EACS: Once-a-day Kaletra can be risky

An analysis of the ARTEMIS trial in which boosted darunavir (DRV/r – Prezista) was compared to boosted lopinavir (LPV/r – Kaletra) indicates that most of the somewhat poorer performance of Kaletra was driven by treatment failures in the minority of patients who took the drug once a day.

A second study comparing the pharmacokinetics of boosted lopinavir with those of boosted atazanavir (Reyataz) found that the poorer performance of once daily Kaletra may be due to the fact that, after 24 hours, blood levels of lopinavir had sunk to levels close to the minimum effective concentration needed for HIV suppression, so that missed doses might easily lead to viral rebound.

The ARTEMIS trial results were reported at last month's ICAAC conference in Chicago. Briefly, about 700 patients were randomised 1:1 to receive either once-daily darunavir tablets plus a 100mg ritonavir capsule or Kaletra tablets either once or twice daily. After 48 weeks 84% of those on DRV/r had viral loads below 50 compared with 78% on LPV/r. This difference was not statistically significant. However in patients who started the trial with viral loads over 100,000, 79% versus 67% of patients became undetectable on DRV/r and LPV/r respectively, and this difference was significant.

In Europe Kaletra is only licensed for twice-a-day dosing, but physicians have the choice of prescribing it twice- or once-daily in the USA. In the trial 267 patients (77%) took it twice-daily, 52 (15%) used it once-daily, and 27 (8%) changed from twice to once a day. Once-daily dosing was the rule, not the exception, in the United States, where two-thirds of the 68 patients took it that way, but was rare elsewhere.

Trial investigator Nathan Clumeck found that the greater failure rate in patients on LPV/r was largely driven by failure in those taking it once a day. The percentage achieving a viral load under 50 was 84% in DRV patients, 81% in lopinavir twice-daily (LPV bid) but 71% in LPV once-daily (qd).

In patients starting with viral loads under 100,000 the difference was not statistically significant (DRV 86% below 50, LPV twice-daily also 86%, LPV once-daily 79%). However in patients with baseline viral load over 100,000 copies/ml, there was a big difference, with 79% of DRV patients, 71% of LPV twice-daily patients, and only 56% of LPV once-daily patients achieving undetectable viral load.

A couple of caveats should be borne in mind. The number of patients taking once-daily LPV was small, and the number with baseline viral load over 100,000 was still smaller – only 18 patients – so the 56% figure indicates that eight out of these 18 failed therapy – a small number on which to base strong conclusions. Furthermore, the choice of whether to prescribe Kaletra once- or twice-daily was not randomised, but chosen by physician and patient, so there may have been other characteristics of once-daily patients, such as poor adherence, that inclined doctors towards a once-daily dose and may have biased the results.

However another study of the pharmacokinetics (drug concentrations achieved in the body) of boosted lopinavir indicates that a once-daily dose may sail too close for comfort to the zone where viral replication may resume. Marta Boffito of London's Chelsea and Westminster Hospital gave 16 HIV-negative volunteers, in turn, atazanavir-plus-ritonavir (300mg ATZ and 100mg RTV) once a day, Kaletra 400/100 mg twice a day, and then Kaletra 800/200 mg once a day, in each case for ten days, then measured the drug concentrations in their blood for 72 hours after the last dose.

She found that no volunteers taking atazanavir/r had concentrations below the minimum effective concentration (MEC) needed for viral replication after 24 hours – but that 44% of volunteers taking Kaletra once-daily did have sub-optimal concentrations by this point.

The MEC of atazanavir was reached on average 40 hours after the last dose, with 25 hours the shortest time seen in the 16 volunteers. The MEC of lopinavir once-daily was reached 25 hours post-dose on average, with a minimum time of 17 hours. For LPV twice-daily the MEC was reached, on average, 18 hours post-dose.

If the next dose was delayed by another twelve hours (if, for instance, patients usually took their dose in the evening, forgot it, then realised the following morning) , then 31% of pateints on atazanavir/r, 81% of those on twice-daily Kaletra , and 100% of those on once-daily Kaletra were below the MEC. Clearly, if this happens repeatedly, treatment failure is a risk.