Held in Mexico City just prior to the International AIDS Society conference, the HBV/HIV Cure Research Forum met, focusing on current and new strategies to achieve HBV and HIV cure, and exploring synergies between the two fields.
Focus on hepatitis B (HBV) cure research
Hepatitis B is a serious disease that affects the liver, caused by the hepatitis B virus (HBV). More than 257 million people are chronically infected with HBV, leading to over 887,000 deaths each year. HBV is also the cause of about 40% of all primary liver cancers. Africa and Asia have the highest burden of HBV, but the disease is found throughout the world.
Like HIV, the HBV reservoir (called “cccDNA,” a circular mini-chromosome) is the single most important barrier to curing HBV infection. HBV infection can be either acute or chronic. HBV replicates in the liver, while HIV replicates in immune cells. Primary HBV infection is often cleared by the immune system, while clearance of primary HIV infection is very rare. While there is a great vaccine for HBV, there is no vaccine for HIV.
Over 90% of people infected with HBV in infancy progress from acute infection to lifelong chronic infection. In contrast, 90% of people infected in adulthood resolve the infection due to strong immune responses. Once chronic HBV is established, individuals can progress to liver disease, including cirrhosis and hepatocellular carcinoma (HCC). Most people living with HBV must take treatment for life. Current treatments include: nucleos(t)ide analogues (i.e., direct-acting antiviral agents that can block the formation of cccDNA), as well as interferons. Current treatments help achieve control of viral replication, but do not reduce the amount of HBV in the body.
While spontaneous resolution of both acute and chronic hepatitis B has occurred, it does not mean that the virus has been completely eliminated from the body. Similar to the HIV cure research field, there are two paradigms being investigated towards an HBV cure: 1) complete elimination of the HBV virus, or 2) inducing host immune responses to control the infection (‘durable control’). Like HIV, durable suppression of HBV (one that can control it) may be easier to achieve than complete elimination of the virus from the body. Durability of an HBV cure-equivalent will depend on the immune system’s ability to fight residual virus.
Similar to HIV, two main approaches being investigated in HBV cure research are immune-based therapies and gene manipulation.
1. Immune-based therapies: These strategies are aimed at improving immune responses to HBV-containing cells.
The agents would also limit progression to cancer from residual HBV. Examples of immune-based approaches include the use of checkpoint inhibitors that regulate the response of the immune system, therapeutic vaccinations, and antibody infusions. Gilead Sciences announced a new potent toll-like receptor 8 agonist (TLR-8) compound (GS-9688) that will soon be tested in humans.
2. Gene manipulation: Gene editing would involve eliminating or disabling the cccDNA reservoir. These would involve anti-HBV nucleic acids, including gene silencers or gene editors (similar to those used in the HIV cure research field—i.e., CRISPR-Cas). Gene editing tools would need to be very specific to prevent off-target effects. Scientists also believe that advances in gene therapy for HBV infection will be informed by progress made in related scientific fields.
None of the HBV cure approaches tested so far have bene able to reach the cccDNA reservoir in the liver. A cure for HBV would involving clearing these HBV reservoirs. As the HBV cure research field expands, we will also need to grapple with ethical issues similar to those found in the HIV cure research field, including minimizing risks of interventions, fair selection of participants, careful use of language, and adequate informed consent. Community and stakeholder engagement in HBV cure research will be critically important. Currently, there is less community engagement in HBV research than in HIV cure research.
Undoubtedly, the discovery of a cure for hepatitis C (HCV) in 2014 re-energized the field of HBV cure research. Scientists believe that HBV will be easier to cure than HIV. Efforts aimed at achieving HBV cure are intensifying, including the creation of the International Coalition to Eliminate Hepatitis B (ICE-HBV) in 2016 to accelerate discovery of an HBV cure.
2019 HIV & HBV Cure Forum, Towards an HIV Cure Initiative: iasociety.org/HIV-Programmes/Programmes/Towards-an-HIV-Cure/Events/2019-HIV-HBV-Cure-Forum
International Coalition to Eliminate HBV: ice-hbv.org
Revill PA, Chisari FV, Block JM, Dandri M, Gehring AJ, Guo H et al. A Global Scientific Strategy to Cure Hepatitis B. Lancet Gastroenterol Hepatology 2019; 4(7): 545–58.
Sugarman J, Revill P, Zoulim F, Yazdanpanah Y, Janssen HL, Lim SG, Lewin SR. Ethics and Hepatitis B Cure Research. Gut. 2017; 66(3): 389–92.