Correspondence

Efavirenz in HIV Infection

N Engl J Med 2000; 342:1290-1291April 27, 2000

Article

To the Editor:

Staszewski et al. (Dec. 16 issue)1 report that “the combination of efavirenz, zidovudine, and lamivudine has greater antiviral activity . . . than the combination of indinavir, zidovudine, and lamivudine.” However, their conclusions may have been overstated. Open-label studies such as theirs are less expensive, are easier to perform, and require fewer pills than randomized studies, but the design may not be adequate to compare two very different treatments, in terms of both the number of pills and the dosage (four pills of indinavir taken three times daily without food and three pills of efavirenz taken once daily). As a consequence, the intention-to-treat analysis (in which patients who discontinued treatment were considered to have had no response) probably overestimates the incidence of failure in the group given indinavir, zidovudine, and lamivudine, since “an unexpectedly high number of patients dropped out of the study for unknown reasons.”

In addition, the analysis based on the treatment received does not consider lack of adherence to the medication, which is the main reason for the failure of treatment with protease inhibitors.2 There has been much in the scientific and general media about both the lipodystrophy syndrome3 associated with treatment with protease inhibitors and the preliminary results of Staszewski et al. with respect to the group given efavirenz, zidovudine, and lamivudine.4 It is possible that the patients' knowledge of their treatment assignments decreased adherence and increased the rate of therapeutic failure. The rate of discontinuation of treatment with indinavir, zidovudine, and lamivudine associated with mild gastrointestinal symptoms contrasts with the rate among the patients in the group given efavirenz, zidovudine, and lamivudine who continued the study after the development of rash that was not severe, suggesting that these patients believed that this combination had greater efficacy. A patient's belief and the dosage and number of pills are major determinants of adherence.2,5

Finally, Staszewski et al. limit their conclusions to patients with moderate immunosuppression and do not resolve the important question of the best treatment for patients infected with the human immunodeficiency virus (HIV) who have severe immunosuppression or high HIV RNA loads. This question was limited to a post hoc analysis. Thus, although therapy based on a nonnucleoside reverse-transcriptase inhibitor may be more convenient in terms of adherence or the likelihood of discontinuation of treatment, a double-blind, randomized study comparing the antiviral efficacy of both types of drugs is still required.

José L. Casado, M.D.
Santiago Moreno, M.D., Ph.D.
Hospital Ramón y Cajal, 28034 Madrid, Spain

5 References

1. 1

   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

2. 2

   Casado JL, Sabido R, Perez-Elias MJ, et al. Percentage of adherence correlates with protease inhibitor treatment failure. Antiviral Ther 1999;4:157-161
   Web of Science | Medline

3. 3

   Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998;12:F51-F58
   CrossRef | Web of Science | Medline

4. 4

   Staszewski S, Morales-Ramirez J, Tashima K, et al. A phase II, multicenter, randomized, open-label study to compare the antiretroviral activity and tolerability of efavirenz (EFV)+indinavir (IDV) versus EFV+zidovudine (ZDV)+lamivudine (3TC) versus IDV+ZDV+3TC. In: Program and abstracts of the Fifth Conference on Retroviruses and Opportunistic Infections, Chicago, February 1–5, 1998. abstract.
   

5. 5

   Blackwell B. Patient compliance. N Engl J Med 1973;289:249-252
   Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Drs. Casado and Moreno raise questions about the open-label design of our study and the potential for a higher dropout rate among patients receiving indinavir, zidovudine, and lamivudine because of concern over the possibility of lipodystrophy or knowledge of early study results. They also ask whether our conclusions can be applied to patients with advanced disease. Their concern is not supported by the data.

Because of the critical relation between adherence and the efficacy of anti-HIV therapy, an open-label design was the correct choice to address the relative, real-world effectiveness of the regimens. A double-blind design would have required an intolerable pill burden that, along with the frequency of the doses, would have rendered the study impossible to perform and perhaps even unethical.

