Occult Hepatitis B Virus Infection and HBV Reactivation After Switching to Long Acting Therapy in Patients With HIV-1

Official title

Occult Hepatitis B Virus Infection and HBV Reactivation After Switching to Long Acting Therapy in Patients Living With HIV-1

Overview

The primary objective of the present project will be to investigate the risk of HBV reactivation (from virological reactivation to overt HBV infection) in HIV-1 carriers with occult HBV infection (OBI, is characterized by the absence of surface antigenemia, HBsAg negativity, with the presence of HBV-core antibody, HBcAb) and switching from antiretroviral therapy (ART) including nucleos(t)ides to long-acting formulation.

Detailed description

Observational prospective, multicenter, single-arm study with additional procedure in people living with HIV-1 and having serological markers of previous HBV infection: anti-core antibodies and/or antibodies against surface antigen (HBsAb) and switching from nucleoside analogue therapy to long-acting therapy including cabotegravir (CAB, HIV-1 integrase inhibitor) + rilpivirine (RPV, non-nucleoside HIV-1 reverse transcriptase inhibitor) intramuscularly 1 time every 2 months.

Primary Objective To study the risk of HBV reactivation from the phase of possible virological reactivation (HBV-DNA \>=10 IU/mL), when the liver enzymes are within normal limits to overt HBV infection. Overt HBV infection is characterized by positive HBV-DNA, possible positivity of surface antigen (HBsAg) with or without altered liver enzymes in HIV-1 patients with OBI, with switch from ART, which includes nucleos(t)ide analogues active on the two HIV/HBV viruses, to the long-term formulation in which nucleos(t)ide analogues active on the two viruses are not included.

Secondary Objectives

* To evaluate the effect, in the context of HBV reactivation, of HBV-RNA as a surrogate marker of the transcriptional activity of the covalently closed circular (cccDNA) which is present as an HBV replication intermediate at the hepatocyte level. * Examine the mutational profile of HBV domains (pre-S1 and S genes, X gene), mutations in the nucleocapsid promoter region and the pre-core/core variant, capable of influencing HBV replication efficiency, including also the analysis of mutants characterized as viral escape.

Exploratory Objectives To study the mutational profile of the regions of the hepatitis B virus (HBV) able to influence replication efficiency.

The study will include subjects living with HIV, followed at the San Luigi Center (Infectious Diseases), IRCCS Ospedale San Raffaele in Milan, Integrated Infectious Risk Management Department, Policlinico S. Orsola-Malpighi in Bologna, and the Department of Mental and Physical Health and Medicine prevention, University of Campania L. Vanvitelli of Naples, who agree to the switch from the current antiretroviral regimen which includes drugs active on HIV/HBV to long acting therapy.

Primary outcome measures

• Quantification of hepatitis B DNA (HBV-DNA) [Time frame: Baseline (start of long-acting therapy) weeks 12, 24 and 48]

Secondary outcome measures (2)

• Quantification of hepatitis B RNA (HBV-RNA) [Time frame: Baseline and at weeks 12, 24 and 48]
• HBV mutational pattern by direct sequencing (Sanger) [Time frame: Baseline and at weeks 12, 24 and 48]

Eligibility criteria

Inclusion criteria

• Age > 18 years
• Informed consent to participate in the study
• HIV infection
• Stable antiretroviral therapy (ART) in the six months prior to enrollment without virological failure defined by HIV-RNA>50 copies/mL in at least two consecutive determinations
• Positive HBV anti-core antibodies (HBcAb) in the absence of hepatitis B surface antigen (HBsAg)
• Absence of mutations associated with resistance to integrase inhibitors (INSTIs) and reverse transcriptase inhibitors (NNRTIs) by HIV genotypic resistance testing
• CD4 Nadir >200 cells/mm3

