Letters to the Editor
To the Editor:
Karlstrom et al1 have conducted a pilot clinical trial of boosted atazanavir monotherapy that put patients at unnecessary risk. First, they switched patients who were taking extremely simple regimens to boosted atazanavir monotherapy without knowing if patients were able to tolerate atazanavir and ritonavir. Second, they allowed patients who were receiving efavirenz or nevirapine to switch directly to boosted atazanavir monotherapy. The terminal half-life of nevirapine and efavirenz can be rather long,2 and both are potent inducers of atazanavir metabolism.3 In addition, the induction caused by nevirapine and efavirenz can persist for a number of days after these drugs are stopped. Because of this negative interaction, patients might have had low levels of atazanavir during the first 4 weeks that were missed by the researchers. Third, patients who took contraindicated medications such as ranitidine and lansoprazole were not immediately discontinued from the trial. It is quite dramatic that of the 5 observed failures, 4 occurred in patients who were switched from efavirenz and the other occurred in a patient who was switched from zidovudine plus lamivudine plus abacavir and who received ranitidine along with boosted atazanavir monotherapy.
We have conducted 2 clinical trials of lopinavir/ritonavir monotherapy for maintenance of HIV suppression. To minimize risk for patients, we first conducted a pilot study to rule out an unacceptable rate of resistance development.4 Results of this small trial were encouraging enough to allow us to conduct an adequately powered trial.5 Forty-eight-week efficacy and resistance outcomes in the OK04 trial compare favorably with other well-accepted simplification strategies. Given these results, we consider that the statement by Karlstrom et al that monotherapy studies of boosted protease inhibitors might be unethical is unfounded. This unfair suggestion might have a negative impact on investigators and patients still enrolled in properly designed monotherapy trials. We respectfully remind Kalstrom et al that such strong statements about unethical research should be reserved for trials in which there is at least some evidence that patients are put at risk that could have been easily avoided.
Jose R. Arribas, MD*
Federico Pulido, MD†
Internal Medicine Service (HIV Unit) *Hospital La Paz †Hospital Doce de Octubre Madrid, Spain
1. Karlstrom O, Josephson F, Sonnerborg A. Early virologic rebound in a pilot trial of ritonavir-boosted atazanavir as maintenance monotherapy. J Acquir Immune Defic Syndr
2. Ribaudo HJ, Haas DW, Tierney C, et al. Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study. Clin Infect Dis
3. Atazanavir package insert, Princeton, NJ, 2007.
4. Arribas JR, Pulido F, Delgado R, et al. Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study). J Acquir Immune Defic Syndr
5. Arribas J, Pulido F, Delgado R, et al. Lopinavir/ritonavir as single-drug maintenance therapy in patients with HIV-viral suppression: 48-week results of a randomized, controlled, open label, clinical trial (OK04 study) [abstract THLB0203]. Presented at: XVI International AIDS Conference; 2006. Toronto.