Tenofovir may linger up to 3 weeks in body: discontinue with caution

Sub-optimal levels of tenofovir (Viread) that could lead to drug resistance may linger in the body for at least three weeks after the drug is discontinued, according to a report in the May edition of Antimicrobial Agents and Chemotherapy. The findings, published by a French and Spanish research group, call into previous assumptions about the safety of discontinuing tenofovir treatment, say the researchers.

The research group originally set out to determine whether the intracellular half-lives of either tenofovir or didanosine (VidexEC) were prolonged when one drug was dosed with the other, since it is known that didanosine plasma concentrations are increased if dosed alongside tenofovir. The study found no evidence that co-administration affected the intracellular half-life of the drugs, which remained the same whether dosed alone or together. Thirty-eight patients receiving one of three regimens (tenofovir alone, ddI alone or tenofovir plus ddI) were compared.

However the researchers found that intracellular concentrations of both drugs remained high for much longer than expected in three patients who discontinued tenofovir treatment. Previous work had suggested an elimination half-life for tenofovir of above 60 hours, but measurements of drug concentrations three weeks after discontinuation showed that whilst tenofovir levels had declined compared to the last day on which the drug was taken, they still lay at around 15-20% of the steady state concentration, indicating that it would have taken at least 7.5 days for half of the drug to be eliminated from the body.

Whilst warning that this value must be established more precisely in a larger scale study, the authors suggest that further guidance is needed on the safe discontinuation of tenofovir, as has already been generated for discontinuation of non-nucleoside reverse transcriptase inhibitors (NNRTIs).

But for patients who miss tenofovir doses, these findings may prove reassuring, since they suggest that tenofovir levels decline so gradually, any reduction over 24-48 hours is unlikely to prove problematic in terms of drug resistance provided that tenofovir is dosed alongside drugs such as 3TC (lamivudine, Epivir), FTC (emtricitabine, Emtriva) and efavirenz (Sustiva), which have similarly slow rates of elimination. Missing doses of tenofovir when it is paired with a protease inhibitor or AZT (zidovudine, Retrovir) might be more likely to give rise to resistance to one of the drugs in the combination, argued pharmacokinetic expert Dr Saye Khoo of Liverpool University, speaking at a recent NAM Clinical Symposium on Controversies in HIV Therapy in London.

This is because when levels of three drugs decline at a similar rate, a drug with a low genetic barrier to resistance (such as 3TC or FTC) is less likely to remain as a single agent that can select drug-resistant virus.