Advances in Hepatitis B Epidemiology and Treatment

Hepatitis B epidemiology and treatment were the focus of several important presentations at the 2026 Conference on Retroviruses and Opportunistic Infections (CROI). Haser and colleagues (Abstract 142) presented data on hepatitis B virus (HBV) reactivation or infection rates in people with HIV (PWH) on tenofovir-sparing antiretroviral therapy (ART). They studied 5779 PWH in the CNICS (Center for AIDS Research [CFAR] Network of Integrated Clinical Systems) cohort who were on non-tenofovir-containing ART, had baseline hepatitis B surface antigen (HBsAg) and surface antibody (HBsAb) testing, and did not have active HBV infection. They used a composite outcome of HBV reactivation or infection, defined as a positive HBsAg or HBV DNA level of 10 IU/L or higher. The median CD4+ count in their cohort was 603 cells/μL and 26% had an unsuppressed HIV viral load (>200 copies/mL). Eighty percent were on ART containing emtricitabine (FTC) or lamivudine (3TC), hereafter referred to as XTC. Fifteen percent of patients had evidence of prior HBV infection with a positive core antibody, 57% had no prior HBV infection, and 29% had an unknown HBV infection status with unknown core antibody values. They observed HBV reactivation or infection in 21 of 5779 patients (0.4%). Most of these events were new HBV infections, with 13 of 21 events occurring in patients with no prior HBV infection (although interestingly, 4 had a positive HBsAb at baseline). Rates of HBV reactivation or infection were lower in those who were on an XTC-containing regimen (0.3%) than in those on ART without HBV activity (0.8%; P=unavailable). Fourteen percent of those with HBV reactivation or infection had liver inflammation with an alanine transaminase (ALT) level of 100 U/L or higher. In a multivariable regression analysis, they found Black race (adjusted odds ratio [aOR], 6.3; 95% CI, 1.5–25.9), Asian race (aOR, 13.7; 95% CI, 1.8–104.6) and CD4+ count below 200 cells/μL (aOR, 3.2; 95% CI, 1.3–7.5) were significantly associated with an increased risk of HBV reactivation or infection. The study authors conclude that HBV reactivation or infection is rare on a tenofovir-sparing ART regimen. Interestingly, HBV reactivation or infection occurred in groups with prior positive HBsAb, suggesting that levels may have waned over time, leading patients to become at risk for HBV acquisition or reactivation. These data suggest some utility in checking hepatitis B serologies periodically, eg, annually, as suggested by the National Institutes of Health HIV/ AIDS Clinical Guidelines,¹ for patients on tenofovir-sparing ART, as well as identifying candidates for hepatitis B vaccination. Moreover, all PWH without active HBV infection but with a negative HBsAb (including those with isolated positive or unknown hepatitis B core antibody [HBcAb]) should be offered adjuvanted hepatitis B vaccine (HepB-CpG) to prevent HBV infection.

Brunet (Abstract 593) presented HIV/HBV coinfection outcomes from the OPERA (Observational Pharmaco-Epidemiology Research and Analysis) cohort of patients on long-acting cabotegravir and rilpivirine (LA CAB/RPV). In their cohort of 5275 participants on LA CAB/RPV, 12% had evidence of previous HBV infection with immunity, 1% of participants had previous HBV infection without immunity, and fewer than 1% had active HBV infection. Overall, follow-up data were limited in those with prior or active HBV infection. In participants with active HBV infection and follow-up data, 52% had reactivation of HBV on LA CAB/RPV; most of these participants were then started on a hepatitis B antiviral drug. HBV reactivation occurred in fewer than 1% of those with prior HBV infection with evidence of immunity and in 3% of those with prior HBV infection but without immunity. They did not find a significant difference in HIV viral suppression among the different HBV infection groups.

