Background: Guidelines support the switch to a two-drug regimen (2DR) in virologically suppressed people with HIV (PWH) on a three-drug regimen (3DR). Randomized clinical trials have not included clinical outcomes in study endpoints. We provide estimates of 3-year clinical risk by means of a target trial emulation using the data of a large cohort of PWH in Italy. Methods: PWH from the Icona Foundation Study who were virologically suppressed (HIV-RNA ≤50 copies/mL) for ≥6 months on a 3DR on or after November 2014, were enrolled (database closure on July 31, 2024). PWH were classified according to therapeutic strategies: switching to 2DR (protease inhibitors or dolutegravir plus lamivudine or dolutegravir plus rilpivirine) or remaining on 3DR (any combination). The primary endpoint was the time to the first clinical composite event (cardiovascular disease [CVD], cancer [AIDS and non-AIDS related], or death). We calculated the difference in 3-year risk between therapeutic strategies, estimated using a weighted non-parametric Kaplan–Meier estimator. Findings: 7672 participants entered the analysis: 629 (8.2%) switching to 2DR and 7043 (91.8%) remaining on 3DR. Over the 3-year follow-up, 408 events were registered (64 CVD, 234 cancer, and 110 deaths). The 3-year adjusted risk estimate was 2.55 (95% CI 1.72, 5.33) in 2DR vs. 4.69 (95% CI 4.48, 6.17) in 3DR. The difference (−2.15% [95% CI −3.56%, −0.20%]) in favor of 2DR was mainly driven by events of non-AIDS related cancer and mortality. Interpretation: This study provides evidence that virologically suppressed PWH can be safely switched to 2DR, and may slightly reduce the 3-year risk of a composite clinical outcome. Funding: The Icona Foundation Study is supported by unrestricted grants from Gilead Sciences, ViiV Healthcare, Merck Sharpe & Dohme.
Risk of clinical events in virologically suppressed people with HIV switching to a two-drug regimen vs. remaining on a three-drug regimen: a target trial emulation / C. Mussini, A. Giacomelli, E. Quiros-Roldan, V. Mazzotta, A. Di Biagio, A. De Vito, A. Costantini, G. D'Ettorre, A. Giacometti, A. Vergori, A. Tavelli, V. Malagnino, A. Castagna, J. Chester, A. Antinori, A. D'Arminio Monforte, A. Cozzi-Lepri, C. Abeli, G. Accardo, L. Alessio, S. Antinori, M. Augello, L. Badia, A. Bandera, V. Barocci, F. Bartalesi, A. Bartoloni, M. Bassetti, G. Battagin, S. Blanchi, N. Bobbio, S.I. Bonelli, P. Bonfanti, V. Bono, S. Bonora, B. Borchi, A. Calcagno, G. Calleri, V. Calvino, M. Camici, G. Canavesi, D. Canetti, M. Capozzi, S. Carrara, A. Cascio, A. Cattelan, R. Cauda, F. Ceccherini-Silberstein, B.M. Celesia, M. Cernuschi, A. Cervo, L. Chessa, A. Cingolani, P. Cinque, I. Coledan, L. Comi, N. Coppola, R. Corsini, M.L. Cosmaro, M.V. Cossu, C. Costa, S. Cretella, S.D. Zoppo, S. De Benedittis, C. Del Borgo, V.L. Del Negro, S. Dell'Isola, G. Di Filippo, C. Di Giuli, G. Di Perri, S. Diotallevi, E.M. Erne, V. Esposito, M. Fabbiani, K. Falasca, I. Fanti, M. Farinella, S. Ferrara, E. Focà, R. Fontana Del Vecchio, D. Francisci, A. Franco, F.M. Fusco, M. Fusto, R. Gagliardini, I. Gentile, N. Gianotti, L. Gianserra, M. Giotta, E. Girardi, A. Gori, S. Graziano, G. Guaraldi, G. Iaiani, R. Iardino, A. Lai, S. Lamonica, S. Lanini, G. Lapadula, A. Latini, C. Lazzaretti, A. Lazzarin, D. Leoni, M. Lichtner, S. Lo