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Background/Aims: Switching from a three-drug regimen (3DR: boosted darunavir [bDRV] and two nucleoside reverse transcriptase inhibitors [NRTIs]) to a two-drug regimen (2DR: bDRV and dolutegravir [DTG]) demonstrated non-inferiority with regard to viral suppression in people living with HIV (PLWH) in the DUALIS study. This sub-analysis focuses on changes in metabolic and renal parameters when sparing the NRTI backbone. Methods: DUALIS was a randomized, open-label, multicenter (27) phase 3-trial. Participants were virologically suppressed (HIV-RNA < 50 copies/mL) on 3DR for at least 24 weeks. Subjects were either switched to DTG 50 mg + bDRV 800 mg (with ritonavir 100 mg) (2DR) or continued their regimen consisting of two NRTIs in combination with ritonavir-bDRV (3DR) once daily. Data of metabolic and renal parameters at baseline and week 48 were compared. Results: The LDL-fraction increased by + 13.3 (−3.0 to +31.3) mg/dL on 2DRs and was stable (−14.0 to +18.0 mg/dL) on 3DRs (p < 0.0010). PLWH gained +2.0 (−0.2 to +4.0) kg and +0.2 (−1.9 to +2.1) kg in body weight on 2DRs and 3DRs, respectively 3 (p = 0.0006). The MDRD eGFR decreased by −7,8 (−17.4 to −0.3) mL/min/1.73m2 and 0.4 (−8.8 to +5.7) mL/min/1.73m2 on 2DRs and 3DRs, respectively (p = 0.0002), while serum levels of cystatin C were stable in both arms (2DR: −0.1 to +0.1 mg/L; 3DR: 0.0 to +0.1 mg/L). Conclusions: While being non-inferior in terms of viral suppression, sparing the NRTI backbone showed a non-favorable profile in metabolic or renal parameters over 48 weeks. [ABSTRACT FROM AUTHOR]

The DUALIS study demonstrated efficacy and safety of switching to dolutegravir plus ritonavir-boosted darunavir (DRV/r) (2DR) as compared to standard-of-care-therapy with two nucleoside reverse transcriptase inhibitors + DRV/r (3DR) in pretreated people living with HIV (PLWH), 48 weeks after switching. This DUALIS sub-study investigates health-related-quality-of-life (HrQoL) in this study-population. The Hospital Anxiety and Depression Scale (HADS) and the Medical Outcome Survey-HIV (MOS-HIV) were used assessing anxiety and depression symptoms, respectively HrQoL. Data were collected at baseline, 4, 24, and 48 weeks after randomization. Outcome scores were dichotomized and used as criteria in longitudinal models identifying differential developments. Odds ratios (ORs) with 95% confidence intervals (CIs) were computed as main measures of effects. ORs<1 indicate better results for HADS, and worse for MOS-HIV scores in the 2DR compared to 3DR group. In total, 263 subjects were randomized and treated (2DR n=131, 3DR n=132; median age 48 years). Significant different progressions could only be found for HADS-Depression scores (OR=.87, 95% CI:.78,.98, p=.02). While HADS-Depression scores decreased in the 2DR group, they increased in 3DR group. This sub-study showed no disadvantages regarding HrQoL in PLWH after switching to DTG+DRV/r. Considering lifelong requirements for antiretroviral medication, close attention to HrQL is required. [ABSTRACT FROM AUTHOR]

