Time to discontinuation of the first highly active antiretroviral therapy regimen: a comparison between protease inhibitor- and non-nucleoside reverse transcriptase inhibitor-containing regimens

Data from a cohort of HIV-positive individuals who were antiretroviral naive at enrolment were analysed to estimate the probability of discontinuing the first highly active antiretroviral therapy (HAART) regimen, comparing protease inhibitor- and non-nucleoside reverse transcriptase-containing regimens. Of the 2002 individuals who began HAART, 857 (42.8%) discontinued their first regimen. No statistically significant difference was found in the time to discontinuation by specific type of regimen, either when considered overall or by specific reason. Although highly active antiretroviral therapy (HAART) is an extremely effective regimen [1–3], it can be discontinued for various reasons, including toxicity and the extensive duration and complexity of treatment [4,5]. Several population-based studies have shown that approximately 25% of patients discontinue therapy within 8–12 months [5–7], but the populations of such studies mainly included individuals treated only with regimens containing protease inhibitors (PI), and very few studies have assessed whether there are differences in discontinuation rates according to the specific combination of drugs used. One recent study [8] reported that the rate of discontinuation was similar when comparing therapy with specific PI to that with non-nucleoside reverse transcriptase inhibitors (NN RTI). Additional knowledge about whether certain HAART regimens are more likely to be discontinued than others is extremely important, in that choosing an initial regimen with a lower probability of being discontinued would increase the probability of therapeutic success. To compare the probability of discontinuing HAART between regimens containing two nucleoside reverse transcriptase inhibitors (NRTI) combined with one PI and those containing two NRTI combined with one NNRTI, we analysed data from a cohort of HIV-positive patients who were antiretroviral naive at enrolment (the Italian Cohort of Antiretroviral-Naive Patients) [9]. The study began in March 1997, and as of 31 May 2000, 4300 individuals had been enrolled. The present analysis includes only those individuals who began an antiretroviral regimen with three antiretroviral drugs (i.e. HAART) and who underwent at least one follow-up visit after starting therapy. The main endpoint of the statistical analysis was the date of discontinuation of HAART, defined as the first time that at least one of the drugs in the regimen was terminated. Time-to-event was defined as the time from the date of starting HAART to the date of discontinuation. For individuals who had not discontinued the initial combination, follow-up times were censored at the last clinical visit. Survival analysis methods were applied: the cumulative probability of HAART discontinuation was estimated using the Kaplan–Meier method, and crude and adjusted relative hazards (RH) of HAART discontinuation were estimated applying Cox proportional hazards models. The analyses were repeated according to the specific reason of discontinuation (i.e. toxicity, failure and non-compliance). Of the 4300 individuals enrolled in the Italian Cohort of Antiretroviral-Naive Patients, 2002 (46.7%) had begun HAART and underwent at least one follow-up visit after starting therapy. The median duration of follow-up was 9.7 months (range 0.10–35.9 months). The majority of patients (n = 1709); 85.4% initiated a PI-containing regimen; the remaining 293 (14.6%) initiated an NNRTI-containing regimen. The median duration of follow-up was 11.0 months (range 0.10–35.9 months) for patients receiving a PI and 5.6 months (range 0.10–27.0) for those receiving NNRTI. No differences were found between the two groups in terms of demographic characteristics (age, sex, and exposure category): the median age was 35 years (range 18–70 years) and nearly 70% were men; the majority of patients were injection drug users, followed by heterosexual contacts and homosexual contacts. The median baseline CD4 cell count and the number of HIV-RNA copies differed between the two groups: the CD4 cell count was 290 × 106/L (range 1–1439) for those undergoing a PI-containing regimen and 428 × 106/l (range 4–1402) for those undergoing an NNRTI-containing regimen; the HIV-RNA levels were 4.7 log10 copies/ml (range 1.1–6.7) and 4.4 log10 copies/ml (range 1.7–6.3), respectively. The proportion of patients in stage C of the Centers for Disease Control and Prevention classification [10] was higher among patients undergoing a PI-containing regimen. A total of 857 (42.8%) patients discontinued their first antiretroviral regimen in the study period: 777 (45.5%) of those undergoing a PI-containing regimen and 80 (27.3%) of those undergoing an NNRTI-containing regimen [95% confidence interval (CI) for the difference in the two percentages 12.4–23.6%]. The main reasons for discontinuation were toxicity (n = 366; 42.7% of all those who discontinued), failure (n = 244; 