Caputo, R. Lolatto, A. Londero, G. Madeddu, P. Maggi, F. Maggiolo, G. Mancarella, G. Marchetti, C. Marelli, R. Marocco, S. Martini, C.M. Mastroianni, I. Mastrorosa, M. Menozzi, B. Menzaghi, D. Messeri, I. Mezzaroma, E. Milano, M.C. Moioli, C. Molteni, A. Mondi, F. Montagnani, S. Nicolè, S. Nozza, G. Nunnari, G. Orofino, A. Pan, G. Parruti, J. Paulicelli, G. Pellicanò, C.F. Perno, A. Perziano, F. Pes, L. Pezzati, S. Piconi, A. Pieri, C. Pinnetti, M.M. Plazzi, N. Policek, E. Pontali, G. Prota, M. Puoti, M. Rivano Capparuccia, V. Rizzo, A. Rodanò, R. Rossotti, R. Rovito, S. Rusconi, D. Russo, Y. Russotto, V. Sangiovanni, N. Sangiovanni, M.M. Santoro, C. Santoro, A. Saracino, L. Sarmati, E. Schiaroli, D. Segala, F. Sozio, V. Spagnuolo, N. Squillace, G. Starnini, C. Stingone, C. Suardi, B. Suligoi, V. Svicher, L. Taramasso, C. Tascini, C. Tincati, C. Torti, M. Trizzino, S. Truffa, J. Vecchiet, P. Viale, D. Vincenti, F. Von Schloesser. - In: ECLINICALMEDICINE. - ISSN 2589-5370. - 86:(2025 Aug), pp. 103368.1-103368.10. [10.1016/j.eclinm.2025.103368]
Risk of clinical events in virologically suppressed people with HIV switching to a two-drug regimen vs. remaining on a three-drug regimen: a target trial emulation
A. Giacomelli;A. D'Arminio Monforte;S. Antinori;M. Augello;A. Bandera;P. Bonfanti;V. Bono;S. Bonora;G. Canavesi;M.V. Cossu;A. Gori;A. Lai;A. Lazzarin;G. Marchetti;B. Menzaghi;M.C. Moioli;C.F. Perno;L. Pezzati;S. Piconi;R. Rossotti;R. Rovito;S. Rusconi;C. Santoro;C. Suardi;L. Taramasso;C. Tincati;
2025
Abstract
Background: Guidelines support the switch to a two-drug regimen (2DR) in virologically suppressed people with HIV (PWH) on a three-drug regimen (3DR). Randomized clinical trials have not included clinical outcomes in study endpoints. We provide estimates of 3-year clinical risk by means of a target trial emulation using the data of a large cohort of PWH in Italy. Methods: PWH from the Icona Foundation Study who were virologically suppressed (HIV-RNA ≤50 copies/mL) for ≥6 months on a 3DR on or after November 2014, were enrolled (database closure on July 31, 2024). PWH were classified according to therapeutic strategies: switching to 2DR (protease inhibitors or dolutegravir plus lamivudine or dolutegravir plus rilpivirine) or remaining on 3DR (any combination). The primary endpoint was the time to the first clinical composite event (cardiovascular disease [CVD], cancer [AIDS and non-AIDS related], or death). We calculated the difference in 3-year risk between therapeutic strategies, estimated using a weighted non-parametric Kaplan–Meier estimator. Findings: 7672 participants entered the analysis: 629 (8.2%) switching to 2DR and 7043 (91.8%) remaining on 3DR. Over the 3-year follow-up, 408 events were registered (64 CVD, 234 cancer, and 110 deaths). The 3-year adjusted risk estimate was 2.55 (95% CI 1.72, 5.33) in 2DR vs. 4.69 (95% CI 4.48, 6.17) in 3DR. The difference (−2.15% [95% CI −3.56%, −0.20%]) in favor of 2DR was mainly driven by events of non-AIDS related cancer and mortality. Interpretation: This study provides evidence that virologically suppressed PWH can be safely switched to 2DR, and may slightly reduce the 3-year risk of a composite clinical outcome. Funding: The Icona Foundation Study is supported by unrestricted grants from Gilead Sciences, ViiV Healthcare, Merck Sharpe & Dohme.
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