Long-term durability of tenofovir-based antiretroviral therapy In relation to the Co-administration of other drug classes in routine clinical practice

Costarelli, S.; Cozzi-Lepri, A.; Lapadula, G.; Bonora, S.; Madeddu, G.; Maggiolo, F.; Antinori, A.; Galli, M.; Di Perri, G.; Viale, P.; D'Arminio Monforte, A.; Gori, A.; Moroni, M.; Andreoni, M.; Angarano, G.; Castelli, F.; Cauda, R.; Iardino, R.; Ippolito, G.; Lazzarin, A.; Perno, C. F.; Von Schloesser, F.; Castagna, A.; Ceccherini-Silberstein, F.; Girardi, E.; Lo Caputo, S.; Mussini, C.; Puoti, M.; Ammassari, A.; Balotta, C.; Bonfanti, P.; Borderi, M.; Capobianchi, M. R.; Cingolani, A.; Cinque, P.; De Luca, A.; Di Biagio, A.; Gianotti, N.; Guaraldi, G.; Lichtner, M.; Marchetti, G.; Marcotullio, S.; Monno, L.; Quiros Roldan, E.; Rusconi, S.; Saracino, A.; Cicconi, P.; Fanti, I.; Galli, L.; Lorenzini, P.; Tavelli, A.; Giacometti, A.; Costantini, A.; Mazzoccato, S.; Santoro, C.; Suardi, C.; Vanino, E.; Verucchi, G.; Minardi, C.; Quirino, T.; Abeli, C.; Manconi, P. E.; Piano, P.; Vecchiet, J.; Falasca, K.; Sighinolfi, L.; Segala, D.; Mazzotta, F.; Cassola, G.; Viscoli, C.; Alessandrini, A.; Piscopo, R.; Mazzarello, G.; Mastroianni, C.; Belvisi, V.; Caramma, I.; Chiodera, A.; Castelli, A. P.; Rizzardini, G.; Ridolfo, A. L.; Piolini, R.; Salpietro, S.; Carenzi, L.; Moioli, M. C.; Tincati, C.; Puzzolante, C.; Abrescia, N.; Chirianni, A.; Guida, M. G.; Gargiulo, M.; Baldelli, F.; Francisci, D.; Parruti, G.; Ursini, T.; Magnani, G.; Ursitti, M. A.; Vullo, V.; D'Avino, A.; Gallo, L.; Nicastri, E.; Acinapura, R.; Capozzi, M.; Libertone, R.; Tebano, G.; Cattelan, A.; Sasset, L.; Mura, M. S.; Rossetti, B.; Caramello, P.; Orofino, G. C.; Sciandra, M.; Bassetti, M.; Londero, A.; Pellizzer, G.; Manfrin, V.

doi:10.1371/journal.pone.0160761

Background: In clinical trials, toxicity leading to tenofovir disoproxil fumarate (TDF) discontinuation is rare (3% by 2 years); however in clinical practice it seems to be higher, particularlywhen TDF is co-administered with ritonavir-boosted protease inhibitors (PI/r). Aims of this study were to assess the rate of TDF discontinuations in clinical practice and to identify factors associated with the risk of stopping TDF. Methods: All antiretroviral treatment (ART)-naive patients initiating a TDF-based regimen were selected from the ICONA Foundation Study cohort. The primary outcome was TDF discontinuation regardless of the reason; secondary outcome measures were TDF discontinuation due to toxicity and selective TDF discontinuation (that is, TDF discontinuation or substitution, maintaining unchanged the remaining antiretroviral treatment). Results: 3,618 ART-naïve patients were included: 54% started a PI/r-based and 46% a NNRTIbased based regimen. Two-hundred-seventy-seven patients discontinued TDF and reintroduced ART within 30 days without TDF. The probability of TDF discontinuation regardless of the reason was of 7.4% (95%CI:6.4-8.5) by 2 years and 14.1% (95%CI:12.2-16.1) by 5 years. The 5-year KM estimates in the PI/r vs. NNRTI group were 20.4% vs. 7.6%, respectively (log-rank p = 0.0001), for the outcome of stopping regardless of the reason, and 10.7% vs. 4.7% (p = 0.0001) for discontinuation due to toxicity. PI/r use and lower eGFR were associated with an increased risk of discontinuing TDF. Conclusion: In our cohort, the frequency of TDF discontinuations was higher than that observed in clinical trials. Co-administration of TDF with PI/r was associated with an increased rate of TDF discontinuations. Further studies are needed to clarify the mechanisms that might have led to this outcome.