Sunday, February 21, 2010

TCAD: A Triple Play Combination


# 4367



From PLOS One  a fascinating look at the application of TCAD (Triple Combination Antiviral Drug) therapy against a variety of influenza viruses in vitro.


A few short years ago Amantadine was the preferred influenza antiviral.  It was cheap, plentiful, and worked pretty well.  


But by late 2005 Amantadine began to lose its effectiveness against the H3N2 seasonal flu virus and some strains of the H5N1 bird flu, possibly as a result of the prophylactic use of the drug by Chinese poultry farmers who routinely included it in their chicken feed for several years.


In January of 2006 the CDC issued a warning to doctors not to rely on Amantadine or Rimantadine to treat influenza.


Tamiflu (Oseltamivir), while far more expensive, became the new treatment standard.  


But within two years seasonal H1N1 began to show growing resistance to Tamiflu as well (although H3N2 remained sensitive).  By the spring of 2009, - in the space of just about a  year – seasonal H1N1 had gone from almost 100% sensitive to the drug to nearly 100% resistant.


With novel H1N1, a new subtype of H3N2 in circulation along with  many clades of H5N1, and a waiting room filled with pandemic contenders (H7N7, H9N2, H10N7) the need for an effective treatment regimen has not diminished.


The choice right now is between using increasingly higher doses of single antiviral (i.e. Oseltamivir) verses a multi-drug regimen.   Last summer, in a PLoS Medicine article, these choices were debated by a number of noted researchers including Dr. Robert Webster.



What Is the Optimal Therapy for Patients with H5N1 Influenza?


Here Webster and Elena Govorkova (both of St. Jude Children's Research Hospital, Memphis Tennessee) argue in favor of a multi-drug approach to treating H5N1 influenza.


Earlier in the year, Webster spoke out against our reliance on just one spear tip when combating a pandemic.


Webster: Better Drugs Needed To Fight A Pandemic

More From Robert Webster On Antiviral Usage


In this second blog entry, I link to an interview of Webster by Trine Tsouderos, staff writer for the Chicago Tribune.   Those original links no longer appear to be valid, but I’ve a quote from the original article below:


On why we shouldn't use just one drug -- Relenza -- to replace Tamiflu when treating this particular strain of flu, as the Centers for Disease Control recommends:

"The future for antivirals for the flu is the use of combination therapy. Nature is teaching us a lesson here. We should have learned from HIV that if you use mono-therapy drugs, you are asking for trouble. It is a stats game. If you use one drug, you will get resistance. But if you use two, it squares your chances. And with three, the chance of resistance goes down, and if you have four, you have a combination that goes on for years and years. With flu, we don't have that luxury, but we can use them in combination already. And we are not doing so."



Which brings us to today’s PLoS One  study, entitled:


Triple Combination of Amantadine, Ribavirin, and Oseltamivir Is Highly Active and Synergistic against Drug Resistant Influenza Virus Strains In Vitro


Nguyen JT, Hoopes JD, Le MH, Smee DF, Patick AK, et al.


Here researchers evaluated the in vitro activity of various antiviral drug combinations against drug resistant influenza viruses.   They found that a triple combination was highly synergistic, and out performed any single or double drug combination.

The three drugs tested were Oseltamivir, Amantadine, and Ribavirin.   Tests were conducted in vitro on MDCK (Madin-Darby Canine Kidney) cells, not on human test subjects.


Ribavirin is the oddball here, as it is not generally used against influenza.  It is used mostly for severe RSV (respiratory syncytial virus) or is given in combination therapy with  interferon to treat hepatitis C.  


Interestingly, even Amantadine – which alone almost had no effect against some of these viruses – when given in combination with these other antivirals significantly improved the antiviral activity.


The Abstract to this study follows (slightly reformatted for readability).  But you may find the entire journal report of interest.



The rapid emergence and subsequent spread of the novel 2009 Influenza A/H1N1 virus (2009 H1N1) has prompted the World Health Organization to declare the first pandemic of the 21st century, highlighting the threat of influenza to public health and healthcare systems.


Widespread resistance to both classes of influenza antivirals (adamantanes and neuraminidase inhibitors) occurs in both pandemic and seasonal viruses, rendering these drugs to be of marginal utility in the treatment modality. Worldwide, virtually all 2009 H1N1 and seasonal H3N2 strains are resistant to the adamantanes (rimantadine and amantadine), and the majority of seasonal H1N1 strains are resistant to oseltamivir, the most widely prescribed neuraminidase inhibitor (NAI).


To address the need for more effective therapy, we evaluated the in vitro activity of a triple combination antiviral drug (TCAD) regimen composed of drugs with different mechanisms of action against drug-resistant seasonal and 2009 H1N1 influenza viruses. Amantadine, ribavirin, and oseltamivir, alone and in combination, were tested against amantadine- and oseltamivir-resistant influenza A viruses using an in vitro infection model in MDCK cells.


Our data show that the triple combination was highly synergistic against drug-resistant viruses, and the synergy of the triple combination was significantly greater than the synergy of any double combination tested (P<0.05), including the combination of two NAIs. Surprisingly, amantadine and oseltamivir contributed to the antiviral activity of the TCAD regimen against amantadine- and oseltamivir-resistant viruses, respectively, at concentrations where they had no activity as single agents, and at concentrations that were clinically achievable.


Our data demonstrate that the TCAD regimen composed of amantadine, ribavirin, and oseltamivir is highly synergistic against resistant viruses, including 2009 H1N1. The TCAD regimen overcomes baseline drug resistance to both classes of approved influenza antivirals, and thus may represent a highly active antiviral therapy for seasonal and pandemic influenza.