Space Out Drug Discontinuations Prior to "Drug Holiday"?

Stephen C. Piscitelli, PharmD


September 20, 2000


If someone on zidovudine/lamivudine (Combivir) and efavirenz wants to go off medications for a "holiday," I presume she should stop the efavirenz and continue the zidovudine/lamivudine for a few days to prevent exposure to just efavirenz. How long should she just take zidovudine/lamivudine before stopping it?

Response from Stephen C. Piscitelli, PharmD

The increasingly popular strategy of structured treatment interruptions (STI) raises the question of how to discontinue antiretroviral therapy when using drugs with differing half-lives. For example, efavirenz has a half-life of 40-55 hours compared with about 2 hours for indinavir.[1,2] Clearly, efavirenz will remain in the body for a much longer period of time. The discontinuation of both agents simultaneously may lead to a situation resembling monotherapy with efavirenz, possibly leading to the development of resistance. Although this risk remains theoretical, many clinicians may choose to discontinue therapy in such a manner that all drugs are eliminated at approximately the same time.The half-life of a drug can be used to estimate how long it will take for a drug to be eliminated from the body as shown in the table below. For example, after 2 half-lives, 75% of a drug has been eliminated.


% of drug eliminated from body















From a clinical standpoint, it is common to assume that a drug is effectively eliminated after 4-5 half-lives. So, in strict pharmacokinetic terms, if we use a half-life of efavirenz of 50 hours, we would conclude that it is eliminated in 250 hours (5 half-lives), or about 10 days. The protease inhibitor indinavir, by contrast, would be eliminated in about 10 hours after stopping therapy. Therefore, if the regimen to be stopped contained both these agents, one might want to discontinue efavirenz first, and then stop indinavir 7-10 days later.For nucleoside analogues, one must consider the intracellular half-life, which is usually much longer than the plasma half-life. This is because these drugs are phosphorylated inside the cell to their active antiviral moiety. For zidovudine/lamivudine, the intracellular half-lives of zidovudine and lamivudine have been reported to be 4 and 12 hours, respectively.


Thus, one could consider zidovudine to have undergone 5 half-lives in approximately 1 day and lamivudine in approximately 2-3 days. In combination with efavirenz, one might therefore consider discontinuing the efavirenz first and then stopping the zidovudine/lamivudine about 7 days later.

This all sounds very simple, but it does not take into account the replication half-life of the virus and the number of replication events that may occur during the interval that the drug is being cleared. This is not critical for drugs with short half-lives. However, for drugs that have extended half-lives such as nevirapine and efavirenz, it may take many days for a relatively minimal amount of drug to be cleared from the body. In this case, for example, if efavirenz is stopped 7 days before stopping zidovudine/lamivudine, half of that interval may involve clearance of residual efavirenz that is already between 87.5% and 96% eliminated from the body. During this period of suboptimal efavirenz therapy, the virus may have a chance to replicate and develop resistance to a suboptimal nucleoside reverse transcriptase inhibitor (NRTI) regimen. This possibility remains unknown but may become more important in an individual undergoing multiple serial STIs. Although only theoretical, clinicians may want to consider a more conservative limit of stopping concomitant NRTIs after only 3 half-lives of efavirenz or nevirapine.

Another important point is that these calculations are only approximations. In addition to some underlying pharmacokinetic assumptions, the half-life from the package insert does not take into consideration the large interpatient variability in drug elimination. Not all patients eliminate drugs at the same rate: some patients may be rapid eliminators with short half-lives while others may eliminate the drugs more slowly with longer half-lives. Despite these limitations, clinicians may use these basic pharmacokinetic principles to space out drug discontinuations in an attempt to minimize the exposure of virus to high and prolonged concentrations of 1 drug in the regimen.