Exclusion criteria

• Any contraindications to the use of one or more long-acting drugs
• Non-expression or withdrawal of informed consent to participate in the study
• Pregnancy
• Lack of HIV genotypic resistance testing
• Virological failure (HIV-RNA >50 copies/mL in at least 2 consecutive determinations) in the 6 months prior to enrollment
• Therapeutic interruptions in the six months prior to enrollment, excluding interruptions lasting less than a month due to tolerability
• CD4 Nadir =<200 cells/mm3
• Presence of biochemical signs of hepatocellular necrosis (AST, ALT > normal values as indicated in laboratory tests).
• Cirrhosis and/or fibrosis score >F3 assessed by transient elastography (FibroScan).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Other

Study locations

Italy · 3 centers

• IRCCS Azienda Ospedaliero-Universitaria di Bologna — Bologna
• IRCCS San Raffaele O.U. Infectious Diseases — Milan
• Università Luigi Vanvitelli della Campania — Naples

Publications

• Morsica G, Bagaglio S, Cicconi P, Capobianchi MR, Pellizzer G, Caramello P, Orani A, Moioli C, Rizzardini G, Uberti-Foppa C, Puoti M, Monforte AD; Hepa I.C.o.N.A the Icona Foundation Study Groups. Viral interference between hepatitis B, C, and D viruses in dual and triple infections in HIV-positive patients. J Acquir Immune Defic Syndr. 2009 Aug 15;51(5):574-81. doi: 10.1097/QAI.0b013e3181add592. PMID 19590432
• Jaeger H, Overton ET, Richmond G, Rizzardini G, Andrade-Villanueva JF, Mngqibisa R, Hermida AO, Thalme A, Belonosova E, Ajana F, Benn PD, Wang Y, Hudson KJ, Espanol CM, Ford SL, Crauwels H, Margolis DA, Talarico CL, Smith KY, van Eygen V, Van Solingen-Ristea R, Vanveggel S, Spreen WR. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 96-week r PMID 34648734
• Huang H, Wang J, Li W, Chen R, Chen X, Zhang F, Xu D, Lu F. Serum HBV DNA plus RNA shows superiority in reflecting the activity of intrahepatic cccDNA in treatment-naive HBV-infected individuals. J Clin Virol. 2018 Feb-Mar;99-100:71-78. doi: 10.1016/j.jcv.2017.12.016. Epub 2018 Jan 6. PMID 29353073
• Carey I, Gersch J, Wang B, Moigboi C, Kuhns M, Cloherty G, Dusheiko G, Agarwal K. Pregenomic HBV RNA and Hepatitis B Core-Related Antigen Predict Outcomes in Hepatitis B e Antigen-Negative Chronic Hepatitis B Patients Suppressed on Nucleos(T)ide Analogue Therapy. Hepatology. 2020 Jul;72(1):42-57. doi: 10.1002/hep.31026. PMID 31701544
• Bagaglio S, Bianchi G, Danise A, Porrino L, Uberti-Foppa C, Lazzarin A, Castagna A, Morsica G. Longitudinal evaluation of occult hepatitis B infection in HIV-1 infected individuals during highly active antiretroviral treatment interruption and after HAART resumption. Infection. 2011 Apr;39(2):121-6. doi: 10.1007/s15010-011-0093-9. Epub 2011 Mar 22. PMID 21424854
• Bagaglio S, Porrino L, Lazzarin A, Morsica G. Molecular characterization of occult and overt hepatitis B (HBV) infection in an HIV-infected person with reactivation of HBV after antiretroviral treatment interruption. Infection. 2010 Oct;38(5):417-21. doi: 10.1007/s15010-010-0032-1. Epub 2010 Jun 9. PMID 20533073
• Clark SJ, Creighton S, Horner M, Smith HM, Portmann B, Taylor C, Cramp ME. Reactivation of latent hepatitis B virus infection with HIV-related immunosuppression. Int J STD AIDS. 2006 Jan;17(1):67-9. doi: 10.1258/095646206775220612. PMID 16409685
• Chamorro AJ, Casado JL, Bellido D, Moreno S. Reactivation of hepatitis B in an HIV-infected patient with antibodies against hepatitis B core antigen as the only serological marker. Eur J Clin Microbiol Infect Dis. 2005 Jul;24(7):492-4. doi: 10.1007/s10096-005-1355-1. PMID 15990987

Identifiers

NCT: NCT06728917 · IRCCS San Raffaele

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