Ultra-Long-Acting (XLA) Antivirals for Chronic Viral Hepatitis.

Viral hepatitis is among the top four global causes of mortality causing 1.4 million deaths each year, exceeding tuberculosis, malaria and HIV. Hepatitis B and C are responsible for 90% of deaths while 10% are caused by other hepatitis viruses. Whereas annual deaths are declining for hepatitis C, they are rising for hepatitis B and D. Only hepatitis B represents the 7th highest cause of mortality worldwide. Spurred by development of curative new antivirals for hepatitis C and expanding access to HBV vaccination, the WHO has committed to eliminating viral hepatitis as a public health threat by 2030. Like the majority of current antivirals, those available for hepatitis B are virostatic. They are capable of suppressing virus replication but cannot eliminate the virus from those infected. Therefore, treatment is lifelong. Long-term medication adherence continues to be a major challenge. Importantly, HBV often reactivates leading to potential life-threatening events in immunosuppressed patients. For hepatitis delta, therapeutic options are limited. However, promising new and effective antivirals are on sight. Recent advances have emerged in medicinal chemistry and drug delivery approaches to produce ultra-long-acting (XLA) antivirals. These can extend antiviral activities from months to one year or even longer. Such new formulations can overcome the challenges of daily dosing and maximize drug exposure. The development of XLA-antivirals targeting viral hepatitis may also facilitate cure strategies.