appropriate means of properly monitoring this unique patient population.

Introduction

HIV affects approximately 1.2 million people in the US. Among these patients, it is estimated that approximately 10% are coinfected with chronic hepatitis B virus (HBV).¹ Both viral infections share similar routes of transmission (eg, blood product exposure or unprotected sexual intercourse); thus, patients with HIV are recommended to undergo HBV screening.² HIV/HBV coinfection poses a global public health threat due to the higher risk of mortality and rapid progression of liver-related complications, such as cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC).³ Liver-related mortality is deemed the second most common cause of death in this patient population. This high disease burden is influenced by countries’ level of development, HIV prevalence, and health disparities.⁴ The US Department of Health and Human Services (HHS) Panel on HBV/HIV coinfections and 2024 Infectious Diseases Society of America guidelines for HIV recommend treating all coinfected patients with hepatitis B antibodies (anti-HBs) with anti-HBV–active antiretroviral therapy (ART).^2,5

Available agents with activity against HBV and HIV include tenofovir alafenamide (TAF, Vemlidy; Gilead Sciences), tenofovir disoproxil fumarate (TDF, Viread; Gilead Sciences), emtricitabine (FTC, Emtriva; Gilead Sciences), and lamivudine (3TC, Epivir, Epivir-HBV; ViiV Healthcare, GSK). Thus, an appropriate regimen to treat coinfection would include TAF or TDF plus 3TC or FTC as the nucleoside reverse transcriptase inhibitor backbone.² In addition to routine HIV care, baseline and routine laboratory monitoring for hepatitis B is recommended every 3 to 6 months, but at a minimum, yearly.^5-7 The proposed treatment goal of chronic hepatitis B is defined by the clearance or loss of its serum surface antigen (HBsAg), known as functional cure.⁸ Functional cure can occur spontaneously, after an acute hepatitis B infection, or during antiviral treatment. Functional cure rates among monoinfected individuals are rare, only affecting 1% to 5% of patients within 7 years of starting ART.^8,9 Studies have shown higher rates of functional cure—up to 10%—among coinfected patients, possibly due to long-term exposure to ART.^10,11 In a prospective cohort study in Zambia, rates of functional cure in coinfected patients receiving tenofovir-containing ART were evaluated. Among 289 patients, with a mean follow-up of 6 years, HBsAg seroclearance rates were approximately 9.5% and 15.4% after 2 and 5 years of ART, respectively.¹² This rate was higher than what is typically observed in tenofovir-treated HBV monoinfections.

Because the most common ART regimens studied in patients with HIV/HBV coinfection included a combination of TDF with 3TC or FTC, this is the most widely recommended treatment.¹³ An increased rate of HBsAg clearance has been associated with favorable clinical outcomes, such as reduced incidence of cirrhosis and HCC.⁸ Because of the risk of flares and serious hepatocellular injury, even after achieving functional cure, it is recommended not to discontinue agents with anti-HBV activity.⁶ It is paramount to revaccinate functionally cured patients to help stimulate the production of anti-HBs, which would ultimately confer protection against HBV flares and possible reactivation. Of note, an anti-HBs level of at least 10 mIU/mL is considered protective against HBV by the CDC.⁶

Moreover, it is essential to evaluate the incidence of functional cure in health care settings where patients coinfected with HIV/HBV are being treated and to ensure that their management is aligned with current guideline recommendations (eg, treatment regimens, frequency of lab monitoring, vaccination completion). The primary objective of this study was to determine the incidence rate of functional cure among HIV/HBV coinfected patients who are taking a tenofovir-based ART regimen.

Methods

Study Design

This was a single-center, prospective, institutional review board–approved, interventional study that included coinfected patients receiving care at the Cone Health Regional Center for Infectious Diseases (RCID) clinic in Greensboro, North Carolina, which serves approximately 1700 patients. The prospective population contained patients with hepatitis B or HIV follow-up appointments between August 1, 2024, and February 28, 2025. It is important to note that coinfected patients are not generally treated by the onsite RCID pharmacists. For this reason, the interventions in this study were conducted remotely. The study population was identified using a report that included patients who were receiving care at the RCID, drawn from a report spanning approximately 10 years. From this report, a review of patients’ ART regimens was conducted to ensure the inclusion of a tenofovir-containing regimen and the remaining inclusion criteria.

Study Population

Patients were included if they were 18 years or older, had confirmed HIV and HBV diagnoses, and were currently receiving care at the RCID clinic. Patients were excluded if they were lost to follow-up at the RCID clinic, diagnosed with hepatitis C viral infection, not receiving treatment with a tenofovir-containing therapy, or currently involved in another research study.

