Immune reconstitution in very advanced HIV patients treated with Dolutegravir vs Darunavir-based triple antiretroviral therapy. The Advanz-4 randomized clinical trial

Abstract

Objectives: The aim of this trial was to compare the immune reconstitution, virologic response, and safety of dolutegravir (DTG)- vs. darunavir (DRV) boosted-based antiretroviral (ART) regimens in very advanced HIV patients.

Methods: Phase IV, randomized (1:1 ratio), open-label trial, including adult (≥18 years) ART-naïve HIV-1+ patients with CD4⁺ cell counts <100 cells/ L from nine hospitals in Spain. Participants were randomized to Lamivudine (3TC)/Abacavir (ABC)/DTG (DTG arm) and 3TC/ABC/DRV + Ritonavir (DRV/r arm).

Primary endpoint: change in the absolute CD4⁺-cells number at 48 weeks. by modified intention-to-treat population.

Trial registration: NCT02337322.

Results: 104 patients (86·5% male, median [IQR] age 41·0 [31·5, 47·0] years) were recruited and randomized to DTG (n=52) and DRV/r arms (n=52). Baseline median (IQR) CD4⁺ cell counts were 41·0 (18·5, 67·5) and 30·0 (11·0, 57·5) cells/ L in the DTG and DRV/r arms. They significantly increased by median (IQR) 172·5 (118·0, 255·3) and 157·0 (66·0, 276·9) cells/ L, respectively (p=0·4299); 29 (55·8%) and 21 (42·9%) (p=0·2343), respectively, reached >200 cells/ L. 41 (78·8%) and 31 (63·3%) patients (p=0·1229) in the DTG and DRV/r arms, respectively, achieved undetectable viral loads at 48 weeks; differences were significant at weeks 4 (p<0·0001) and 12 (p=0·0190). Inflammation (TNF-alpha) and bacterial translocation (sCD14) markers decreased more in the DTG arm, a median (IQR]) -8 (-11, -4) vs -5 (-9, -3) pg/mL (p=0·0357) and -972 [-1334, -508] vs -544 [-1128, -292] μg/mL (p=0·0565), respectively, at 48 weeks. Discontinuation rates were higher in the DRV/r arm (3/52 [5.8%] vs. 9/51 [18,4%]; p=0·0526).

Conclusions: DTG/3TC/ABC is safe and efficacious in very advanced ART-naïve HIV+ patients, induced a faster virological response, and was superior to the DRV/r regimen in reducing inflammation and bacterial translocation markers at 48 weeks.