To the Editors:
Nonnucleoside reverse transcriptase inhibitors (NNRTIs), mainly efavirenz, are a first choice in first-line therapy. However, because of their low genetic barrier, complete class resistance is believed to take place after the appearance of a single NNRTI-associated mutation and is frequently observed.1 Possibly, because of the large use of NNRTI-based therapies, NNRTI-associated mutations are the most common primary resistance mutations detected in antiretroviral therapy (ART)-naive patients worldwide in recent years,2 suggesting that there is room for new NNRTI with different mutation pattern.
Therefore, we investigated the potential for use of etravirine (ETR), a new NNRTI with high genetic barrier, as part of first-line therapy, by estimating its predicted activity in ART-naive patients by means of 4 currently available interpretation systems.3,4
All ART-naive patients in the Icona Foundation cohort (the national cohort including patients from 65 clinical centers) and the “Lazzaro Spallanzani” National Institute for Infectious Diseases, for whom at least 1 genotypic test was performed before the initiation of ART, were included in this analysis (Appendix 1).
To predict the ETR activity 4 different methods were used. First of all, the most recent score was derived from the analysis of the data from DUET-1 and DUET-2 trials, including 17 reverse transcriptase mutations with given different weights, based on virological response and in vitro resistance.5 Specifically, a score of 3 was given to mutations Y181I/V; 2.5 to L100I, K101P, Y181C, M230L; 1.5 to E138A, V106I, G190S, and V179F; and a score of 1 to V90I, V179D/T, K101E/H, A98G and G190A mutations. A sequence was predicted to be fully resistant to ETR if such score was ≥4 and intermediate resistant if between 2.5 and 3.5.
Alternatively, the Monogram score, obtained from assessing genotype-phenotype concordance, included 30 mutations also with different weights. Four mutations merited a weighting score of 4, L100I, K101P, and Y181C/I; a score of 3 were assigned to E138A/G, V179E, G190Q, M230L, and K238N; a score of 2 to K101E, V106A, E138K, V179L, and Y188L; and a score of 1 was assigned to V90I, K101H, V106M, E138Q, V179D/F/M, Y181F, V189I, G190E/T, H221Y, P225H, and K238T. A cumulative score ≥4 defines resistance.6
Finally, the most recent versions of the REGA (V7.1.1, http://www.rega.kuleuven.be/cev/) and ANRS (V17, http://www.hivfrenchresistance.org) interpretation systems were also used, and concordance between all these described interpretation systems was assessed in a descriptive fashion.
Independent factors associated with the risk of having predicted ETR resistance were identified using a multivariable logistic regression, including, as patients covariates, demographic information, and virological, immunological and clinical data.
Overall, 1792 patients, who underwent resistance test between 1999 and 2008, were included. The main characteristics of the patients were as follows: 75% males; median age 37 (range 18-74) years; 16% intravenous drug users, 26% homosexuals, 34% heterosexuals, 24% not reported; 15% Centers for Disease Control and Prevention C (CDC-C) stage; median CD4 count 299 (range 1-1562) cells per cubic millimeter of blood; median log HIV RNA 4.9 (range 1.7-7.0); non-B subtypes 15%; and median time from first HIV test before genotypic resistance test 3 months (range 0-16 years).
Major International AIDS Society-USA mutations (http://www.iasusa.org/resistance_mutations) for efavirenz and NVP were detected in 51 patients (2.9%) as follows: the K103N mutation was the most frequent with 30 patients (2%); L100I, 7 (0.4%); G190A/S, 11 (1%); V108I, 6 (0.3%); Y181C, 5 (0.3%), P225H, 2 (0.1%); V106A, 1 (0.1%); and no patient harbored V106M, Y181I, or Y188C/L/H.
The predicted ETR susceptibility in all patients and in patients harboring NNRTI mutations at genotype is reported in Table 1. As observed, the prevalence of predicted full resistance to ETR was low ranging from 0.05% (ANRS V17) to 1% (Monogram) in the whole sample and from 2% to 4%, in those for whom major NNRTI mutations were also detected, regardless of the interpretation system used excluding Monogram score that indicated a prevalence of 25%.