Real-world data from the OPERA cohort suggest that HIV/HBV coinfected patients should be monitored closely, and that although LA injectables are an effective treatment for HIV, those with active HBV infection are likely to have reactivation and should be on an antihepatitis B agent at the start of LA CAB/RPV. It is reassuring that HBV reactivation is rare in those demonstrating immunity, but the reactivation rate of 3% in those with prior HBV infection without immunity suggests a rare but important complication for which to monitor. These individuals should be offered an adjuvanted hepatitis B vaccine. Those without prior hepatitis B infection but who are switching to LA CAB/RPV should be prioritized for a HepB-CpG vaccine series to prevent HBV infection.

Wang (Abstract 588) presented hepatitis B outcome data in chronic hepatitis B patients taking pevifoscorvir sodium, an investigational antiviral drug with a dual mechanism of action of inhibition of HBV pregenomic RNA encapsulation and blockage of HBV covalently closed circular DNA (cccDNA) establishment. Twenty-one patients with chronic hepatitis B were given once-daily pevifoscorvir sodium for 96 weeks, then taken off the agent for 8 weeks and switched to a nucleoside or nucleotide analogue. By week 96, they found 100% of patients with hepatitis B e-antigen (HBeAg) positivity had suppressed HBV viral loads (target detected under the lower quantification limit or not detected). At week 96, 89% of the participants with a negative HBeAg had a suppressed HBV viral load. They observed sustained decreases in hepatitis B antigens and HBV RNA levels during the 8-week period off pevifoscorvir, suggesting that the antiviral agent may decrease HBV cccDNA levels. A phase II study of pevifoscorvir compared with nucleoside/nucleotide analogue monotherapy in hepatitis B patients is currently underway.

Currie and colleagues (Abstract 587) demonstrated the safety and efficacy of VRON-0200, an investigational immunomodulator that targets HBV core and polymerase (Pol) proteins but not the HBsAg. They administered VRON-0200 alone or VRON-0200 plus investigational antiviral drugs to a cohort of adults with ongoing active HBV infection (with a positive HBsAg). They observed a decline in the HBsAg level around day 28 after receipt of VRON-0200, with 85% of participants having sustained or continued declines at the end of the study (360 days). They observed a similar decline in the combination treatment cohort, with continued declines for 1 month after receipt of the investigational antiviral drug. A phase IIB study is underway to continue studying the use of VRON-0200 to prime the anti-HBV immune response followed by an antiviral drug to boost the response, with the goal of a functional cure for hepatitis B.

Marks and colleagues (Abstract 591) presented data from regional analyses from the ACTG (Advancing Clinical Therapeutic Globally for HIV/AIDS and Other Infections; formerly AIDS Clinical Trials Group) 5379 BEe-HIVe (B-Enhancement of HBV Vaccination in Persons With HIV) study. BEe-HIVe is a phase III randomized clinical trial comparing the seroprotective response from the HepB-CpG vaccine with the response from a standard 3-dose aluminum hydroxide adjuvant (HepB-alum) vaccine in PWH who had previously not responded to the Hep-B alum vaccine. This trial previously showed superior seroprotection with the HepB-CpG vaccine over the Hep-B alum vaccine.² In analyses across Africa, Asia, Brazil, and the US, they observed higher rates of seroprotection with the HepB-CpG vaccine than the Hep-B alum vaccine in all regions except Brazil (due to the low sample size). They observed variations in age at first hepatitis B vaccination, which likely contributed to some of the differences in seroprotection rates seen by region.

