HBV reactivation after switching to cabotegravir plus rilpivirine therapy among people living with HIV: do not forget the reservoir

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In 2022, the WHO estimated that 254 million people were living with chronic HBV infection. Among these individuals, approximately 2.7 million were also living with HIV (PWH).1 Current ART strategies are increasingly focused on reducing overall drug exposure to minimize potential long-term toxicities. Simplification of therapeutic strategies such as dual therapy or long-acting (LA) regimens also allows people to improve their quality of life.2 However, withdrawal of antiretrovirals with dual anti-HBV and anti-HIV activity such as tenofovir disoproxil fumarate or tenofovir alafenamide, lamivudine or emtricitabine from ART regimens in coinfected individuals exposes them to an increased risk of HBV reactivation. We report a case of HBV reactivation in a PWH and with isolated anti-HBc seropositivity following simplification to LA ART. A 47-year-old man of sub-Saharan origin, employed as a warehouse worker, was diagnosed with HIV-1 infection in 2004 (CDC stage A3). At that time, serological testing revealed evidence of resolved HBV infection, with isolated anti-HBc antibodies. ART with tenofovir disoproxil fumarate, emtricitabine and efavirenz was initiated the same year. HIV replication was well controlled until 2012, when the patient discontinued ART for 5 years. In 2017, HIV viral load was 5.5 log10 copies/mL and the nadir CD4 cell count was 7.2 cells/mm3, when he resumed ART with abacavir, lamivudine and dolutegravir. The serological profile showed the presence of isolated anti-HBc antibodies. No HBV DNA was measured at the time of ART re-initiation. HIV genotyping did not detect any antiretroviral resistance mutations, and the viral load was <20 copies/mL after 6 months of treatment. After several years of sustained virological suppression and with the availability of LA regimens, the patient expressed a desire to simplify his ART. HBV serology confirmed the persistent isolated anti-HBc antibodies without anti-HBs antibodies. He was offered HBV vaccination, as recommended by many current guidelines.3,4 He received a first dose of HBV vaccine (ENGERIX B® 20 µg) 1 month before the start of the oral lead-in (LI) phase of cabotegravir (30 mg q24h) and rilpivirine (25 mg q24h) and a second dose 1 month later. At the time of switching to LA injectable cabotegravir (600 mg every 2 months) and rilpivirine (900 mg every 2 months), 2 months after completion of the oral lead-in phase, the patient had an ALT level of 42 IU/mL and an HBV viral load above 8 log10 IU/mL. The CD4 cell count was 190 cells/mm3. Clinically the patient remained asymptomatic, but the ALT level reached 2338 IU/L. Tenofovir disoproxil fumarate (245 mg q24h) was added to his LA regimen 1 month after the HBV reactivation, resulting in a drastic decrease of HBV viral load (Table 1). Six months after HBV reactivation, the serological profile was negative for HBs antigen and showed isolated anti-HBc antibodies. HBV viral load was undetectable and ALT level dropped to 18 IU/L. HBV Sanger genome sequencing identified a genotype E, and neither mutation of immune escape nor resistance was observed in surface antigen and reverse transcriptase domains, respectively. The sequence has been deposited into Genbank. It is available under the following accession number: PX453184. Summary of patient’s virological, immunological and pharmacological data over time ABC, abacavir; CAB, cabotegravir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; LA, long-acting; LI, oral lead-in; RPV, rilpivirine; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine; (−), negative; (+), positive. This case illustrates that HBV reactivation can occur rapidly after discontinuation of anti-HBV therapy in virologically suppressed PWH. The patient had been on long-term lamivudine therapy prior to switching to LA ART without evidence of reactivation. However, just 2 months after lamivudine was removed, his HBV viral load rose sharply.5 To date, no cases of reactivation in persons with HBV genotype E have been reported, where genotype data are available.6 Reactivation even years after apparent resolution of HBV infection is well recognized in immunosuppressed individuals and is attributed to the persistence of covalently closed circular DNA (cccDNA) in hepatocyte nuclei.7 These findings underscore the importance of assessing HBV serology before any modification or reduction of ART. To date, there is no way of eradicating HBV reservoirs, but research is moving towards the goal of HBV cure. In individuals with isolated anti-HBc seropositivity, switching to molecules that are not active against HBV may be considered if the benefits of this change outweigh the potential risk of HBV reactivation.3 The simplification should be done with caution and close monitoring of HB surface antigen (HBsAg), HBV viral load and transaminases, as recommended by guidelines.3,8 Although vaccination represents an additional strategy to prevent HBV reactivation,9 vaccination guidelines regarding people with isolated anti-HBc antibodies are based on small-scale studies,10 and vaccine responses in PWH are generally lower than in the general population.11 The recent vaccine HepBCpG (HEPLISAV-B®, Dynavax), which uses CpG1018, a TLR9 (Toll-like receptor) agonist as adjuvant, appears to offer promising results. It showed impressive results in PWH who did not respond to a complete HBV vaccine series, with a seroconversion rate of 99% after three doses of HepBCpG and 78.1% of persons achieving an anti-HBs titre >1000 mIU/mL.12 Guidelines are increasingly incorporating the use of HEPLISAV-B into their recommendations.3 This vaccine is authorized in many regions (the USA, the EU, Great Britain), but its commercialization outside the USA needs to be further developed, for example in the EU. This case of reactivation highlights the need to improve and harmonize the management of PWH presenting anti-HBc antibodies in order to prevent future cases of reactivation. Several cases and small series have recently been reported following the switch to a cabotegravir/rilpivirine injectable regimen.13–16 The risk of HBV reactivation in patients with an isolated HBc serological profile appears to be low in this context, particularly when anti-HBs antibodies are present. The risk appears to be higher in individuals with recent HBsAg seropositivity17 or low CD4 nadir count,18 and HBV reactivation after the withdrawal of an anti-HBV/HIV drug can lead to very serious complications, as already reported.19 In conclusion, the risk of HBV reactivation in PWH with isolated anti-HBc seropositivity should not be overlooked. Switching to ART without agents active against HBV must be done with caution, depending on the patient's profile, and should be closely monitored. This work was supported by the Agence Nationale de Recherches sur le SIDA et les hépatites virales|Maladies Infectieuses Emergentes (ANRS|MIE). A.F. has reported presentation fees from Gilead, ViiV Healthcare and MSD. E.T. has reported travel grants from Gilead and ViiV Healthcare and consultancy for Gilead, Abbvie and ViiV Healthcare. G.P. has received travel grants, consultancy fees and honoraria from Gilead Sciences, ViiV Healthcare, Merck and Takeda. R.P. has received travel grants and advisory fees from Gilead, ViiV Healthcare and Merck. V.C. has received travel grants, research funding and advisor’s honoraria from Gilead, ViiV Healthcare, MSD and Moderna. V.P. has received travel grants and advisor’s honoraria from Gilead, ViiV Healthcare and MSD. All other authors: none to declare.

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