The prevalence of predicted intermediate resistance to ETR was also generally low: 0.05%-3% in the whole sample population and 2% among patients with major NNRTI mutations, with the exception of the Rega interpretation system (41%), the only including the K103N among mutations that can partially reduce ETR susceptibility.
Full or intermediate ETR resistance according to any score was found in 59 of 1792 patients (3.3%). At multivariable analysis, it was associated with log HIV RNA > 5 at baseline [OR: 3.8 vs. ≤4 logs; 95% confidence interval (CI): 0.98-14.4, P = 0.05], detection of ≥1 thymidine analogous mutation (TAM) (OR: 4.5 vs. no TAM; 95% CI: 1.2-11.7; P <0.001), and ≥1 NNRTI IAS mutation (OR: 38.5 vs. no mutation; 95% CI: 17.7-84.0; P < 0.0001), whereas CD4 count >350 per cubic millimeter of blood was inversely associated to ETR resistance (OR: 0.4 vs. CD4 ≤ 200; 95% CI: 0.2-0.96; P = 0.04).
In conclusion, the detection of mutations predictive of full or intermediate ETR resistance is infrequent in ART-naive patients and, therefore, provided that ETR will be considered in the future as a candidate in first-line therapy, even in patients with primary resistance to previous NNRTI. Nevertheless, a formulation of ETR with a reduced number of pills and daily administrations seems desirable to make it become an attractive alternative to currently recommended NNRTI.
Patients with high viral load and low CD4 count were more likely to have an ETR resistant virus, but the risk of ETR resistance was also related to the detection of TAMs and NNRTI mutations, suggesting that ETR resistance may have been transmitted from patients who have accumulated mutations during prolonged failure of NNRTI-containing regimen.
Mauro Zaccarelli, MD*
Andrea Antinori, MD*
Alessandro Cozzi-Lepri, PhD†
Cristina Mussini, MD‡
Guido Palamara, MD§
Maria Mercedes Santoro, PhD∥
Vincenzo Spagnuolo, MD¶
Antonella d'Arminio Monforte, MD#
Carlo Federico Perno, MD*
Francesca Ceccherini-Silberstein, PhD∥
*Istituto Nazionale per le Malattie Infettive “Lazzaro Spallanzani” (IRCCS) Rome, Italy
†University College London Royal Free Campus, London, United Kingdom
‡Azienda Policlinico and Università di Modena e Reggio Emilia, Modena, Italy
§Istituto Dermatologico “San Gallicano” (IRCCS) Rome, Italy
∥Dipartimento di Medicina Sperimentale, Università di Tor Vergata, Rome, Italy
¶Clinica Malattie infettive, Istituto “San Raffaele” (IRCCS) Milano Italy
#Clinica di Malattie Infettive, Dipartimento di Medicina Chirurgia e Odontoiatria, Azienda Ospedaliera-Polo Universitario San Paolo, Università di Milano, Milan, Italy, for the ICONA Foundation Study Group
1. Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1. Top HIV Med
2. Shet A, Berry L, Mohri H, et al. Tracking the prevalence of transmitted antiretroviral drug-resistant HIV-1: a decade of experience. J Acquir Immune Defic Syndr
3. Lazzarin A, Campbell T, Clotet B, et al; DUET-2 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomized, double-blind, placebo-controlled trial. Lancet
4. Madruga JV, Cahn P, Grinsztejn B, et al; DUET-1 study group. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomized, double-blind, placebo-controlled trial. Lancet
5. Vingerhoets J, Peeters M, Azijn H, et al. An update of the list of NNRTI mutations associated with decreased virological response to etravirine: multivariate analysis of the pooled DUET-1 and DUET-2 clinical trial data. XVII International Drug Resistance Workshop, June 10-14 2008, Sitges Spain [abstract], Antivir Ther
. 2008;13(Suppl 3):A26.
6. Benhamida J, Chappey C, Coakley E, et al. HIV-1 genotype algorithms for prediction of etravirine susceptibility: novel mutations and weighting factors identified through correlations to phenotype. XVII International HIV Drug Resistance Workshop, June 10-14 2008, Sitges, Spain [abstract], Antivir Ther
. 2008;13(Suppl 3):A132.
