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A potential strategy to design new treatment regimens for Hepatitis C

Hepatitis C is a severe liver disease that affects more than 130 million people worldwide. There is currently no vaccine for the disease, making it one of the most deadly viral infections prevalent today.

Dr. Narendra Dixit and his team from the Department of Chemical Engineering, Indian Institute of Science, have been studying the dynamics of hepatitis C viral infections for over ten years. Using mathematical and computational models, the latest study has shown why two different types of antiviral drugs can be used in concert to treat the disease.

At the core of this recent finding is the idea of 'synergy' between drugs. “Synergy is when two or more drugs act in concert such that when administered together, they are needed at much lower doses than if they are used individually to produce the same effect”, explains Dr. Dixit. This knowledge can change the design of drug regimens against the hepatitis C virus in future.

Usually synergy between drugs occurs when both drugs impinge on the same pathway or if they ultimately complement each other in their action. Narendra Dixit, along with his PhD student, Pranesh Padmanabhan, has cracked a recent biological mystery – how a class of drugs called entry inhibitors (EIs) are synergistic with other classes of drugs. The catch is that EIs are synergistic with many types of drugs that act in vastly different ways. Since it is unlikely that EIs impinge on every one of the pathways inhibited by these varied classes of drugs, the observed synergy simply could not be explained until now.

“Diseases caused by viruses like HCV are very difficult to treat; accurate animal models of the disease are unavailable and most research is carried out in petri dishes in vitro”, says Dr. Dixit.

The team hypothesised that a broader mechanism -- unrelated to the exact effects of the drugs themselves -- contributed to this synergy. Populations of cells often differ in their expression of molecules that are targeted by anti-viral therapeutic agents. The study argues that the heterogeneity (variation) in the number of targets in infected cells is what contributes to anti-viral drug synergy. What this means is that when the targets of two drugs are present at varying levels in a cell population, the drugs exhibit synergy irrespective of their mechanisms of action.

“This (target cells contributing to drug synergy) is a new concept in HCV, but could be a much more generic phenomenon. In principle, any two drugs whose targets exhibit heterogeneity may be synergistic” emphasizes Dr. Dixit. “While designing drug combinations, target heterogeneity would be an important factor to account for. It doesn’t matter what you target, it looks like the drugs will act in synergy if their target levels vary from cell to cell!” he exclaims. This could change the combinations and dosages in which drugs are administered, not only in HCV infections, but also against bacterial, viral or even cancer-related pathologies.

According to the World Health Organisation, close to 500,000 people die every year due to hepatitis C-related liver diseases. The disease can remain asymptomatic for decades, and is sometimes detected only when symptoms of severe liver damage emerge. With several types of drugs against HCV in the development and efficacy testing pipeline, it is important to ensure that the latest drugs are used to provide the greatest potency with minimal side effects. In this respect, the discovery of how drug synergy works is not one for HCV researchers alone. Today, multi-drug therapy is used to treat almost every clinical syndrome and the latest work of Dr. Dixit’s team lends hope that every human affliction will in future be met with the best possible combination of drugs available.

About the authors:

Dr. Narendra Dixit is an Associate Professor in the Department of Chemical Engineering, Indian Institute of Science, Bangalore. Pranesh Padmanabhan did his PhD with Dr. Dixit.

e-mail: narendra@chemeng.iisc.ernet.in

About the paper:

The research titled “Modeling suggests a mechanism of synergy between hepatitis C virus entry inhibitors and drugs of other classes” was published online in CPT Pharmacometrics and Systems Pharmacology (2015).