Hep B Treatment

Hepatitis B Treatment

Not necessarily a life-long commitment

There is a common view that once you start hepatitis B treatment, you will be on it for life. This is changing. In recent years, numerous studies have been done looking into the notion of a functional cure for hepatitis B which, when achieved, means therapy can be stopped. What is functional cure? Current hepatitis B treatment cannot completely cure the disease; the aim of current therapy is to suppress the virus sufficiently to prevent liver cirrhosis, liver failure or liver cancer, and thus improve survival. The hepatitis B virus embeds bits of itself in the host cell, allowing it to reactivate and replicate. Current therapy cannot eradicate this remnant of the virus, which is known as the covalently combined closed DNA (cccDNA). For complete cure to happen, the cccDNA must be eliminated, not merely silenced. The virus also produces other bits of itself in its replication process. Some hepatitis B treatment drugs target various parts of this process, while others seek to enhance the body’s immune system to fight against the virus. A functional cure is a state where the other elements of the virus are eliminated or reduced to the point where the risk of adverse outcomes such as liver failure, is minimal, even though the cccDNA remains. People who have chronic hepatitis B have various bits of the virus in their blood as a result of the virus replication process. The presence or absence of these bits act as markers for working out which stage the disease is at. One of these bits, known as the hepatitis B surface antigen (HBsAg) is the key marker that a person has chronic hepatitis B. Studies have shown that the level at which it exists in the blood is a good indicator of whether the disease is under control. Generally speaking, the indicators that treatment is working in achieving the goals of maintaining liver health and improving survival are: • normal ALT levels, • loss of hepatitis B surface antigen (HBsAg), • undetectable hepatitis B

DNA, and • the appearance of hepatitis B e-antibodies (antiHBe). Do these indicators, or end points as they are referred to, really lead to better outcomes for people? According to Prof Lim Seng Gee, Director of Hepatology at the National University of Singapore, meta-analysis

shows significant benefits from the loss of HBsAg: • 72% reduction in liver decompensation, • 70% reduction in liver cancer, and • 78% reduction in liver transplant or death. These outcomes apply across all sub groups including coinfection, treatment history and race (ethnicity). The idea of looking for functional cure is that when it is achieved, treatment can stop. But why stop treatment at all? There are a few reasons why treatment cessation is being considered, even though the treatment is working to successfully suppress the virus. Long-term therapy presents challenges, including: • Risk of developing resistance to the drugs, • Significant side effects such as bone loss and kidney damage • Cost of treatment (for the individual if drugs are not subsidised, or for the health system if they are). This factor is an important consideration in countries with limited health resources. • Adherence: for all sorts of individual reasons, sticking to long-term treatment can often be a problem Accepting that functional cure is something to aim for, there are a range of strategies being looked at to get there. These include • using current drugs that target the replication process (nucleoside analogues), • using pegylated interferon (pegIFN), • using nucleosides and pegIFN in combination or in sequence, or • stopping nucleoside analogues. Studies show that while a combination of pegIFN and nucleoside analogues (NA) produce the best outcomes, with over 6.5% achieving HBsAg loss, and that pegylated interferon clearly outperformed NAs, the overall results of less than 10% indicates that new therapies are needed to achieve functional cure. However, there are exciting possibilities in the strategy of stopping nucleoside analogue treatment. Studies have shown that when those treatments are stopped, there is a rebound of HBV DNA and ALT and this stimulates body’s immune response which then reduces the HBsAg level. The likelihood of HBsAg loss is related to the level of HBsAg at the end of treatment. The lower the HBsAg, the higher the chances of HBsAg loss. With quantitative HBsAg levels of less than 100 IU/mL, the surface antigen loss ranged from 21% to 58.5% (see table, above). For people on hepatitis B treatment, the big concern is whether the virus will reactivate once treatment ceases. Studies have shown that when the immune system is suppressed, the virus will reactivate in

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