Correspondence

Enfuvirtide, an HIV-1 Fusion Inhibitor

N Engl J Med 2003; 349:1770-1771October 30, 2003

Article

To the Editor:

In the T-20 vs. Optimized Regimen Only Study 1 (TORO 1), reported by Lalezari et al. (May 29 issue),1 enfuvirtide, when added to an optimized salvage antiretroviral regimen, increased by 12 percent the proportion of patients who had undetectable plasma human immunodeficiency virus type 1 (HIV-1) RNA levels at week 24. Ninety-five percent adherence to antiretroviral therapy is key for sustained treatment success; adherence, or the lack thereof, is largely driven by toxic effects.2-4 Enfuvirtide caused injection-site reactions in 98 percent of the patients, although only 3 percent discontinued therapy as a result. Adherence to enfuvirtide therapy was at least 85 percent in 93 percent of patients; the authors state that there “was a high rate of adherence . . . suggesting that injection-site reactions were not treatment-limiting.”

It is unknown whether injection-site reactions of any severity reduce absorption of enfuvirtide or adherence to therapy and thus affect long-term virologic potency. The authors do not state what proportion of the patients received all the enfuvirtide injections or whether any regimen- or patient-related factors were associated with a greater likelihood of virologic success. In particular, was an increased frequency or size of injection-site reactions or increased pain with such reactions associated with a greater rate of virologic failure? If so, was the association related to reduced absorption, reduced adherence, or both?

Andrew Carr, M.D.
St. Vincent's Hospital, Sydney 2010, Australia
acarr@stvincents.com.au

4 References

1. 1

   Lalezari JP, Henry K, O'Hearn M, et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 2003;348:2175-2185[Erratum, N Engl J Med 2003;349:1100.]
   Full Text | Web of Science | Medline

2. 2

   Ammassari A, Trotta MP, Murri R, et al. Correlates and predictors of adherence to highly active antiretroviral therapy: overview of published literature. J Acquir Immune Defic Syndr 2002;31:Suppl 3:S123-S127
   CrossRef | Web of Science | Medline

3. 3

   McNabb J, Ross JW, Abriola K, Turley C, Nightingale CH, Nicolau DP. Adherence to highly active antiretroviral therapy predicts virologic outcome at an inner-city human immunodeficiency virus clinic. Clin Infect Dis 2001;33:700-705
   CrossRef | Web of Science | Medline

4. 4

   Carrieri P, Cailleton V, Le Moing V, et al. The dynamic of adherence to highly active antiretroviral therapy: results from the French National APROCO cohort. J Acquir Immune Defic Syndr 2001;28:232-239
   Web of Science | Medline

To the Editor:

The studies by Lalezari et al. (TORO 1) and Lazzarin (TORO 2)1 showed an incremental decrease in viral load that was attributable to enfuvirtide and that was in addition to the decrease due to optimized conventional antiretroviral therapy in patients with drug-resistant HIV-1 infection. Could the extent of resistance, measured by the number of primary mutations associated with resistance to the three drug classes rather than the less informative genotypic score, be related to the virologic outcome to identify the characteristics of patients who were most likely to benefit from enfuvirtide? This seems important, given the 94 percent rate of mutations conferring resistance to enfuvirtide among those with virologic failure and suboptimal viral suppression.2 Was the rate of enfuvirtide resistance similarly high among patients who had a favorable response but had persistent viremia?

