New HBV Drugs and Non-Viral Liver Disease in HIV-Positive People
Chronic hepatitis B (HBV) infection affects 350 million people worldwide and causes more than 600,000 deaths per year. Despite the prevalence of this virus, it is still poorly understood. Several challenges include achieving a cure, understanding the natural history and reducing the risk of hepatocellular carcinoma.
In a session on hepatology highlights for HIV doctors, Patrick Kennedy from Queen Mary College London reviewed the current understanding of chronic HBV infection, as well as advances in treatment.
The immune response to HBV characterises different phases of the natural course of infection, which includes: 1) immune tolerance; 2) immune clearance; 3) immune control; and then typically 4) immune escape.
Dr. Kennedy proposed that the immune regulatory marker PD1 might be involved in the establishment and maintenance of immune tolerance to HBV as both HBV antigen and T cells are present in the liver during the tolerant phase, but inflammatory cells fail to be recruited to the tissue. PD-1 expression on T cells is high in these patients. During this phase damage occurs to the liver that involves collagen deposition. Therefore, these phases should be regarded as non-inflammatory and inflammatory, rather than tolerant and active.
Current therapies are non-curative for the majority of people and include pegylated interferon (peg-IFN) and nucleoside analogies. While treatment can bring about long-term viral suppression, sustained immune control is limited. In contrast to single drug therapy, sequential nucleoside therapy with peg-IFN results in a greater decline in tissue HBV surface antigen as well as increasing the function of NK cells.
New classes of therapies are in development for chronic HBV. These include antiviral drugs that target sites in the viral life cycle: viral entry; clearance of viral cccDNA from the nucleus; and suppression of HBV DNA, RNA and/or proteins. Other therapies for HBV might utilise boosting HBV-specific adaptive immunity by blocking PD-1, or with HBV therapeutic vaccines, or engineered T cells that have high affinity receptors for HBV. Another approach is the development of antibodies tailored to deliver cytokines, such as interferon, to the interior of hepatocytes, making them resistant to infection. Clinical trials of these approaches are currently ongoing.
The end of the presentation included a brief overview of non-alcohol fatty liver disease (NAFLD), which is an emerging problem in long-term HIV infection and was the subject of considerable discussion at this conference. As much as 30% of the population may have NAFLD, which is thought to be caused by high blood lipids. Of those, 12-40% may develop non-alcoholic steatohepatitis (NASH), which probably results from inflammation or inflammatory mediators (though not necessarily originating in the liver). Approximately 15-20% of people with NASH develop liver cirrhosis, which is fatal in 50% of cases and a further 7% may then develop hepatocellular carcinoma. The main interventions are management of metabolic syndrome, and management of cardiovascular risk factors.
Kennedy P. Hepatitis B virus -- the role of new drugs and non-viral liver disease in HIV. 22nd Annual BHIVA Conference, 19-22 April 2016, Manchester. Invited lecture.
www.bhiva.org/documents/Conferences/2016Manchester/Presentations/160419/PatrickKennedy.pdf (PDF slides)