Advances in Hepatitis D Epidemiology and Treatment

Wyles and colleagues (Abstract 141) presented data from the MYR301 trial, a multicenter randomized phase III trial looking at safety and efficacy of bulevirtide (BLV), an investigational drug for the treatment of hepatitis D in PWH or without HIV. They enrolled adults with chronic hepatitis D virus (HDV) infection with detectable HDV RNA level with or without cirrhosis (Child-Turcotte-Pugh score, <7), with an ALT level below 10 times the upper limit of normal. A total of 150 participants were enrolled across 3 treatment arms: 2 mg BLV; 10 mg BLV; or delayed treatment until week 48, followed by initiation of 10 mg BLV. Efficacy was defined as virologic response with an undetectable HDV viral load or a decline of 2log¹⁰ or more from baseline HDV viral load, a biochemical response with normalized ALT, or a combined virologic and biochemical response. There were no significant differences in baseline characteristics among the treatment arms, with nearly 50% of participants enrolled with cirrhosis at baseline, similar baseline mean HDV RNA levels, and about 53% to 65% of participants on antiviral treatment for hepatitis B. Two participants had triple infection with HIV, HBV, and HDV. Through week 144, virologic response rates were 73% in the 2 mg BLV arm, 76% in the 10 mg BLV arm, and 92% in the delayed treatment arm. Fifty-nine percent of participants in the 2 mg BLV arm reached the ALT normalization endpoint compared with 60% in the 10 mg BLV arm and 58% in the delayed treatment arm. Combined response rates (viral and biochemical response) ranged from 54% to 58% among the 3 treatment arms (P-values and CIs not provided). When looking at undetectable HDV RNA level as an endpoint by week 144, about 50% of the participants receiving 10 mg BLV (at enrollment or delayed) had undetectable HDV RNA level compared with 29% in the 2mg BLV group. At week-96 follow-up (after BLV had been stopped), about 20% of the participants across treatment groups had sustained undetectable HDV RNA level.

No serious adverse events related to BLV were reported in this study, and the most common adverse events observed were injection-site reactions, vitamin D deficiency, and headache. Most notably, ALT flares related to HDV rebound were observed after coming off BLV, and most occurred within the 6-month period after stopping BLV. The 2 participants with HIV, HBV, and HDV infection responded to BLV, ie, they achieved the combined virologic and biochemical response endpoint and had HDV RNA suppression to below 50 IU/mL at week 144. Ultimately, this study showed that BLV use for HDV infection was safe and effective, particularly with regard to virologic response.

Alberola and colleagues (Abstract 590) conducted a nationwide cohort study examining characteristics of people with hepatitis D in Spain. Of the 589 individuals who tested positive for HDV, 19% had HIV and 20% had concomitant hepatitis C. The individuals with hepatitis D in the cohort who underwent transient elastography had a mean liver stiffness of 10.4 kPA. In general, the cohort had evidence of advanced fibrosis; 26% had a fibrosis-4 (FIB-4) score above 2.67. Rates of active HDV infection were significantly higher in PWH than in those without HIV (P <.05).

Advances in Hepatitis C Epidemiology and Treatment

Haders (Abstract 589) presented pharmacokinetic data in animal models of a novel investigational oral direct-acting nonnucleoside inhibitor, MDL-001, with in vitro activity against HBV and hepatitis C virus (HCV). One dose of oral MDL-001 was able to reduce HCV RNA viral load for up to 28 days, equivalent to daily sofosbuvir 50 mg/kg. MDL-001 levels in liver tissue exceeded the 90% effective concentration (EC90) range. The investigators did not observe any toxicity in the 400 animals receiving MDL-001. This study showed promising preclinical data of a novel single-dose oral agent showing efficacy against hepatitis C and safety in animal models.

Arshad and colleagues (Abstract 610) presented pharmacokinetic data from an LA formulation of glecaprevir (GLE)/pibrentasvir (PIB) administered via intraparticle coformulations, interparticle mixing (discrete particles) in a single injection, or discrete injections in an animal model. They observed improved pharmacokinetics in the group receiving GLE/PIB intraparticle coformulations, with concentrations of the drugs remaining at the therapeutic level in plasma measurements for 8 weeks after administration. The pharmacokinetics of the intraparticle formulation did not vary by route of administration (intramuscularly or subcutaneously). The interparticle mixing group did not demonstrate an extended half-life of GLE or increased PIB exposure as seen in the coformulated group and a previous study.³ The study authors concluded that with intraparticle coformulation, the decreased solubility of PIB impairs GLE release, leading to an improved half-life of GLE. GLE is hypothesized to increase the bioavailability of PIB. Overall, the synergistic effect seen in this study holds promise for coformulations of LA GLE/ PIB that can be given in 1 dose.