Data collected for this evaluation were obtained from the institution’s electronic medical record (EMR). Patient characteristics included age, sex, race, year of HIV and HBV diagnoses, current ART regimens, and duration of current ART regimen. Baseline and current labs collected included HIV RNA, HBV DNA, HBsAg, CD4 count, and aspartate aminotransferase/alanine aminotransferase. For patients with functional cure, the date of achievement was collected. For patients eligible to receive the HBV vaccine (functional cure without the presence of anti-HBs), hepatitis B vaccine (recombinant), adjuvanted (Heplisav-B; Dynavax Technologies), the vaccination series dates and dates of detectable anti-HBs production post vaccination were also collected.

Study Protocol

Before the start of this project, the RCID physicians were made aware of the intervention and shared oversight for the overall monitoring of this population. The standard workflow was as follows: If a patient coinfected with HIV/HBV was identified as not on a tenofovir-containing therapy, the pharmacist reached out to their provider to get their therapy changed to a regimen containing tenofovir. For all patients meeting the inclusion criteria, the pharmacist verified that they had follow-up appointments scheduled in their EMR. For patients whose last appointment was 6 to 12 months prior and who did not have an upcoming appointment noted in the last charted RCID progress note, the pharmacist contacted the RCID-certified medical assistant to schedule an office visit.

Subsequently, HBsAg and/or anti-HB labs were ordered by the pharmacist 1 to 3 weeks before patients’ appointments. These labs were noted as a future order, and appointment notes were attached to the new encounter as a reminder to collect the labs. Within 24 to 48 hours of patients’ visits, providers were notified of these orders via secure EMR messaging. Approximately 3 to 5 days after appointments, the pharmacist reviewed patients’ charts to ensure that the labs ordered were collected. Upon verification, the pharmacist recorded lab results and identified any patients who met the primary end point. Patients who did not meet the primary end point must undergo continual monitoring of their HBsAg beyond the completion of this research project.

For patients found to have functional cure of hepatitis B (nonreactive HBsAg) with an antibody level below the CDC threshold of 10 mIU/mL, the pharmacist ordered a hepatitis B vaccination for their follow-up appointment. Revaccination was not completed for patients with full immunity against HBV. For patients requiring revaccination, anti-HB status on the hepatitis B titer test was evaluated 1 to 2 months after the last vaccine dose to confirm antibody production post vaccination.

Study Objectives and Data Analysis

The primary outcome of this study was the incidence of HBsAg loss among included patients coinfected with HIV/HBV, defined by a negative HBsAg result. The secondary outcome was lab stewardship within the RCID clinic, measured as the proportion of labs ordered relative to the proportion collected. Subgroup analyses included a description of functionally cured patients, relating to the proportion of those who completed the hepatitis B revaccination series and the incidence of HBV antibody production after revaccination (determined by positive anti-HBs on a hepatitis B titer test). For the statistical analysis, descriptive statistics were used to analyze categorical variables. The primary outcome was analyzed using the Clopper-Pearson method to calculate binomial 95% CIs.

Results

A total of 111 coinfected patients were evaluated for inclusion in this study. Seventy-four were excluded due to not being coinfected with HIV/HBV, death/hospice, participation in another research study, or not being a current RCID patient (lost to follow-up/no-show, moved/relocated, death). The Figure details the exclusion breakdown. Overall, 37 patients met the inclusion criteria. All coinfected patients were appropriately maintained on a tenofovir-based regimen.

Regarding the primary outcome, 2 (5.4%) patients achieved functional cure, as indicated by a negative HBsAg result (95% CI, 0.7%-18.2%). Functional cure was achieved after approximately 5 years since their HBV diagnosis and after 3 to 6 years of their current ART regimen. Regarding the secondary outcome, labs were ordered for 31 appointments. The remaining 6 patients were unable to be evaluated because their appointments fell outside the study period. Overall, labs were collected in approximately 74% (n = 23) of appointments due to logistical constraints related to the standard laboratory workflow. For example, during patient office and laboratory visits, lab technicians were unable to view future orders for some patients.

Furthermore, the subgroup analysis examined the characteristics of the 2 patients who achieved functional cure of HBV. Patient 1 was aged 46 years and had received a diagnosis of HBV infection 4 years previously and HIV infection 12 years previously. In addition, this patient was appropriately initiated and maintained on a tenofovir-based therapy (BIC/F/TAF). Patient 2 was aged 58 years and had received a diagnosis of HBV and HIV infections 5 years previously. They were also appropriately initiated (EVG/c/F/TAF) and maintained (BIC/F/TAF) on a tenofovir-based therapy. A description of these patients’ characteristics is presented in Table 1.

