Virological Response and Resistance Profile in Highly Treatment-Experienced HIV-1-infected Patients Switching to Dolutegravir Plus Boosted Darunavir in Clinical Practice

Daniele Armenia; Yagai Bouba; Roberta Gagliardini; Lavinia Fabeni; Vanni Borghi; Giulia Berno; Alessandra Vergori; Stefania Cicalini; Cristina Mussini; Andrea Antinori; Francesca Ceccherini-Silberstein; Carlo Federico Perno; Maria Mercedes Santoro

Disclosures

HIV Medicine. 2021;22(6):519-525. 

In This Article

Abstract and Introduction

Abstract

Objectives: We evaluated the virological response and resistance profile in combined antiretroviral therapy (cART)-experienced HIV-1-infected patients starting a dual therapy with dolutegravir (DTG) and boosted darunavir (bDRV) for the first time.

Methods: Survival analyses were used to evaluate virological success (VS) and virological rebound (VR) in viraemic and virologically suppressed patients, respectively. Major resistance mutations (MRMs) and genotypic susceptibility score (GSS) were evaluated at baseline and after switch.

Results: Overall, 130 patients [62 (47.7%) viraemic; 68 (52.3%) virologically suppressed] were retrospectively analysed. At the moment of switch, 81.5% accumulated one or more MRM [protease inhibitor (PI), 35.7%; nucleoside(t)ide reverse transcriptase inhibitor (NRTI), 77.5%; non-NRTI, 69.0%; integrase inhibitor (INI), 10.1%), but 77.7% harboured strains fully susceptible to DTG + bDRV. In viraemic patients, the overall probability of VS by 12 months of treatment was 91.7%. In virologically suppressed patients, the overall probability of VR was 10.5% by 24 months after therapy start. Patients with previous time under virological suppression ≤ 6 months showed a higher VR probability compared with others (37.5% vs. 6.7%, P < 0.002). Among 13 non-responding patients for whom a genotypic resistance test result at failure was available, only two (15.4%) accumulated further resistance in integrase (Y143C/H/R; S147G and N155H) and protease (V32I, L33F, I54L).

Conclusions: In highly treatment-experienced patients, the use of dual therapy based on DTG + bDRV appears to be a very good regimen for switch therapy, with a high rate of virological control in both viraemic and virologically suppressed patients. Among non-responding patients, the selection of further resistance is a rare event.

Introduction

The use of modern combined antiretroviral therapy (cART) has led to unprecedented success in the control of viral replication among people living with HIV/AIDS, thanks to the advent of potent and high genetic barrier antiretrovirals. As a result of the continuous quest for simpler regimens and more convenient therapy, the standard triple therapy is being challenged by the use of two-drug regimens (2DR), and today it is possible to consider switching a person from one effective regimen to a simplified one.[1–3] Following this paradigm shift, the 2DR is increasingly used for both optimization and in salvage reverse transcriptase inhibitor (RTI)-sparing regimens. Given that it is fundamental to maintain virological suppression without jeopardizing future treatment options, a full patient's ART history including cumulative resistance and time of virological suppression before switch should always be considered.[4] In this regard, regimens containing protease inhibitors (PIs) or second-generation integrase inhibitors (INIs) are the best candidates for 2DR in switch strategies due to their exceptional efficacy and high genetic barrier. The use of dolutegravir (DTG) or ritonavir/cobicistat-boosted darunavir (bDRV) in combination with lamivudine or rilpivirine are supported by large clinical trials,[5–9] and are recommended as part of a 2DR switch for maintenance of virological suppression.[4,10] Nowadays, due to their long treatment history, certain failing patients with a high resistance level (e.g. with exhausted RTI options) might need to switch to potent but tolerable and simple treatments. They might therefore have an advantage in switching to a 2DR containing high genetic barrier drugs such as DTG and DRV. So far, only one clinical trial has investigated a 2DR switch based on DTG + bDRV, in which individuals having documented major DRV or INI resistance were excluded.[11] The observational studies reporting this combination had a limited sample size, and frequently showed partial information about previous drug resistance.[12–18] Based on these considerations, we evaluated the virological response and resistance profile in cART-experienced HIV-1-infected individuals in Italy starting dual therapy with DTG + bDRV for the first time.

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