Correspondence

Initial Treatment of HIV-1 Infection

N Engl J Med 2008; 359:970-971August 28, 2008

Article

To the Editor:

In their study comparing three different regimens for initial treatment of human immunodeficiency virus type 1 (HIV-1) infection, Riddler et al. (May 15 issue)1 state that 19 patients died, but the authors report deaths according to study group only in the Supplementary Appendix. These data indicate that nine patients died in the efavirenz group, seven in the nucleoside reverse-transcriptase inhibitor (NRTI)–sparing group, and three in the lopinavir–ritonavir group, but causes of death are not reported. Neither a pairwise comparison of death in the three study groups nor a comparison between the two groups receiving efavirenz (the efavirenz and NRTI-sparing groups) and the lopinavir–ritonavir group is presented. It is reassuring that previous randomized studies comparing efavirenz with a protease inhibitor or nevirapine have not suggested excess mortality among patients assigned to efavirenz.2-4 More detailed information about mortality in the three treatment groups in the study reported by Riddler et al. would be of clinical value.

Thomas R. Schulz, M.B., B.S.
Victorian Infectious Diseases Reference Laboratory, Melbourne, VIC 3050, Australia
thomas.schulz@mh.org.au

Alan C. Street, M.B., B.S.
Royal Melbourne Hospital, Melbourne, VIC 3050, Australia

4 References

1. 1

   Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 2008;358:2095-2106
   Full Text | Web of Science | Medline

2. 2

   van Leth F, Phanuphak P, Ruxrungtham K, et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 2004;363:1253-1263
   CrossRef | Web of Science | Medline

3. 3

   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 | Medline

4. 4

   Squires K, Lazzarin A, Gatell JM, et al. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr 2004;36:1011-1019
   CrossRef | Web of Science | Medline

To the Editor:

Riddler et al. report that at week 96 in their study, patients in the efavirenz group were less likely to have virologic failure than those in the lopinavir–ritonavir group. No information is given to assess whether such virologic benefit was maintained in patients with a low baseline CD4 cell count. Protease inhibitors are perceived by some as better drugs for patients with HIV infection whose disease is in an advanced stage.1 Thus, we would be interested in data on the probability of no virologic failure in patients with a low CD4 cell count stratified according to the antiretroviral regimen.

Emanuele Nicastri, M.D., Ph.D.
Pasquale Narciso, M.D.
Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani, 00149 Rome, Italy
nicastri@inmi.it

Massimo Andreoni, M.D.
University Tor Vergata, 00133 Rome, Italy

Dr. Nicastri reports receiving lecture fees from GlaxoSmithKline; Dr. Narciso, lecture fees from Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, and GlaxoSmithKline; and Dr. Andreoni, lecture and consulting fees from Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Pfizer, Merck, Roche, and Tibotec. No other potential conflict of interest relevant to this letter was reported.

1 References

1. 1

   Nicastri E, Palmisano L, Sarmati L, et al. HIV-1 residual viremia and proviral DNA in patients with suppressed plasma viral load (<400 HIV-RNA cp/ml) during different antiretroviral regimens. Curr HIV Res 2008;6:261-266
   CrossRef | Web of Science | Medline

Author/Editor Response

Schulz and Street request specific causes of death to determine whether there were associations according to treatment group. There was no significant difference in the time to death among the three treatment groups (P>0.24 for the overall comparison). Of 19 deaths (9 in the efavirenz group, 3 in the lopinavir–ritonavir group, and 7 in the NRTI-sparing group), 6 deaths were potentially HIV-related (those due to infection, cancer, and myelopathy), and 6 were non–AIDS-defining events (2 related to cancer and 1 each to cardiac, respiratory, hepatic, and infectious disorders); the 7 remaining deaths were not disease-related (i.e., accidents and non–HIV-drug-related overdoses). The varied causes of death and their infrequency make it difficult to discern differences in the patterns of death across the treatment groups.

Nicastri and colleagues inquire about the effect of a low baseline CD4 cell count on the virologic outcome according to treatment group. There were no significant between-group differences in the time to virologic failure among patients with a baseline CD4 cell count of less than 100 cells per cubic millimeter. The proportions of patients without virologic failure at 96 weeks were 69% (95% confidence interval [CI], 59 to 79) in the efavirenz group, 66% (95% CI, 55 to 76) in the lopinavir–ritonavir group, and 64% (95% CI, 54 to 74) in the NRTI-sparing group.

We would like to clarify some points made by Hirschel and Calmy in the editorial1 that accompanied our article. Specific NRTI agents were not assigned by the protocol; they were selected by the site investigator for each patient. The development of extended-release stavudine was halted because of manufacturing difficulties, not because of an increased risk of pancreatitis. In addition, the editorial states initially that limitations of our study “cast doubt on the future applicability of the study's findings” but then concludes that the study results “challenge the 40% of clinicians who start antiretroviral therapy with a protease inhibitor. . . .” We agree that the study results should alter recommendations for optimal initial therapy of HIV-1 infection, which was its intent.

Sharon A. Riddler, M.D.
University of Pittsburgh, Pittsburgh, PA 15213
riddler@dom.pitt.edu

Richard Haubrich, M.D.
University of California, San Diego, San Diego, CA 92103

John W. Mellors, M.D.
University of Pittsburgh, Pittsburgh, PA 15213

1 References

1. 1

   Hirschel B, Calmy A. Initial treatment for HIV infection -- an embarrassment of riches. N Engl J Med 2008;358:2170-2172
   Full Text | Web of Science | Medline