Elizabeth R. Jenny-Avital, M.D.
Jacobi Medical Center, Bronx, NY 10461
jennyavita@aol.com

2 References

1. 1

   Lazzarin A, Bonaventura C, Cooper D, et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med 2003;348:2186-2195
   Full Text | Web of Science | Medline

2. 2

   Petrella M, Wainberg MA. Might the M184V substitution in HIV-1 RT confer clinical benefit? AIDS Rev 2002;4:224-232
   Medline

Author/Editor Response

To address Dr. Carr's questions, we used the combined TORO 1 and TORO 2 data base1 to identify patients who had an injection-site reaction of at least grade 3 (i.e., a severe reaction, requiring analgesics or limiting usual activities) over the 24-week period of enfuvirtide treatment. Fifty-nine of the 627 patients in the combined population (9.4 percent) had one or more grade 3 injection-site reactions that required analgesia or that limited daily activities. Rates of virologic failure during this period were only minimally higher among these patients than among those without grade 3 injection-site reactions (54.2 percent vs. 44.5 percent). Complete (100 percent) adherence to the enfuvirtide regimen appeared to be unaffected by whether a grade 3 injection-site reaction occurred. Complete adherence to enfuvirtide therapy was reported by 67.8 percent of the patients with grade 3 injection-site reactions, as compared with 71.4 percent of those without such reactions. Overall, 71 percent of the patients reported 100 percent adherence to enfuvirtide therapy.

Drug pharmacokinetics in TORO 1 and TORO 2 were determined by sparse sampling at three prespecified times when sampling was unlikely to coincide with a grade 3 injection-site reaction. On the basis of this study, it is not possible to determine how the severity of injection-site reactions influenced the absorption of enfuvirtide. Dr. Carr also asks whether regimen- or patient-related factors were associated with the virologic outcome. Approximately 560 different optimized background regimens were prescribed to the combined intention-to-treat populations, with no one regimen predominating. It is therefore not possible to determine the contribution of any specific regimen. A recent analysis from the combined TORO 1 and TORO 2 data set2 showed the benefit of enfuvirtide combined with optimized background therapy as compared with optimized background therapy alone among all the subgroups studied, with an improved magnitude of response in patients with less advanced disease and less treatment experience.

In response to Dr. Jenny-Avital's query, the design and analysis of the TORO studies emphasized sensitivity scores rather than number of mutations because the sensitivity score also takes into account the actual optimized background chosen for the patient according to the resistance profile seen. However, unpublished data from the combined TORO 1 and TORO 2 data set show a correlation between the number of base-line mutations and the genotypic sensitivity score (r = –0.64) and phenotypic sensitivity score (r = –0.66). Changes in plasma viremia observed among subgroups according to the number of mutations mirrored those observed according to the genotypic sensitivity score. The TORO analyses did not examine enfuvirtide resistance among patients who had a response at 24 weeks. This question is under evaluation in an ongoing, 48-week analysis.

We would also like to make it clear that in both studies, all the authors had full access to the data, reviewed the analyses, and participated in the decisions about publication.

Jacob P. Lalezari, M.D.
Quest Clinical Research, San Francisco, CA 94115
drjay@questclinical.com

Adriano Lazzarin, M.D.
San Raffaele Vita-Salute University, 20127 Milan, Italy

Miklos Salgo, M.D., Ph.D.
Roche, Nutley, NJ 07110-1199

2 References

1. 1

   Delfraissy J-F, Montaner J, Eron J, et al. Summary of pooled efficacy and safety analyses of enfuvirtide (ENF) treatment for 24 weeks in TORO 1 and TORO 2 phase III trials in highly active antiretroviral (ARV) treatment-experienced patients. In: Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections, Boston, February 10–14, 2003:260. abstract.
   

2. 2

   Montaner J, DeMasi R, Delehanty J, et al. Analysis of virological response of enfuvirtide in TORO: implications for patient management. Antiviral Ther 2003;8:Suppl 1:S212-S212 abstract.
   

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   Alberta Samuele, Alexandra Kataropoulou, Marco Viola, Samantha Zanoli, Giuseppe La Regina, Francesco Piscitelli, Romano Silvestri, Giovanni Maga. (2009) Non-nucleoside HIV-1 reverse transcriptase inhibitors di-halo-indolyl aryl sulfones achieve tight binding to drug-resistant mutants by targeting the enzyme–substrate complex. Antiviral Research 81:1, 47-55
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