In fact, Salpini and colleagues showed that HBV virological reactivation is a frequent event in HBsAg-negative/anti-HBc-positive PLWH switching to TDF/TAF sparing therapy [22]. The study included 101 HBsAg-negative/anti-HBc-positive patients with HIV infection from the ICONA Cohort, virologically suppressed for HIV > 12 months. Patients were tested for HBV DNA and HBV RNA within 12 months after the therapeutic switch. After TDF/TAF withdrawal, HBV virological reactivation occurred in a relevant proportion (40%) of patients. A longer duration of TDF/TAF withdrawal correlated with a progressive increase in serum HBV-DNA, supporting the progressive enhancement of HBV replicative activity. The risk of virological HBV reactivation (HBV-R) was associated with the status of HBV reservoir at T0 (still under TDF/TAF based cART), with a higher risk in patients with cryptic HBV-DNA at T0 (serum HBV-DNA > 1 IU/mL). Low levels of anti-HBs (<100 mIU/mL) were the only factor correlated with cryptic HBV-DNA by multivariate analysis. Moreover, HBV reactivation was modulated by the extent of HIV-mediated immunocompromise. In fact, lower nadir CD4+ T cell counts (<100 cells/mm3) correlated with an increased risk of HBV-R, as confirmed by multivariable analysis, suggesting that a weakened immune response is a driver for re-uptake/enhancement of HBV replicative activity [22].
 
These findings highlight the importance of a proper screening and continuous monitoring of HBsAg-negative/anti-HBc-positive patients with HIV infection (particularly if considered for a therapeutic switch not including TDF/TAF), and that ultrasensitive assays for serum HBV-DNA , with novel HBV biomarkers (HBV-RNA, quantitative anti-HBc), can optimize the management of HBsAg-negative/anti-HBc-positive patients with HIV infection.
 
Additionally, HBV reactivation with consequent development of hepatitis B may occur in patients undergoing immune-suppressive therapies [23]. Therefore, anti-HBc-positive PLWH, untreated with HBV-active antiretroviral therapy (ART), but receiving low-risk immunosuppressive therapy, should be monitored for HBV-DNA and HBsAg for early detection of HBV reactivation while patients treated with potent immunosuppressive therapy (B-cell-depleting agents for lymphoma/leukemia or stem-cell or solid organ transplantation) should receive TDF/TAF therapy to prevent HBV reactivation.
 
22. Salpini R., D’Anna S., Alkhatib M., Piermatteo L., Tavelli A., Quiros E., Cingolani A., Papalini C., Carrara S., Malagnino V., et al. Reactivation of hepatitis B virus is a frequent event in anti-HBc positive/HBsAg-negative HIV-infected patients switching to Tenofovir sparing therapy as revealed by highly sensitive HBV assays; Proceedings of the 14th Congress National—ICAR; Montreal, QC, Canada. 30 May–3 June 2022. [Google Scholar]
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9506102/ New Markers in Monitoring the Reactivation of Hepatitis B Virus Infection in Immunocompromised Hosts 

 
In the last few years, new biomarkers, such as anti-HBs and anti-HBc titres, HBV core-related antigen (HBcrAg), ultra-sensitive HBsAg evaluation and HBV RNA, have been used in patients with an HBV infection to evaluate their diagnostic and prognostic potential. The aim of this review is to evaluate the published results on the use of new infection markers in the diagnosis and monitoring of HBV reactivation over the course of immunosuppressive treatments.
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784136/
 
by multivariate analysis, an anti-HBc IgG titer >4.4 COI was correlated with cccDNA detection (OR: 8.516, p = 0.009). Thus, such a threshold can be indicative of cccDNA persistence in the liver of patients with a resolved HBV infection. It is conceivable that such cccDNA can drive the production of viral antigens (albeit at minimal levels) capable of stimulating anti-HBc production.
 
In only two studies was the anti-HBc titre correlated with reactivation in the immunocompromised host, and it is always associated with the presence or absence of antibodies to HBsAg.

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