Regarding their baseline labs, hepatitis B e-antigen was not collected in either patient, which would have provided additional insight into predicting the incidence of functional cure. The baseline HBV DNA level for patient 1 was undetectable, whereas that of patient 2 was less than 10 IU/mL (Table 1). These findings are indicative of HBV suppression; however, because their HBsAg was reactive at baseline, they did not have complete clearance of the virus. An important therapy end point for patients after achieving HBV cure is the development of antibodies (Table 2). Interestingly, both patients were ineligible to receive the hepatitis B vaccine because they both developed anti-HBs at the time of their HBsAg seroconversion. Additionally, patient 2 developed an anti-HBs level of 10 mIU/mL, indicative of complete protection against HBV. However, it is unknown whether patient 1 reached this threshold because the appropriate quantitative anti-HB was not ordered.

Discussion

In this study, functional cure was rare, with an incidence rate of approximately 5%. This result was lower than the rates reported in primary literature, likely due to the low sample size, large exclusion, and short follow-up period. As with historical data, a functional cure was achieved after long-term use of tenofovir-based ART. A single-center study in China, which included patients on at least 12 months of ART therapy, found HBsAg seroclearance rates of 11.3% with a median follow-up of approximately 5 years.⁴ Other studies have also identified HBV functional cure incidence rates; however, this was primarily with a follow-up period of 2 to 10 years. There are currently no reported data on anticipated functional cure rates within a time span that aligns with this study’s duration. In addition, this study showed that HBV revaccination eligibility heavily depends on the appropriate ordering of quantitative rather than qualitative surface HBV antibody labs.

Although this study did not evaluate long-term clinical outcomes after HBsAg clearance in patients coinfected with HIV/HBV, there have been several studies assessing this aspect of their disease course. A more recent prospective observational cohort study conducted in Zambia demonstrated that long-term adherence to tenofovir-based ART led to positive outcomes.¹² This included significant regression rates of liver fibrosis and cirrhosis, no cases of hepatocellular carcinoma, and seroclearance rates of approximately 15.4% over a follow-up period of 6 years. It can be extrapolated that the 2 patients who achieved functional cure of hepatitis B in our study likely have an improved prognosis relating to liver-related mortality.

One practice-changing area identified in this study concerned oversight of HBV lab monitoring in coinfected patients. This study revealed a lack of standardization in this area. Several coinfected patients had not had recent labs for a few years since their initial HBV diagnosis. For example, for patient 1, there was an approximately 5-year gap between their last HBV-related labs and those obtained in this study, despite having regular office visits at the RCID clinic. Therefore, this study can be used to encourage more frequent hepatitis B monitoring that aligns with HHS guidelines (ie, annual labs).⁵

There were several limitations to this study. The low functional cure incidence observed at the RCID was likely underrepresented, as most patients were excluded due to lost to follow-up, absence of coinfection, patient death, or participation in a separate research study. Incidence rates are projected to be higher with a longer study period or follow-up. A major limitation was the unexpectedly low number of labs collected from patients. Due to the remote nature of this study, there was difficulty in coordinating with the RCID laboratory. For example, there were several instances during post office visit evaluations, where the laboratory had to be contacted to add to blood collections. It was later discussed with an RCID-registered nurse that the laboratory’s workflow standard precludes collecting labs ordered as “future” orders; thus, technicians typically collect active labs ordered on the same day as patients’ office visits. However, after enforcing their suggestion to enter appointment reminder notes in patients’ charts, this issue remained. Lastly, we were unable to test the revaccination portion of our study protocol, which was a major portion that had been highly anticipated. In retrospect, it could have been a best practice to include the ordering of quantitative anti-HB with HBsAg, to be able to determine whether functionally cured patients have developed antibody levels that are considered fully protective.

Future Directions

Moreover, several future directions can be drawn from this study. Lab stewardship practices need improvement; thus, we plan to encourage standardized monitoring of HBV-specific labs in coinfected patients by implementing a workflow protocol similar to the one previously outlined. Ultimately, this would help identify coinfected patients who will eventually require revaccination to achieve complete immunity against hepatitis B. In addition, it is reasonable to assume that future clinical scenarios may arise involving medication management of coinfected patients (eg, starting immunosuppressive therapy for rheumatoid arthritis or adjusting ART after HBV cure). Therefore, additional guidance will be created to address these situations. Moreover, to help facilitate overall monitoring of coinfected patients, appropriate collection of HBV labs, administration of HBV revaccinations when appropriate, and opportunities to incorporate current clinical pharmacists into the aforementioned workflow will be established.

Conclusion

The findings of this study had important implications for the current practice at the RCID clinic. Our results add new local evidence about the incidence of functional cure of hepatitis B in patients coinfected with HIV and validate the need for universal HBV therapy in this population. The current literature has primarily focused on functional cure of HBV at the global or national level. This study sheds light on current regional practices for managing this unique patient population and offers new insights into how to improve functional cure surveillance at the local level. It also provides measures that can be enforced at the local level to improve the identification of these patients, timely monitoring of HBV labs, and appropriate oversight, ultimately improving their overall clinical prognosis.

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