Drugs that prevent entry of the Hepatitis C virus (HCV) into the host cells are equally effective as other drugs, finds a new study from the Indian Institute of Science (IISc), Bengaluru, published recently in the Proceedings of the National Academy of Sciences. These drugs, called entry inhibitors, when combined with drugs that prevent the multiplication of the virus inside the host cell, or direct-acting antivirals, can be a potent combination for treating the infection.The Hepatitis C virus (HCV) infects the liver and spreads mainly through infected needles. Estimates suggest up to 1% of the Indian population may be infected with HCV. A large number of afflicted people develop chronic infection, and sometimes even liver cancer.
A study published in early 2017 by Japanese researchers reported that a combination of three direct-acting antivirals was most powerful in treating the infection in the lab and ranked various drug combinations according to their potency. Such studies help find candidates for clinical trials.
They tested these drugs in the lab in cell culture systems called HCV replicons, which have all the properties of the virus but do not have an outer structure. “A consequence of this was that they could test all the drugs that blocked various steps in the replication process, but not drugs that could block the entry of the virus inside the cell,” said Dr. Narendra Dixit, professor in the Department of Chemical Engineering at IISc and a lead author of the new study.
He and his student Pranesh Padmanabhan asked if the rankings determined by the Japanese study are really the best or if including the entry inhibitor drugs can actually change the optimum drug combinations.
Th e IISc team mathematically analysed previously published data for entry inhibitors showing how infected cells are affected when exposed to different doses of drugs for a certain time. They showed that they could rank the different entry inhibitor drugs on a scale, similar to that used for HIV drugs, instantly showing which drug was more potent.
Based on this ranking, they found the potency of the entry inhibitors spanned the range seen for direct acting antivirals, with some drugs being almost as powerful as the best direct-acting drugs.
“Entry inhibitors are a big deal because these are also mimics of the antibodies that our body produces. That is one of the ways in which our immune system works,” said Prof. Dixit. Another advantage is that they reduce the emergence of drug resistant mutations, a big disadvantage of direct-acting antivirals.
Considering this finding, the Japanese group who performed the original drug-combination study added entry inhibitors to their cocktail of drugs. They reported that a three-drug combination that included an entry inhibitor was equally powerful as the previous best three-drug combination.
“Direct acting antivirals in combination with entry inhibitors may further strengthen the armoury against HCV by both inhibition of the virus and reducing the risk of drug resistance,” said Dr. Guruprasad Medigeshi, an associate professor at the Translational Health Science and Technology Institute (THSTI), who was not involved in the study. The original observations were extended by mathematical modelling, which is turn was validated experimentally. It is, according to him, “a classic example of multidisciplinary research.”