Lack of impact of protease inhibitor resistance-associated mutations on the outcome of HIV-1-infected patients switching to darunavir-based dual therapy

Abstract

Background: Little is known about the impact of baseline resistance-associated mutations (RAMs) on the outcomes of alternative therapeutic strategies such as dual regimens. We assessed the efficacy of boosted darunavir plus raltegravir (DRV + RAL) dual regimen as a simplification strategy in virologically suppressed patients with protease inhibitors RAMs.

Methods: Retrospective, multicentre study on the evolution of 228 heavily pretreated patients who switched to boosted DRV + RAL according to genotypic sensitivity score (GSS). Patients were classified as full susceptible (GSS = 2; n = 177), or with reduced darunavir susceptibility (GSS < 2; n = 51).

Results: Median (range) number of prior antiretroviral regimens was 9 (6–14), with a median (range) of 2 (1–3), 4 (3–6), and 5 (2–9) major mutations to non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, and protease inhibitors, respectively. The median time of virological suppression before simplification was 49 months (IQR 39.8–63.5). Patients with reduced darunavir GSS showed a higher number of protease inhibitors-RAMs (9.3 vs 4.5, p < .01) and were suppressed for longer time (median, 61 months). At week 96, the rate of virological failure was low (two cases, 0.9%; 95% confidence interval, CI, 0.4–2.7%), and the efficacy, excluding non-virological reasons, was 96.8% (95%CI, 90.2–98.4%), without differences according to GSS or protease inhibitors-RAMs. Furthermore, significant improvements in CD4+ counts and CD4/CD8 ratio were observed (p < .01) in both groups.

Conclusions: Treatment simplification to a dual regimen of boosted DRV + RAL after long-term virological suppression was not associated with a high risk of treatment failure, even in patients harbouring protease inhibitors-resistant HIV infection.

Keywords:

• Dual therapy
• raltegravir
• darunavir
• switching
• simplification
• resistance

Acknowledgments

We would like to thank Ana Abad (Hospital Universitario Ramón y Cajal, Madrid, Spain) for her important contribution to database management.

Disclosure statement

N.E. has received honoraria for lectures or advisory boards and has received payment for educational presentations from Janssen-Cilag, Gilead Sciences, ViiV Healthcare, Bristol-Myers Squibb, Abbvie and MSD. JCL has provided consultancy services to ViiV and Gilead and has received payments for lectures or educational presentations from MSD, Gilead, Janssen and ViiV. M.M. has received honoraria for lectures or advisory boards to ViiV Healthcare, Merck-Sharp & Dome, Gilead Sciences and Janssen Cilag, and has received payment for educational presentations from Abbvie, Gilead Sciences, Janssen Cilag, Merck-Sharp & Dome and ViiV Healthcare. For the remaining authors, none was declared. All research was conducted within the guidelines of ethical principles and local legislation.

Writing group

BIRDi study group author contributions: JLC and PV conceived and designed the study, and were responsible for patient enrolment, data analysis and drafted and finalized the article, and JLB, RM, EN and NE were responsible for patient enrolment, clinically followed up patients and helped to write the work. All co-authors revised the manuscript, read and approved the final version.

Members of the BIRDi study group

Hospital Universitario Ramón y Cajal, Madrid: José L Casado, Pilar Vizcarra, Marta Monsalvo. Hospital Clínic de Barcelona: José Luis Blanco. Hospital Universitario La Paz, Madrid: Rocío Montejano, José Ignacio Bernardino; Hospital Universitari Germans Trias i Pujol, Badalona: Eugenia Negredo, Jordi Puig. Hospital Universitario Virgen del Rocío, Sevilla: Nuria Espinosa. Hospital Universitario La Fe, Valencia: Marta Montero, Iván Castro; Complexo Hospitalario Universitario de A Coruña, A Coruña: Álvaro Mena, Ángeles Castro. Hospital Clínico Universitario Virgen de la Victoria, Málaga: Rosario Palacios. Hospital General Universitario Gregorio Marañón, Madrid: Juan Carlos López Bernaldo de Quirós, Francisco Tejerina, Leire Pérez Latorre, Margarita Ramírez; Hospital Clínico San Carlos, Madrid: Jorge Vergas, María J Tellez. Hospital Clínico Universitario de Valencia, Valencia: Pepa Galindo, Ramón Ferrando Vilalta. Fundación Jiménez Diaz, Madrid: Alfonso Cabello. Hospital General Universitario de Valencia, Valencia: Miguel García Deltoro, Purificación Rubio Cuevas. Hospital Universitario Puerta de Hierro, Madrid: Alberto Diaz de Santiago, Sara de la Fuente Moral.

Additional information

Funding

This study was supported by the MSD Investigator-Initiated Studies Program (MISP) under grant number 57180.