Correspondence
Substitution for Protease Inhibitors in HIV Therapy
N Engl J Med 2003; 349:2460-2461December 18, 2003
- Article
To the Editor:
Martínez et al. (Sept. 11 issue)1 report that among patients who switched to efavirenz from a protease inhibitor, 29 (18.6 percent) subsequently discontinued efavirenz without virologic failure. This proportion is considerably in excess of that reported by Staszewski et al. in the pivotal study that established the superior efficacy of efavirenz in comparison with indinavir (4 percent).2
My colleagues and I have found that switching to efavirenz from a protease inhibitor is less well tolerated by patients who have acquired human immunodeficiency virus (HIV) infection through intravenous drug use than by other patients, with a 25 percent rate of discontinuation during the first month after the switch.3 The reasons are speculative: lower tolerance of the neuropsychiatric side effects of efavirenz or withdrawal symptoms related to the effects of efavirenz.4
In the study by Staszewski et al.,2 less than 10 percent of the patients were in the category of transmission through intravenous drug use. In contrast, our study and the study by Martínez et al. included many such patients. I would be interested to know whether the apparently lower tolerance of efavirenz in the trial by Martínez et al. was concentrated in the subgroup of patients with current or former intravenous drug use.
4 ReferencesBernard Hirschel, M.D.
Geneva University Hospital, CH-1211 Geneva, Switzerland
bernard.hirschel@hcuge. ch 1
Martinez E ,Arnaiz JA ,Podzamczer D , et al. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with human immunodeficiency virus infection. N Engl J Med 2003;349:1036-1046
Full Text | Web of Science | Medline2
Staszewski S ,Morales-Ramirez J ,Tashima KT , et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. N Engl J Med 1999;341:1865-1873
Full Text | Web of Science | Medline3
Hirschel B ,Flepp M ,Bucher HC , et al. Switching from protease inhibitors to efavirenz: differences in efficacy and tolerance among risk groups: a case-control study from the Swiss HIV Cohort. AIDS 2002;16:381-385
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Marzolini C ,Troillet N ,Telenti A ,Baumann P ,Decosterd LA ,Eap CB . Efavirenz decreases methadone blood concentrations. AIDS 2000;14:1291-1292
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To the Editor:
One limitation of the study by Martínez et al. may have an effect on interpretation of the results. There was no fourth, control group of patients who continued to take their previous highly active antiretroviral therapy (HAART). Because there was no significant change in the proportions of patients with lipodystrophy during follow-up, the authors concluded that switching from a protease inhibitor to one of the three study medications in order to ameliorate body-fat abnormalities was not a useful strategy.
Careful prospective studies show that the incidence of lipodystrophy increases with the duration of exposure to HAART, with approximately a 57 percent increase per six months of additional exposure.1 Thus, the inclusion of a control group of patients who continued to take a protease inhibitor might have shown that switching to one of the study drugs was beneficial, since the overall severity of lipodystrophy did not progress over the next 12 months. In addition, some differences in the study outcomes could be attributable to differences in compliance with the drug regimen, a factor that was not assessed in the trial.
1 ReferencesErian Mikhail, M.D.
Olive View–UCLA Medical Center, Sylmar, CA 91342
gchavez@ucla.edu 1
Martinez E ,Mocroft A ,Garcia-Viejo MA , et al. Risk of lipodystrophy in HIV-1 infected patients treated with protease inhibitors: a prospective study. Lancet 2001;357:592-598
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Author/Editor Response
The incidence of discontinuation of the study drug because of adverse effects was higher in the efavirenz group (27 patients [17 percent] discontinued the study drug) and in the nevirapine group (26 [17 percent]) than in the abacavir group (9 [6 percent], P=0.01 by the chi-square test). The higher incidence of adverse effects in the efavirenz and nevirapine groups would have compensated for the lower virologic efficacy in the abacavir group if an intention-to-treat analysis (with noncompletion equivalent to failure) had been performed. Dr. Hirschel asks how many of the instances of drug discontinuation in the efavirenz group were among patients who had acquired HIV infection through intravenous drug use. Among the 171 intravenous drug users included in the study, only the rate of discontinuation of nevirapine was significantly higher than that among nonusers (28 percent vs. 9 percent, P=0.04 by Fisher's exact test), not the rates of discontinuation of efavirenz (25 percent vs. 17 percent, P=0.3 by Fisher's exact test) or abacavir (6 percent vs. 6 percent, P=1.00 by Fisher's exact test).
Our study was designed to determine the best substitute for a protease inhibitor in patients with a virologic response who wished to change the protease-inhibitor component of their regimen, for whatever reason. The main objective of the study was to perform a head-to-head comparison among nevirapine, efavirenz, and abacavir as potential candidates for a simplified regimen. Accordingly, a fourth control group of patients who continued to use a protease inhibitor was not considered. Dr. Mikhail points out that the lack of an increase in the prevalence of lipodystrophy at 12 months, as compared with base-line values, can be interpreted as a potential beneficial effect. However, this effect has not been demonstrated in studies that included objective measurements of body fat and in which there was a control group of patients who continued to use a protease inhibitor.1
The patients included in our study had long-term, stable, optimal virologic responses with their protease-inhibitor–containing therapies, and they participated in the trial because of the appeal of switching to a simpler regimen with potential equivalence to their protease-inhibitor–containing regimen. Although we assumed that the rate of compliance among these patients was high, Dr. Mikhail is right in stating that no specific assessment of drug compliance was performed.
1 ReferencesEsteban Martínez, M.D.
Elisa de Lazzari, B.Sc.
José M. Gatell, M.D.
Hospital Clínic–Institut d'Investigacions, Biomediques August Pi i Sunyer, 08036 Barcelona, Spain
esteban@fundsoriano.es 1
Ruiz L ,Negredo E ,Domingo P , et al. Antiretroviral treatment simplification with nevirapine in protease inhibitor-experienced patients with HIV-associated lipodystrophy: 1-year prospective follow-up of a multicenter, randomized, controlled study. J Acquir Immune Defic Syndr 2001;27:229-236
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