Clinical trial NCT06728917: 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
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: HBV (Hepatitis B Virus)
HIV Infection
Keywords: Occult hepatitis B virus infection
long acting therapy
people living with HIV-1
HBV reactivation
Lead sponsor: IRCCS San Raffaele
Sponsor class: OTHER
Collaborators: name: IRCCS Azienda Ospedaliero-Universitaria di Bologna
name: Università Luigi Vanvitelli della Campania
First posted: 2024-12-11
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 50 subjects will participate to the study, 30 subjects enrolled at the San Luigi Center (Unit of Infectious Diseases), IRCCS Ospedale San Raffaele in Milan, 10 subjects enrolled at Integrated Infectious Risk Management Department, Policlinico S. Orsola-Malpighi in Bologna, and 10 at the Department of Mental and Physical Health and Medicine prevention, University of Campania L. Vanvitelli of Naples.

Brief summary: 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.

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).

Primary outcomes:
measure: Quantification of hepatitis B DNA (HBV-DNA)
timeFrame: Baseline (start of long-acting therapy) weeks 12, 24 and 48
Secondary outcomes:
measure: Quantification of hepatitis B RNA (HBV-RNA)
timeFrame: Baseline and at weeks 12, 24 and 48
measure: HBV mutational pattern by direct sequencing (Sanger)
timeFrame: Baseline and at weeks 12, 24 and 48
Other outcomes:
measure: Measurement of number of amino acid and/or nucleotide substitution.
timeFrame: Baseline (start of long-acting therapy) weeks 12, 24 and 48
Locations:
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero-Universitaria di Bologna
city: Milan
country: Italy
facility: IRCCS San Raffaele O.U. Infectious Diseases
city: Napoli
country: Italy
facility: Università Luigi Vanvitelli della Campania
Study officials:
affiliation: IRCCS San Raffaele
name: Antonella Castagna, Prof, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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 results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet HIV. 2021 Nov;8(11):e679-e689. doi: 10.1016/S2352-3018(21)00185-5. Epub 2021 Oct 11.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Onorato L, Pisaturo M, Camaioni C, Grimaldi P, Codella AV, Calo F, Coppola N. Risk and Prevention of Hepatitis B Virus Reactivation during Immunosuppression for Non-Oncological Diseases. J Clin Med. 2021 Nov 8;10(21):5201. doi: 10.3390/jcm10215201.
citation: Hu KQ. Occult hepatitis B virus infection and its clinical implications. J Viral Hepat. 2002 Jul;9(4):243-57. doi: 10.1046/j.1365-2893.2002.00344.x.
citation: Mulrooney-Cousins PM, Michalak TI. Persistent occult hepatitis B virus infection: experimental findings and clinical implications. World J Gastroenterol. 2007 Nov 21;13(43):5682-6. doi: 10.3748/wjg.v13.i43.5682.
citation: Ramezani A, Mohraz M, Aghakhani A, Banifazl M, Eslamifar A, Khadem-Sadegh A, Velayati AA. Frequency of isolated hepatitis B core antibody in HIV-hepatitis C virus co-infected individuals. Int J STD AIDS. 2009 May;20(5):336-8. doi: 10.1258/ijsa.2008.008377.
citation: Pisaturo M, Onorato L, Russo A, Coppola N. Prevalence of occult HBV infection in Western countries. J Med Virol. 2020 Dec;92(12):2917-2929. doi: 10.1002/jmv.25867. Epub 2020 Jun 29.
citation: Santos EA, Yoshida CF, Rolla VC, Mendes JM, Vieira IF, Arabe J, Gomes SA. Frequent occult hepatitis B virus infection in patients infected with human immunodeficiency virus type 1. Eur J Clin Microbiol Infect Dis. 2003 Feb;22(2):92-8. doi: 10.1007/s10096-002-0868-0. Epub 2003 Feb 18.
citation: Nunez M, Rios P, Perez-Olmeda M, Soriano V. Lack of 'occult' hepatitis B virus infection in HIV-infected patients. AIDS. 2002 Oct 18;16(15):2099-101. doi: 10.1097/00002030-200210180-00024. No abstract available.
citation: Raimondo G, Pollicino T, Cacciola I, Squadrito G. Occult hepatitis B virus infection. J Hepatol. 2007 Jan;46(1):160-70. doi: 10.1016/j.jhep.2006.10.007. Epub 2006 Nov 7.