Efavirenz may linger for up to eight weeks after treatment stops

Levels of efavirenz (Sustiva) sufficient to cause drug resistance may linger for at least eight weeks after it is stopped in some people who have a genetic predisposition to clear the drug from the body very slowly, according to researchers from St George’s Hospital, London, and Liverpool University, who report their findings in the October 15^th edition of AIDS.

The findings are likely to add to concerns over the wisdom of treatment interruptions in patients taking efavirenz, the most commonly prescribed drug for first-line treatment in much of the developed world.

The research group report the case of an African woman who suddenly stopped efavirenz treatment because she feared that she was pregnant (efavirenz may cause birth defects if the foetus is exposed to the drug during the first 13 weeks of development). Four weeks later she informed her doctor, and at this time still had undetectable viral load. Her viral load remained undetectable eight weeks after stopping and did not rebound until sampling took place twelve weeks after therapy ceased, by which time it had risen to 2031 copies/ml.

Efavirenz concentrations remained high for at least four weeks after stopping treatment, at which point drug levels still lay within the range that would be considered effective. Remarkably, viral load still remained undetectable at week 8, when efavirenz levels had fallen from 1837ng/ml to 296ng/ml. Unfortunately a blood sample was not available for therapeutic drug monitoring at week 12.

A mutation associated with efavirenz resistance (M230L/M) was detectable at week 12, but this virus was part of a mixed population of mutant and wild-type virus. The classic mutations associated with efavirenz resistance did not emerge despite an extended period of monotherapy with the drug.

The patient’s slow clearance of efavirenz had been noted during a previous treatment interruption. In 1999 the patient interrupted treatment for almost six months, and her viral load remained below 400 copies/ml 28 days after stopping a regimen of ddI (didanosine, Videx), hydroxyurea, 3TC (lamivudine, Epivir) and efavirenz. At this time efavirenz levels were still around 995ng/ml, just below the level considered to be effective.

In order to identify whether a specific genetic profile was associated with efavirenz clearance, genotyping of the enzymes associated with efavirenz clearance was carried out. The patient proved to have a CYPB26 genotype that is highly unusual in Caucasians (G516T heterozygous, A785 homozygous, all other polymorphism sites wild type), occurring in less than 1% of the population. Its frequency in Africans is unknown, and its association with efavirenz clearance has not been established, although a single polymorphism at G516T is already known to be associated with slower efavirenz clearance in black Africans.

The authors suggest that current UK recommendations to cover the efavirenz tail-off period with Kaletra for 14 days or to discontinue efavirenz 14 days prior to the dual nucleoside analogue backbone may not be appropriate for all patients.

“It may be clinically inappropriate to guess the period of drug cover required, particularly in those from at risk groups. Monitoring the decay of plasma drug concentrations (ideally with as rapid a turnaround as possible) may be a wiser approach to manage NNRTI treatment interruptions.”