Sunday, September 25, 2016

Does Resistance to One Antiviral Indicate Resistance to Another

            Infection by the Hepatitis B virus causes the liver disease Hepatitis B, which can lead to liver failure and cancer.  A simple vaccine can reduce chances of infection, but in places with widespread poverty many people can’t afford the cost of a vaccine.  Subsequently, in such places infection rates remain consistently high leading to an estimated 240 million people worldwide who are chronically infected and 686,000 people who die as a result of Hepatitis B every year.[1]  Due to the epidemic of chronically infected Hepatitis B patients, antiviral drugs have been developed to help prevent the onset of Hepatitis B.  One particular type of antiviral is called a nucleoside analogue.  Such antivirals work by inhibiting viral replication through the use of an alternative DNA subunit, which can be incorporated into viral DNA and subsequently blocks a virus’ own replication machinery.[2]  Nucleoside analogues are exceedingly useful therapies until mutations in the virus’ genetic material causes resistance to the antivirals. 
            A paper[3] published in the journal Nature in July of 2016 by Liu et al. details the usefulness of a specific nucleoside analogue, Entecavir, for treatment of a chronic Hepatitis B infection.  The researchers examined the effectiveness of Entecavir treatment in participants who had never been treated with a nucleoside analogue compared to those who had been treated with one, either lamivudine (LAM) or adefovir dipivoxil (ADV).  The study was conducted over 5 years on 89 individuals from China who were infected with Hepatitis B for at least 6 months and were only treated with Entecavir.  Statistical analysis was used to determine if Entecavir lead to viral remission as associated with prior treatment with LAM, prior history of LAM-resistance, prior history of partial virus resistance to ADV, and prior history of primary treatment failure to ADV. 
            The results of the study indicated that anyone who had never been treated with a nucleoside analogue before exhibited complete viral remission with only a minimal chance of developing resistance.  This is opposed to patients previously treated with a nucleoside analogue, who still responded well to Entecavir but at a lower rate of remission.  The sample group was further characterized by experience with LAM and ADV.  Interestingly, individuals previously treated with LAM, with or without developing resistance, were successfully treated for Hepatitis B, as were ADV patients with partial resistance.  However, ADV-experienced patients who had failed previous treatment had a significantly reduced probability of achieving viral remission when treated with Entecavir. 
            The study by Liu et al. provides important support for reducing antiviral resistance as a result of overuse.  Chronic Hepatitis B can be effectively treated with antivirals, like Entecavir, but for those who failed the first line treatment, doctors should carefully choose the next course of therapy.  By not just prescribing any antiviral when someone has an infection, hopefully the current issue with widespread antibiotic resistance can be avoided, or at least minimized, in regards to antivirals.  The results of the paper strongly support conscientious and judicious use of antiviral drugs.  
            The treatment distinction suggested by Liu et al. for patients with different histories is also indicative of the future of medicine.  Previous means of treating a disease involved a one-size fits all approach.  For example, the paper discusses how ADV was the primary means of treatment for chronic Hepatitis B in China for the past decade.  If a patient was diagnosed with Hepatitis B, he or she was most likely given ADV without deliberation.  However, as the results of the study indicated, such an approach is not effective due to acquired resistance.  Thus, it is important for those in the healthcare profession to consider a patient’s personal history prior to treatment in order to successfully treat an infection, instead of relying on a generalized approach. 
In order to facilitate the growth of personalized medicine, basic research into the conditions affecting the success of a particular treatment is necessary.  Liu et al. provided important information on a specific drug, but the study was limited by size, as acknowledged by the researchers.  Future research should be more wide spread, meaning more antivirals examined in a larger number of participants with different conditions.  Such work would allow for the development of a comprehensive set of guidelines regarding the use of antivirals.  Analysis of a large set of treatment results could be the beginning of a global initiative for stemming antiviral resistance by providing personalized treatment.

[1] http://www.who.int/mediacentre/factsheets/fs204/en/
[2] https://livertox.nlm.nih.gov/NucleosideAnalogues.htm
[3] Liu, K. et al. A five years study of antiviral effect of entecavir in Chinese chronic hepatitis B patients. Sci. Rep. 6, 28779; doi: 10.1038/srep28779 (2016).

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