Evolution of the serologic and virologic course of occult HBV infection in therapy experienced HIV co‐infected patients

Abstract

We investigated how the natural course of occult hepatitis B virus (HBV) infection (OBI) may evolve during HIV co-infection and long term HBV-active HAART. From a cohort of 181 HIV infected patients who were consecutively recruited over a 5 year period, 28 HBV co-infected patients with sequential sera (n = 98) were identified. Iterative HBV serology and viral loads were determined before and during treatment. The viral HBsAg gene was then serially amplified, directly sequenced, and molecularly characterized. Persistent detection of anti-HBs did not result in a modification to the clinical course of OBI. In contrast, reactivation of chronic HBV infection, hepatic enzymatic flares and cases of HBV reinfection were evident among anti-HBs negative OBI patients, and this was a notable finding. Of the 14 chronic HBV infected patients, eight progressed to persistent OBI after initiation of HBV-active HAART, increasing the number of patients with OBI in the study. Long term HBV-active HAART was not found to have a notable impact on low level viremia during OBI. While the HBsAg gene sequences isolated from chronic HBV infection were genetically stable over time, OBI-associated variants (sP111R, sT127P, sY161F) were neither stable nor predominant during the course of infection. This study is the first of its kind from South Africa to show the occurrence of hepatic enzymatic flares, HBV reactivation, and reinfection in HAART-exposed HIV co-infected patients with OBI. Among the cases studied, there was further evidence that OBI-associated variants may not play a significant role in the pathogenesis of OBI.

Cryptic HBV Replicative Activity Is Frequently Revealed in Anti-HBc-Positive/HBsAg-Negative Patients with HIV Infection by Highly Sensitive Molecular Assays, and Can Be Predicted by Integrating Classical and Novel Serological HBV Markers

“…In particular, around 30% of anti-HBc-positive/HBsAg-negative HIV-infected patients has a cryptic serum HBV-DNA by ddPCR despite pharmacological pressure (median value of 4 (1-15) IU/mL). This result is in line with a previous study, led in South Africa, showing a persistently detectable serum HBV-DNA in 10/14 anti-HBc-positive/HBsAg-negative HIV-infected patients despite an HBV-active cART [27]. It is known that, in anti-HBc-positive/HBsAg-negative patients, anti-HBV immune responses play a key role in controlling cccDNA transcriptional activity and, in turn, in promoting cccDNA silencing [12].…”

Persistence and risk factors of occult hepatitis B virus infections among antiretroviral therapy-naïve people living with HIV in Botswana

“…Most of the studies on the impact of HBV/HIV coinfection in natural disease progression were carried out in the HBsAg-positive individuals as in the studies described above. In contrast, there is a paucity of data on OBI natural disease progression owing to the few longitudinal studies on OBI, especially in Africa, where different genotypes/subgenotypes of HBV and subtypes of HIV circulate ( Amponsah-Dacosta et al, 2018 ; Singh et al, 2019 ). A study in China followed seven OBI-positive blood donors, and all were HBV DNA negative at 1-year follow-up, without an intervention ( Ye et al, 2016 ).…”

Impact of Lamivudine-Based Antiretroviral Treatment on Hepatitis B Viremia in HIV-Coinfected South Africans

“…Human-immunodeficiency-virus (HIV) infection alters the course of the hepatitis B virus (HBV) disease by increasing the rate of chronicity, enhancing HBV replication, and accelerating liver-related morbidity and mortality [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]. In addition, HIV complicates the diagnosis of HBV infection by generating atypical serological presentations, such as occult HBV infection (OBI), defined as the detection of viral DNA in the blood in the absence of hepatitis B surface antigen (HBsAg) [ 2 , 8 , 9 ]. HBsAg prevalence in HIV-positive South African pregnant women ranges from 3.4% to 6.2% [ 10 , 11 ].…”

“…Lamivudine is commonly associated with HBV resistance mutations, whereas tenofovir is not [ 14 ]. In addition, patients with seronegative OBI (i.e., negative for all serological markers) may maintain persistent low-level HBV viremia during long-term lamivudine-containing ART, resulting in the reactivation of chronic HBV infection (CHB) and hepatic enzyme flares [ 9 ]. Furthermore, after initiation of lamivudine-containing ART, patients with overt CHB may progress to persistent OBI [ 9 ], which may be misinterpreted as HBV suppression if follow-up testing only consists of HBsAg.…”

“…In addition, patients with seronegative OBI (i.e., negative for all serological markers) may maintain persistent low-level HBV viremia during long-term lamivudine-containing ART, resulting in the reactivation of chronic HBV infection (CHB) and hepatic enzyme flares [ 9 ]. Furthermore, after initiation of lamivudine-containing ART, patients with overt CHB may progress to persistent OBI [ 9 ], which may be misinterpreted as HBV suppression if follow-up testing only consists of HBsAg. Although the cost of tenofovir is significantly declining, it remains relatively expensive compared to lamivudine, and access to tenofovir is limited in many African countries.…”