Immune reconstitution in very advanced HIV patients treated with dolutegravir vs. darunavir-based triple antiretroviral therapy: the Advanz-4 randomized clinical trial.

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/μL 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+ cell number at 48 weeks in the modified intention-to-treat population.

TRIAL REGISTRATION: NCT02337322.

RESULTS

In total, 104 patients (86.5% male, median (interquartile range [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 39.5 (16.0, 72.9) and 29.0 (8.0, 60.0) cells/μL in the DTG and DRV/r arms. They significantly increased by median (IQR) 206.5 (154.4, 310.5) and 180.0 (89.4, 314.0) cells/μL, respectively (p 0.2549); 29 (55.8%) and 21 (42.9%) (p 0.2343) patients, respectively, reached >200 cells/μL. Of the patients, 41 (78.8%) and 31 (63.3%) (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 0.0009). Inflammation and bacterial translocation markers decreased more in the DTG arm, 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 virologic response, and was superior to the DRV/r regimen in reducing inflammation and bacterial translocation markers at 48 weeks.