There was no indication that patients receiving indinavir, zidovudine, and lamivudine dropped out of the study for reasons other than the well-established toxicity of the study drugs. The better tolerability of the regimen that included efavirenz, zidovudine, and lamivudine could be attributable to the more transient toxicity associated with efavirenz, as compared with the chronic gastrointestinal and urologic toxicity associated with indinavir. At the time the study was conducted, the patients would have been more likely to have continued a regimen that included a protease inhibitor, since protease inhibitors had not yet been associated with lipodystrophy but had been shown to decrease mortality in patients with HIV infection.1 The nonnucleoside reverse-transcriptase inhibitors were viewed with skepticism owing to the poor results of trials involving other drugs of this class.2 It is unlikely that knowledge of early study results could have affected outcome, and the first presentation of our results occurred in July 1998,3 not February 1998.4 In fact, we withdrew the abstract referred to by Casado and Moreno4 and opted for a later presentation to avoid any possible effect on the study results.3 Finally, discontinuation for such reasons would not have affected the analyses based on the treatment received; these analyses yielded conclusions similar to those of the intention-to-treat analysis.

The analysis of efficacy in patients with high base-line viral loads was made possible by the fact that the patients had to have a minimal viral load entry of more than 10,000 copies of HIV RNA per milliliter, unlike the criteria used in other studies.2,5 Ad hoc analyses showed no significant difference in the antiviral effect between patients with high viral loads or low CD4 cell counts (data not shown) and the general population of patients in the study.

The study was expanded to include 1266 patients with up to two years of follow-up data. This change allowed us to perform Kaplan–Meier analyses, which confirmed the superiority of the regimen of efavirenz plus two reverse-transcriptase inhibitors over the regimen of indinavir plus two nucleoside reverse-transcriptase inhibitors, according to both the time to treatment failure and the duration of response.6

Douglas J. Manion, M.D.
Nancy M. Ruiz, M.D.
Dupont Pharmaceuticals Company, Wilmington, DE 19808

Schlomo Staszewski, M.D.
Klinikum der J.W. Goethe Universität, 60596 Frankfurt, Germany

6 References

1. 1

   Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338:853-860
   Full Text | Web of Science | Medline

2. 2

   Montaner JSG, Reiss P, Cooper D, et al. A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS trial. JAMA 1998;279:930-937
   CrossRef | Web of Science | Medline

3. 3

   Staszewski S, Morales-Ramirez J, Flanigan T, et al. A phase II, multicenter, randomized, open-label study to compare the antiretroviral activity and tolerability of efavirenz (EFV)+indinavir (IDV) versus EFV+zidovudine (ZDV)+lamivudine (3TC) versus IDV+ZDV+3TC at 24 weeks. In: Program and abstracts of the 12th World AIDS Conference, Geneva, June 28–July 3, 1998. abstract.
   

4. 4

   Staszewski S, Morales-Ramirez J, Tashima K, et al. A phase II, multicenter, randomized, open-label study to compare the antiretroviral activity and tolerability of efavirenz (EFV)+indinavir (IDV) versus EFV+zidovudine (ZDV)+lamivudine (3TC) versus IDV+ZDV+3TC. In: Program and abstracts of the Fifth Conference on Retroviruses and Opportunistic Infections, Chicago, February 1–5, 1998. abstract.
   

5. 5

   Katlama C, Murphy R, Johnson V, et al. The ATLANTIC study: a randomized open-label study comparing two protease inhibitor-sparing antiretroviral strategies vs. a standard PI-containing regimen. In: Program and abstracts of the 6th Conference on Retroviruses and Opportunistic Infections, Chicago, January 31–February 4, 1999. abstract.
   

6. 6

   Staszewski S, Morales-Ramirez JO, Goddofsky EW, et al. Longer time-to-treatment failure and durability of response with efavirenz + ZDV + 3TC: first analysis of full 1266 patient cohort from Study 006. In: Program and abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, September 26–29, 1999. abstract.