National Institute for Infectious Diseases ‘Lazzaro Spallanzani’ Group
R. Acinapura, A. Ammassari, A. Antinori (Co-Chair), G. Anzidei, F. Baldini, R. Bellagamba, A. Bertoli, E. Boumis, F. Ceccherini-Silberstein, S. Cerilli, R. D'Arrigo, P. De Longis, G. D'Offizi, F. Forbici, S. Galati, M. L. Giancola, E. Girardi, C. Gori, G. Liuzzi, P. Lorenzini, P. Marconi, S. Mosti, P. Narciso, V. Neri, E. Nicastri, C. F. Perno (Co-Chair), P. Sette, M. P. Trotta, V. Tozzi, U. Visco-Comandini, and M. Zaccarelli.
Icona Foundation Study Group
Governing Body: M. Moroni (Chair), G. Carosi, R. Cauda, F. Chiodo, A. d'Arminio Monforte, G. Di Perri, M. Galli, R. Iardino, G. Ippolito, A. Lazzarin, F. Mazzotta, R. Panebianco, G. Pastore, and C. F. Perno.
Steering Committee: A. Ammassari, A. Antinori, C. Arici, C. Balotta, P. Bonfanti, M. R. Capobianchi, A. Castagna, F. Ceccherini-Silberstein, A. Cozzi-Lepri, A. d'Arminio Monforte, A. De Luca, C. Gervasoni, E. Girardi, S. Lo Caputo, F. Maggiolo, R. Murri, C. Mussini, M. Puoti, and C. Torti.
Statistical and Monitoring Team: A. Cozzi-Lepri, I. Fanti, T. Formenti, M. Prosperi
Participating Physicians and Centers: M. Montroni, A. Giacometti, A. Costantini, A. Riva (Ancona), U. Tirelli, F. Martellotta (Aviano-PN), G. Pastore, N. Ladisa (Bari), F. Suter, F. Maggiolo (Bergamo), F. Chiodo, G. Verucchi, C. Fiorini (Bologna), G. Carosi, G. Cristini, C. Torti, C. Minardi, D. Bertelli (Brescia), T. Quirino, C. Abeli (Busto Arsizio), P. E. Manconi, P. Piano (Cagliari), E. Pizzigallo, M. Dalessandro (Chieti), G. Carnevale, S. Lorenzotti (Cremona), F. Ghinelli, L. Sighinolfi (Ferrara), F. Leoncini, F. Mazzotta, M. Pozzi, S. Lo Caputo (Firenze), G. Pagano, G. Cassola, G. Viscoli, A. Alessandrini, R. Piscopo (Genova), F. Soscia, L. Tacconi (Latina), A. Orani, R. Rossotto (Lecco), D. Tommasi, P. Congedo (Lecce), A. Chiodera, P. Castelli (Macerata), M. Galli, A. Lazzarin, G. Rizzardini, I. Schlacht, A. d'Arminio Monforte, A. L. Ridolfo, A. Foschi, A. Castagna, S. Salpietro, S. Merli, S. Melzi, M. C. Moioli, P. Cicconi, T. Formenti (Milano), R. Esposito, C. Mussini (Modena), A. Gori, A. Borrello (Monza), N. Abrescia, A. Chirianni, C. M. Izzo, M. De Marco, R. Viglietti, E. Manzillo (Napoli), C. Ferrari, P. Pizzaferri (Parma), F. Baldelli, G. Camanni (Perugia), G. Magnani, M. A. Ursitti (Reggio Emilia), M. Arlotti, P. Ortolani (Rimini), R. Cauda, M. Andreoni, A. Antinori, G. Antonucci, P. Narciso, V. Tozzi, V. Vullo, A. De Luca, M. Zaccarelli, R. Acinapura, P. De Longis, M. P. Trotta, M. Lichtner, F. Carletti, (Roma), M. S. Mura, G. Madeddu (Sassari), P. Caramello, G. Di Perri, G. C. Orofino (Torino), E. Raise, F. Ebo (Venezia), G. Pellizzer, and D. Buonfrate (Vicenza).