Hepatitis B Infection in People Living With Human Immunodeficiency Virus: A Global Challenge Needing More Research

This is the authors' abstract. We don't add key points for this paper.

(See the Major Article by Leumi et al on pages 2799–806.) Both human immunodeficiency virus (HIV) and hepatitis B virus (HBV) are chronic persistent infections, share routes of transmission, require lifelong antiviral therapy, and are more common in low- and middle-income countries (LMICs). Coinfection with both viruses has significant implications for clinical management. HIV dramatically increases mortality and accelerates liver disease progression compared with people living with chronic HBV alone [1]. With HBV-active antiretroviral therapy (ART) that suppresses replication of both viruses, overall and liver-related mortality has dramatically reduced, but rates of morbidity and mortality are still elevated among this group (reviewed in Singh et al [2]). Understanding the global burden of HIV/HBV coinfection therefore has important implications for policy makers, clinical practice guidelines and training, and prevention strategies. In this edition of Clinical Infectious Diseases, Bigna et al performed a meta-analysis to estimate the prevalence of HBV infection (defined as detection of HBV surface antigen [HBsAg]) in people living with HIV (PLWH), at a national, regional, and global level. Prevalence is reported with confidence and prediction intervals. They rated studies for degree of bias and conducted sensitivity analyses excluding those with high bias, which mirrored their overall results, illustrating the robustness of their findings. The authors analyzed 354 published studies from 87 countries and included data from 836 644 PLWH. They demonstrate a global prevalence of HBV in PLWH of 8.4%, with an estimated 3 136 500 PLWH infected with HBV globally and a quarter of those hepatitis B e antigen positive, meaning they are more likely to transmit HBV. There was a large variation in national prevalence, ranging from 1.4% to 42%. Prevalence was found to be associated with human development index rating of countries, with prevalence highest at 10.4% among countries with a low development index, and lower at 6.6% in highly developed countries. The prevalence of HBV increased from 7.3% in countries with HIV prevalence ≤1% to 9.7% in countries with HIV prevalence >1%. Together the data demonstrate that the greatest burden of HIV/HBV coinfection exists in the countries of highest need. Significant gaps in available data were found in some regions. The studies included represent less than half of all available countries, with no studies available from 108 nations and some regions poorly represented [2]. In Eastern Europe and central Asia, only 1 study was identified, from Ukraine. In these regions, prevalence of chronic HBV in the general population is high, estimated at >10%, and HIV testing and treatment levels are very low [3–6]. This gap in knowledge is highly significant and will need to be specifically addressed in future work. The authors also identified that there are limited data among prisoners, sex workers, and transgender people, making estimates within these groups unreliable. Not only may rates of coinfection in these groups be particularly high, these key populations often have the lowest access to treatment and prevention programs globally [7]. The stigma around identity, compounded with difficulties engaging and retaining in care, is a dangerous combination that is likely to result in increased morbidity, mortality, and ongoing transmission of both HIV and HBV. The prevalence rate of 8.4% of HBV infection in PLWH reported here is higher than the 3.5% overall global estimated hepatitis B prevalence found in modeling studies and meta-analyses [8, 9]. In addition, the authors did not see a significant change in HBV prevalence in PLWH over time, even though the studies included participants recruited between 1984 and 2016. This was surprising given that over that period, there has been increased uptake of HBV vaccination and, in some settings, increasing availability of antiviral therapy for both HIV and HBV. One possible explanation could be the lower response rates to HBV vaccination among PLWH than in the general population, and that immunity to HBV following vaccination may also wane more rapidly [10]. Although various strategies have been developed to enhance HBV vaccine efficacy in PLWH, including an increase in the number from 3 to 4 doses or an increase in the dose from 20 μg to 40 μg, in many settings these vaccine modifications would not be available. Understanding the prevalence of HBV in PLWH is critically important in relation to clinical management. All PLWH should be tested for chronic HBV infection with HBsAg prior to initiation of ART, as this has implications for the choice of antiviral therapy. Surprisingly, testing for HBsAg in PLWH is often not performed routinely, despite treatment guidelines recommending this [11, 12]. HIV rapid testing has become increasingly sensitive and specific and is now widely used for diagnosis of infection in a range of settings. Although point-of-care tests exist for diagnosis of HBV infection, they are less widely available and performance characteristics are not as good as those for HIV. Management of HIV/HBV coinfection requires the use of HBV-active ART, which includes 2 active nucleos(t)ide reverse transcriptase inhibitors (NRTIs), most commonly tenofovir disoproxil fumarate or tenofovir alafenamide with lamivudine or emtricitabine [13]. Currently, dual NRTI with a third agent is recommended for management of HIV/HBV coinfection. These agents are now widely available as first-line treatment for HIV infection in many LMICs; however, second-line therapy is less likely to include drugs with activity against HBV as well as HIV [14]. The use of lamivudine alone in HIV/HBV coinfection is associated with high rates of drug resistance and should be avoided [15]. Among a study of HIV/HBV-coinfected individuals from Taiwan commencing therapy from 2012 to 2016, a third of PLWH were started on ART containing lamivudine as the only HBV-active agent [16]. Two drug regimens for HIV, specifically dolutegravir with either lamivudine or rilpivirine, have recently been shown to be effective [14] and may soon become more widely used due to the possibility of lower side effects and potential for reduced cost. Widespread rollout of these regimens could lead to inadvertent use of them in those with HIV-HBV co-infection with significant implications for the emergence of HBV resistance in people living with HIV-HBV. Finally, HBV vaccination must also be a priority for PLWH who are HBsAg negative and have no evidence of prior infection with HBV (ie, anti-hepatitis B core antibody negative). This is important as horizontal transmission of HBV in PLWH compared to HIV-uninfected adults is associated with a higher rate of chronic infection [17]. Ambitious global strategies to tackle both HIV and chronic HBV have been promoted by the Joint United Nations Programme on HIV/AIDS and the World Health Organization (WHO), respectively. Current HIV targets are for 95% of people to be diagnosed, 95% of people to receive ART, and 95% of people to have viral load suppression by 2030. The WHO global targets for viral hepatitis are to reduce new cases by 90% as well as reduce deaths by 65% by 2030 [18]. The high prevalence of HBV coinfection, particularly in low-income countries and in countries with HIV prevalence >1%, highlighted in this manuscript are a reminder that additional interventions may be needed to reach these targets, specifically in people living with HIV and HBV. This study highlights that HIV/HBV coinfection is common, understudied, and a significant issue for some of the poorest countries globally. There are large gaps in our knowledge of the distribution of infection, and in particular the prevalence of HBV in PLWH in Eastern Europe and Central Asia and among key vulnerable groups. It has been recognized for almost 20 years that people living with HIV and HBV have particularly high rates of morbidity and mortality, and this persists even with the availability of suppressive ART. It may be time to develop a new global strategy that specifically targets HIV/HBV coinfection. Potential conflicts of interest.