Combination antiretroviral regimens continue to fail in some patients [1, 2]. Here we consider a factor that may be important; ie how patients stop therapy. We previously postulated that if one drug in a regimen has a significantly longer half-life than others, and all agents are stopped simultaneously [3] then the patient will be taking essentially ‘functional monotherapy’after the shorter half-life drugs are eliminated (Fig. 1a). The probability of resistance emerging will depend on:(i) the drug’s genetic barrier;(ii) the magnitude of viral replication when the drug remains at a concentration capable of inducing resistance; and (iii) the length of time the drug remains in the zone of resistance selection.

To prevent resistance emerging, stopping the drug with the longer half-life before the other regimen components has been suggested [3–5], but for how long? In some cases resistance to the longer half-life agent still occurs despite this approach [6]. With the development of drugs with extended half-lives, eg tenofovir and emtricitabine, it will become more difficult to provide guidance on stopping drug combinations, especially those with very disparate half-lives.