Discontinuing tenofovir in antiretroviral therapy (ART) may expose people living with HIV to hepatitis B virus (HBV)-related risks, including reactivation in those previously exposed and infection in those who are susceptible, according to a systematic review and meta-analysis.
“Studies have shown that tenofovir, when employed as either ART or HIV pre-exposure prophylaxis (PrEP), confers a protective effect against incident HBV infection,” noted first author Dr Amir Mohareb from Massachusetts General Hospital, Boston, Massachusetts, US, and colleagues.
“This review found several reports of HBV transmission after tenofovir cessation in people with HIV, and this risk likely depends on immunologic and exposure characteristics of the participants,” Mohareb and colleagues added.
The meta-analysis included 22 observational studies that reported baseline HBV serologic data in participants with HIV and one of the following HBV risk categories: active HBV co-infection (positive HBV surface antigen [HBsAg]), resolved HBV infection (positive HBV core antibody [HBcAb] without HBsAg), and susceptibility to HBV infection (negative HBsAg, HBcAb, and HBV surface antibody [HBsAb]).
“These serologically defined categories encompass the majority of people living with HIV, particularly adults in HBV-endemic countries where 60 percent to 74 percent have one of these serologic profiles,” Mohareb and colleagues noted.
For active and resolved HBV infection categories, studies included people who discontinued tenofovir during follow-up. For the HBV-susceptible category, studies involved people who discontinued tenofovir or who were always treated with tenofovir-sparing ART.
Meta-analysis findings
Among participants with resolved HBV infection, the pooled HBV reactivation rate after tenofovir cessation was 1.17 per 100 person-years. Of note, studies employing active surveillance of HBV serologic markers after tenofovir cessation reported higher reactivation rates than studies employing a passive surveillance strategy for HBV reactivation or without a uniformly applied monitoring strategy (3.79 vs 0.35 per 100 person-years; p<0.001). [EClinicalMedicine 2026;doi:10.1016/j.eclinm.2026.104075]
Among participants with HIV and susceptibility to HBV infection, new HBV infections following transition to tenofovir-sparing ART occurred at a rate of 1.63 per 100 person-years.
In participants with active HBV co-infection, few studies have evaluated tenofovir discontinuation outside of the context of short-term interruptions. Tenofovir interruptions were associated with increases in HBV DNA (median, 2.52 log10 IU/mL) and severe hepatitis flare (ALT 218 IU/L and bilirubin 23.1 mg/dL).
Egger’s test showed no significant evidence of publication bias across the included studies (p=0.216).
Clinical implications
“People with HIV are increasingly being treated with ART regimens that do not use tenofovir, either in the form of two-drug oral or long-acting injectable ART. These ART regimens have a similar efficacy and improved safety profile or are preferred by patients,” according to Mohareb and colleagues. “The evidence synthesized by this review provides guidance for clinicians and health systems that are transitioning people with HIV to tenofovir-sparing ART regimens.”
Mohareb and colleagues recommended that all people with HIV considering a switch to tenofovir-sparing ART undergo updated HBV serologic testing prior to discontinuing tenofovir in order to mitigate HBV-related risks.
For people with resolved HBV infection or isolated HBcAb positivity, Mohareb and colleagues stressed the importance of regular monitoring after tenofovir cessation. “HBV reactivation events can be missed in settings that do not undertake regular monitoring of HBV serologic markers and HBV DNA after tenofovir cessation,” they said.
“While the current evidence is insufficient to provide a specific monitoring strategy, we recommend that laboratory monitoring for HBV reactivation should occur at least twice within the first year after tenofovir cessation, if possible, and ideally longer as delayed HBV reactivation has been reported in some studies,” they added.
Meanwhile, people with active HBV co-infection are at risk for liver-related complications, such as cirrhosis, hepatocellular carcinoma, and early mortality. So, staying on tenofovir-containing ART, consistent with current guidelines, is best, Mohareb and colleagues noted.
“It is possible that select people with HIV-HBV co-infection may be safely monitored off tenofovir (ie, those with minimal baseline HBV activity, as evidenced by undetectable viral loads and low HBsAg levels), but more data are needed before it can be scaled to widespread practice,” they added.
As for individuals who are susceptible to HBV and on a tenofovir-sparing regimen, Mohareb and colleagues emphasized that hepatitis B vaccination remains the single most important line of defence against infection.
Conventional recombinant HBV vaccine with aluminium yields seroprotection of between 40 percent to 70 percent after 1 year, with lower estimates for people with low CD4 cell counts and other evidence of immunosuppression. However, a novel two-dose CpG conjugant vaccine has been shown to provide more than 95-percent seroprotection. [JAMA Netw Open 2021;4:e2121281; JAMA 2025;333:295-306]
“Expanded availability of this novel vaccine formulation to HBV-endemic regions may help the successful scale-up of tenofovir-sparing ART regimens for eligible persons in those regions,” Mohareb and colleagues said.