Background Dolutegravir (DTG) and boosted darunavir (bDRV) are potent antiretrovirals with a high resistance barrier and might be valuable switch options for people with HIV (PWH). Methods DUALIS, a randomized, open-label, phase 3b, noninferiority clinical trial, compared the switch to DTG + bDRV (2DR) with continuation of 2 nucleoside reverse transcriptase inhibitors (2NRTI) + bDRV (3DR). PWH with HIV RNA <50 copies/mL taking 2NRTI + bDRV (3DR) for ≥24 weeks (1 accepted blip <200 copies/mL) were randomized to either switch to DTG 50 mg + DRV 800 mg (boosted with 100 mg of ritonavir) or continue taking 3DR. The primary end point (PE) was the proportion of HIV RNA <50 copies/mL at week (W) 48. Change in NRTI backbone was not classified as failure. The estimated sample size for PE analysis was 292; the noninferiority margin was ≤–10.0%. Results In total, 263 subjects were randomized and treated (2DR n = 131, 3DR n = 132; 90.1% male; 89.7% Caucasian; median age [interquartile range], 48 [39–54] years). At W48, 86.3% (n = 113/131) of the 2DR subject and 87.9% (n = 116/132) of the 3DR subjects had HIV RNA <50 copies/mL; the difference between arms was –1.6% (95.48% CI, based on the adjusted alpha level accounting for the interim analysis at W24, –9.9% to +6.7%; discontinuations due to adverse events: 2DR, 4.6% [n = 6]; 3DR, 0.8% [n = 1]). Kaplan-Meier estimates of confirmed HIV RNA ≥50 copies/mL at W48 were 1.6% (n = 2) in the 2DR and 3.1% (n = 4) in the 3DR group. Development of treatment-emergent resistance was not observed. Conclusions Switching to DTG + bDRV was noninferior to continuing 3DR in subjects already treated with bDRV. [ABSTRACT FROM AUTHOR]

A rearranged TCR α transgene remains transcriptionally inactive in rag-2–/– thymocytes but can be induced by CD3-mediated signals with concomitant maturation of double-negative (DN) thymocytes to the CD4+CD8+ double-positive (DP) stage. Reciprocally, the same signals silence pre-TCRα (pTα) expression. In normal C57BL/6 thymocytes, TCRα expression is not detected in DN thymocytes while, in contrast, TCRβ expression is initiated at the most immature c-kit+CD44+CD25- stage and continues throughout thymocyte development. pTα expression is first detected at the intermediate c-kit±CD44+CD25+ DN stage, increases during transition to the more mature c-kit-CD44-CD25+ stage and is lost at the DP stage. Thus, although TCRβ and pTα expression are independent, the pre-TCR complex mediates signals controlling the appearance of αβ TCR through selective regulation of TCRα and pTα genes. [ABSTRACT FROM AUTHOR]

Background/Aims: Switching from a three-drug regimen (3DR: boosted darunavir [bDRV] and two nucleoside reverse transcriptase inhibitors [NRTIs]) to a two-drug regimen (2DR: bDRV and dolutegravir [DTG]) demonstrated non-inferiority with regard to viral suppression in people living with HIV (PLWH) in the DUALIS study. This sub-analysis focuses on changes in metabolic and renal parameters when sparing the NRTI backbone. Methods: DUALIS was a randomized, open-label, multicenter (27) phase 3-trial. Participants were virologically suppressed (HIV-RNA < 50 copies/mL) on 3DR for at least 24 weeks. Subjects were either switched to DTG 50 mg + bDRV 800 mg (with ritonavir 100 mg) (2DR) or continued their regimen consisting of two NRTIs in combination with ritonavir-bDRV (3DR) once daily. Data of metabolic and renal parameters at baseline and week 48 were compared. Results: The LDL-fraction increased by + 13.3 (-3.0 to +31.3) mg/dL on 2DRs and was stable (-14.0 to +18.0 mg/dL) on 3DRs ( p  < 0.0010).PLWH gained +2.0 (-0.2 to +4.0) kg and +0.2 (-1.9 to +2.1) kg in body weight on 2DRs and 3DRs, respectively 3 ( p  = 0.0006).The MDRD eGFR decreased by -7,8 (-17.4 to -0.3) mL/min/1.73m 2 and 0.4 (-8.8 to +5.7) mL/min/1.73m 2 on 2DRs and 3DRs, respectively ( p  = 0.0002), while serum levels of cystatin C were stable in both arms (2DR: -0.1 to +0.1 mg/L; 3DR: 0.0 to +0.1 mg/L). Conclusions: While being non-inferior in terms of viral suppression, sparing the NRTI backbone showed a non-favorable profile in metabolic or renal parameters over 48 weeks.