Abstracts 612 through 617 presented various studies attempting to improve HCV infection testing and linkage to care. Several studies showed that rapid or point-of-care testing improved HCV infection testing rates, and at times, hepatitis C diagnoses. Blair and colleagues (Abstract 615) examined time to treatment initiation based on point-of-care HCV infection testing compared with standard laboratory testing in American Indian populations in Oklahoma. In the point-of-care group (with test results available in 1 hour), the mean time to treatment initiation was significantly shorter (18.2 days) than the laboratory standard-of-care group (92.4 days; P <.0001), with a 4-fold decrease in time to initiation of treatment in the point-of-care group compared with the laboratory standard-of-care group (hazard ratio [HR], 4.22; P <.0001). Overall treatment initiation rates did not differ among the 2 groups (P = .5). In this vulnerable population, rapid testing led to a faster time to treatment, which can aid HCV elimination efforts.

Perez Elias (Abstract 612) presented data from a cluster-randomized trial of rapid HCV testing at primary care centers in Spain. They observed HCV infection rates over a 4-month period, then observed HCV infection rates over a 4-month intervention period with a control arm, a rapid HCV testing arm, and a self-administered risk questionnaire followed by rapid testing arm. They observed significantly higher increases in HCV infection testing in the rapid testing arm (incidence rate ratio [IRR], 2.07; 95% CI, 1.47–2.92; P <.001) and in the rapid testing plus self-administered questionnaire arm (IRR, 2.36; 95% CI, 2.12–2.62; P <.001) than in the observation phase. Although not significant, the study authors observed increased rates of new hepatitis C diagnoses in the rapid testing arm (IRR, 2.98; 95% CI, 0.97–9.13; P = .055) and in the rapid testing plus questionnaire arm (IRR, 2.75; 95% CI, 0.94–7.99; P = .063). Rapid testing for HCV infection paired with self-administered questionnaires appears to increase HCV screening rates and may lead to the recognition of new hepatitis C diagnoses.

Vue and colleagues (Abstract 613) examined HCV infection testing rates in emergency departments in California with an opt-out testing system compared with the previous opt-in approach. They observed large increases in number of patients tested, rates of positive hepatitis C antibody, and rates of positive HCV RNA level (P-values and CIs not provided). The trends in this study show that opt-out HCV infection testing in emergency rooms can be an effective approach in improving HCV infection testing rates.

Gallo and colleagues (Abstract 617) examined HCV infection testing turnaround times and linkage to care with a point-of-care HCV infection test administered in the emergency room in Miami, Florida. This point-of-care test decreased turnaround time of a hepatitis C diagnosis by 92% compared with standard laboratory-based testing, which led to increased same-visit linkage to care rates (P-values and CIs not provided). These results, in addition to those from Vue and colleagues, suggest that point-of-care opt-out strategies in emergency departments can greatly improve linkage to care outcomes.

Silver and colleagues (Abstract 616) showed that a volunteer-based linkage-to-care program in Los Angeles, California, was able to link 52% of study participants to care (P-values and CIs not provided), suggesting that community-based volunteer programs could be an effective outreach method. A pharmacist-led approach was presented by Bhattacharya (Abstract 614) in an emergency department in a Veterans Affairs hospital in Los Angeles, California. They observed improved rates of linkage to care after pharmacist-led intervention, along with improved rates of sustained virologic response (SVR) and decreased rates of HCV viremia. Creative approaches to linkage to care programs may be key in HCV elimination efforts.

Advances in Hepatitis E Treatment

Hepatitis E treatment remains a challenge because there are no antiviral drugs for hepatitis E virus (HEV) infection available. Huang and colleagues (Abstract 596) presented in vitro data from 2 investigational antiviral drugs for HEV infection. They observed high levels of active metabolite in hepatocytes of 2 prodrugs, AT-2490 and AT-587. These drugs were shown to have increased potency over sofosbuvir and ribavirin against HEV. They did not observe any toxicity in vitro. These 2 drugs may remain promising candidates for future study for hepatitis E treatment.