28.5%), and non-compliance (n = 197; 23.0%); other reasons (i.e. mainly treatment intensification or regimen simplification) were reported for 26 (3.0%) patients; the reason was unknown for 24 (2.8%) patients. The cumulative probability of discontinuing the first regimen at one year after initiating therapy was 37.6% (95% CI 25.3–39.9%). No significant difference was found in the time to discontinuation between PI-containing and NNRTI-containing regimens, both when considering discontinuation overall and by specific reason (Fig. 1). The crude RH of discontinuing HAART for any reason among individuals undergoing an NNRTI-containing regimen compared with those undergoing a PI-containing regimen was 0.97 (95% CI 0.77–1.22%). When adjusting for possible confounders (age, sex, exposure category, Centers for Disease Control and Prevention stage, CD4 cell count and number of HIV-RNA copies), the RH of discontinuation slightly decreased (adjusted RH = 0.85; 95% CI 0.63–1.15%). The results were similar when considering separately discontinuation for toxicity and for non-compliance, whereas the RH of discontinuation for failure tended to decrease in those undergoing an NNRTI-containing regimen compared with those undergoing a PI-containing regimen (adjusted RH 0.61; 95% CI 0.31–1.20%).Fig. 1.: Kaplan–Meier curves by initial regimen. Highly active antiretroviral therapy (HAART) containing protease inhibitor (PI, —) or non-nucleoside reverse transcriptase inhibitor (NNRTI, - - - -). (a) Estimate of time to discontinuation because of toxicity; (b) estimate of time to discontinuation because of failure; (c) estimate of time to discontinuation because of non-compliance.Men were found to be approximately 30% less likely than women to discontinue for any reason (RH 0.77; 95% CI 0.64–0.94%), and this tendency was confirmed for the three specific reasons for discontinuation. A higher baseline number of HIV-RNA copies was significantly associated with a higher probability of discontinuing for failure and for non-compliance. In conclusion, when considering discontinuation for toxicity or non-compliance, no difference was found in the probability of discontinuation by the type of initial regimen. When the reason for discontinuation was failure, individuals undergoing an NNRTI-containing regimen tended to be less likely than those undergoing a PI-containing regimen to discontinue HAART, although the difference was not statistically significant. Additional follow-up will be necessary to confirm this difference and to determine its reasons. *The Italian Cohort of Antiretroviral-Naive Patients Study Group Italy: Ancona: M. Montroni, G. Scalise, A. Costantini, M.S. Del Prete; Aviano (PN): U. Tirelli, G. Nasti; Bari: G. Pastore, M.L. Perulli; Bergamo: F. Suter, C. Arici; Bologna: F. Chiodo, F.M. Gritti, V. Colangeli, C. Fiorini, L. Guerra; Brescia: G. Carosi, G.P. Cadeo, F. Castelli, C. Minardi, D. Vangi; Busto Arsizio: G. Rizzardini, G. Migliorino; Cagliari: P.E. Manconi, P. Piano; Catanzaro: T. Ferraro, A. Scerbo; Chieti: E. Pizzigallo, F. Ricci; Como: G.M. Vigevani, L. Pusterla; Cremona: G. Carnevale, A. Pan; Cuggiono: P. Viganò, M. Mena; Ferrara: F. Ghinelli, L. Sighinolfi; Firenze: F. Leoncini, F. Mazzotta, S. Ambu, S. Lo Caputo; Foggia: G. Angarano, B. Grisorio, S. Ferrara; Galatina (LE): P. Grima, P. Tundo; Genova: G. Pagano, N. Piersantelli, A. Alessandrini, R. Piscopo; Grosseto: M. Toti, S. Chigiotti; Latina: F. Soscia, L. Tacconi; Lecco: A. Orani, G. Castaldo; Lucca: A. Scasso, A. Vincenti; Mantova: A. Scalzini, F. Alessi; Milano: M. Moroni, A. Lazzarin, A. Cargnel, F. Milazzo, G. Rizzardini, L. Caggese, A. d'Arminio Monforte, S. Melzi, F. Delfanti, B. Carini, B. Adriani, S. Garavaglia, C. Moioli; Modena: R. Esposito, C. Mussini; Napoli: N. Abrescia, A. Chirianni, O. Perrella, M. Piazza, M. De Marco, V. Montesarchio, E. Manzillo, S. Nappa; Padova: P. Cadrobbi, R. Scaggiante; Palermo: A. Colomba, V. Abbadesse, T. Prestileo, S. Mancuso; Pavia: G. Filice, L. Minoli, F.A. Patruno Savino, R. Maserati; Perugia: S. Pauluzzi, F. Baldelli; Pesaro: E. Petrelli, A. Cioppi; Piacenza: F. Alberici, M. Sisti; Pisa: F. Menichetti, A. Smorfa; Potenza: C. De Stefano, A. La Gala; Ravenna: T. Zauli, G. Ballardini; Reggio Emilia: L. Bonazzi, M.A. Ursitti; Rimini: R. Ciammarughi, S. Giordani; Roma: L. Ortona, F. Dianzani, G. Ippolito, A. Antinori, G. Antonucci, S. D'Elia, P. Narciso, N. Petrosillo, V. Vullo, A. De Luca, L. Del Forno, M. Zaccarelli, P. De Longis, M. Ciardi, G. D'Offizi, F. Palmieri, M. Lichtner, M.R. Capobianchi, E. Girardi, P. Pezzotti, G. Rezza; Sassari: M.S. Mura, M. Mannazzu; Taranto: F. Resta, A. Chimienti; Torino: P. Caramello, A. Sinicco, M.L. Soranzo, S. Quaglia, M. Sciandra, B. Salassa; Varese: D. Torre, C. Basilico; Verbania: A. Poggio, G. Bottari; Venezia: E. Raise, S. Pasquinuci; Vicenza: F. De Lalla, G. Tositti. UK: London: A. Cozzi Lepri, A.N. Phillips. Maria Dorruccia Patrizio Pezzottia Benvenuto Grisoriob Cristina Minardic M. Stella Murod Vincenzo Vulloe Antonella d'Arminio Monfortef for the Italian Cohort of Antiretroviral-Naive Patients Study Group*