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Mixed results from combination therapy

As we head into winter, it is time to consider treatment options for influenza. Some clinical virologists assumed that combination treatment would be superior to monotherapy [1], but recently published data from a large randomised controlled trial suggest otherwise [2]. For the winter of 2008/ 2009, adult patients who presented to general practitioners within 36 hours of symptom onset were randomised to receive oseltamivir, zanamivir or the combination, using placebo oseltamivir tablets and placebo zanamivir inhalation to maintain blinding. The primary endpoint was loss of detectable influenza RNA by RT-PCR in nasal swabs taken on day 2 of treatment. The secondary endpoint was the time to resolution of symptoms. The results showed that oseltamivir monotherapy was significantly superior to the combination for both the primary and secondary endpoints. Most influenza viruses during that winter were of H3N2 subtype and none was pandemic H1N1 [2]. These results are important in their own right but also beg the question of why some combinations of antivirals work for some viruses but not for others. There are many potential advantages of drug combinations [3]. Two drugs may exhibit synergy, defined as a greater therapeutic response than seen when each component is administered separately, but there is remarkably little evidence for this from randomised controlled trials. Instead, drugs frequently show additive effects that are less impressive than true synergy. Additive effects are still desirable however, especially when conventional treatment is prolonged and/or prone to the selection of resistant strains. In such cases, adherence may be improved by combining two or more drugs into a single tablet such as zidovudine plus lamivudine, zidovudine plus lamivudine plus abacavir and efavirenz plus tenofovir plus emtricitabine. In addition, inclusion of low-dose ritonavir with lopinavir can reduce the hepatic metabolism of the latter when the former inhibits cytochrome P450 enzymes. Such combinations of drugs represent the mainstay of HIV therapy and many clinical virologists are familiar with their