Resistance implications of monotherapy with lopinavir/r (Kaletra)

3 August 2006. Related: Conference reports, Drug resistance, Intl Drug Resistance Workshop 15 Sitges 2006.

Simon Collins, HIV i-Base

Resistance results were presented from two randomised studies of patients who failed on lopinavir/r (Kaletra) monotherapy.

The MONARK study randomised 136 treatment naive patients with baseline viral load <100,000 copies/mL to either lopinavir/r monotherapy (n=83) or lopinavir/r+AZT+3TC (n=53), with follow-up for 96 weeks.

Mean duration of follow up for this analysis was 64 weeks (range 48-96 weeks). Resistance testing was performed following rebound >500 copies/mL after achieving <50 copies/mL, or >1 log from nadir of <400 copies/mL, or after study discontinuation.

A significantly greater percentage of patients receiving monotherapy had viral rebound or poor suppression, therefore qualifying for resistance testing: 21/83 vs 3/53 (25% vs 6%). In the monotherapy arm, two patients showed protease mutation changes from their baseline sequence: one showed M46I on viral rebound at week 40, and the second developed L10F/L and V82A/V mixtures at week 72 after extended duration of low-level viraemia (VL <500 copies/mL). One patient in the 3-drug arm developed M184V resistance to 3TC, but with no change in protease.

The authors emphasised that resistance to lopinaivr/r when used in 3-drug regimens is very rare (ie no cases out of 654 patients in 4 registrational trials and only a single case report has been published), but that other case reports of development of PI resistance mutations have been reported from monotherapy studies. They concluded that the barrier for the selection of PI resistance with LPV/r monotherapy may be lower than with lopinavir/r-based 3-drug regimens.

Hackett and colleagues presented resistance data from a second 96-week monotherapy study, that randomised 155 antretroviral-naive patients 2:1 to either lopinavir/r 400/100mg twice daily (n=104) or efavirenz 600mg once daily (n=51), both with background AZT+3TC. At 24 weeks, and after 3 consecutive undetectable viral load tests <50 copies/mL, 92/104 (88%) of lopinavir/r patients discontinued AZT+3TC and continued on lopinavir/r monotherapy. Median follow-up in this interim analysis was median of 56 weeks (IQR 47-64 weeks).

9/92 (10%) patients on monotherapy had confirmed viral load rebound > 400 copies/mL. Of the 8 evaluable resistance test results, 2 patients developed PI mutations. One patient rebounded at week 40 (16 weeks after reducing to monotherapy) with L10F, M46L, L63P. Further mutations accumulated in this patient (V82A, and I54V were detected at week 48) after the investigator, contrary to the study protocol, continued the patient on monotherapy. The second patient rebounded with extensive PI and RTI resistance 4 weeks after reducing to monotherapy at week 40. Subsequent retesting of baseline and on-treatment samples, indicated re-establishment of pre-existing mutations, which should have been identified at baseline as exclusion criteria.

However, despite baseline resistance, both patients had successfully suppressed viral load <50 copies/mL while on triple therapy, but rebounded after reduction to lopinavir/r monotherapy.

This led the authors to caution that while the risk of resistance with lopinavir/r monotherapy was low, it was higher than with lopinaivr/r based 3-drug combination. They also cautioned against the applicability of lopinavir/r monotherapy even after induction therapy in patients with previous ARV exposure, independently of whether resistance was detected at baseline, or in populations where the risk on infection with drug-resistant HIV is an issue.

Comment

Virological and clinical responses from several small ritonavir-boosted PI monotherapy studies generated hope for the potential of simplified treatment irrespective of previous or concomitant nucleoside use.

Of these, lopinavir/r has received most attention, as toxicity limited the use of indinavir/r monotherapy and potency is a concern for atazanavir/r monotherapy; but these studies were small (generally <20 patients), non-randomised and uncontrolled.

This is also the first significant data on resistance implications with this strategy. The results indicate that background nucleosides contribute something, and support a stronger caution against lopinavir/r monotherapy for treatment-experienced patients.

Final results will be important for both studies. Baseline resistance was only presented for treatment failures in the first study, and no comparative data was provided on the rate of failure for patients using efavirenz in the second study.

Also, although semantics are not the focus of the research, the use of the term ‘deintensification’ – used in both these presentations – probably isn’t helpful when describing reduction therapy.

References:

1. Norton M et al Drug resistance outcomes in a trial comparing lopinavir/ritonavir (LPV/r) monotherapy to LPV/r + zidovudine/lamivudine (MONARK Trial). XV International Drug Resistance Workshop, 13-17 June 2006, Sitges, Spain. Abstract 74.
2. Hackett JR Jr et al. Selection of protease inhibitor (PI) resistance mutations during virological failure of lopinavir/ritonavir (LPV/r) monotherapy in an induction-maintenance study. XV International Drug Resistance Workshop, 13-17 June 2006, Sitges, Spain. Abstract 75.