Dolutegravir/Lamivudine versus Tenofovir Alafenamide/Emtricitabine/Bictegravir as a Switch Strategy in a Real-Life Cohort of Virogically Suppressed People Living with HIV.

BACKGROUND: The aim of the study is to evaluate the effectiveness, safety, and tolerability of a two-drug regimen (2-DR) dolutegravir/lamivudine (DTG/3TC) versus a three-drug regimen (3-DR) tenofovir alafenamide/emtricitabine/bictegravir (TAF/FTC/BIC) in a real-life cohort of HIV-1 virologically suppressed treatment-experienced (TE) people living with HIV (PLWH). METHODS: This was a single-center, retrospective, observational study analyzing adult TE PLWH who started the 2-DR or 3-DR between January 2018 and January 2023. All PLWH with a viral load (VL) <50 copies/mL at the time of switching, and a follow-up of more than 6 months or interruption of treatment at any time, were included. RESULTS: A total of 324 PLWH were included; of these, 110 (34%) were on the 2-DR and 214 (66%) were on the 3-DR. Most patients remained on therapy in both groups (93.6% 2-DR versus 90.2% 3-DR) and, at the last control, 99.1% achieved VL < 50 copies/mL with the 2-DR versus 97.2% with the 3-DR (p = 0.260). No virological failures occurred in either group. Adverse events occurred in a few cases: four (3.6%) in the 2-DR group and five (2.3%) in the 3-DR group (p = 0.500). The median follow-up-time was 19.6 months for the 2-DR and 27.5 months for the 3-DR. CONCLUSION: Our study shows a similar effectiveness and safety profile in virologically suppressed PLWH switching to DTG/3TC or TAF/FTC/BIC.

Bictegravir/Tenofovir Alafenamide/Emtricitabine: A Real-Life Experience in People Living with HIV (PLWH).

BACKGROUND: Bictegravir (BIC), a recently introduced integrase inhibitor, is available in a single tablet regimen with tenofovir alafenamide (TAF) and emtricitabine (FTC) (BIC-STR). This study aimed to describe a real-life experience with BIC-STR. METHODS: We retrospectively analyzed the data of people living with HIV (PLWH) on antiretroviral therapy (ART) with BIC-STR followed by the Clinic of Infectious Diseases of Perugia (Perugia, Italy) from September 2019 to February 2023. RESULTS: 270 PLWH were enrolled with a median follow-up time on BIC-STR of 2.2 years (IQR 1.2-2.7). In the overall population, in treatment-experienced (N = 242), in treatment-naïve (N = 28), and in population with age > 60 years old (N = 86), we observed that CD4 cell count improved in absolute number, percentage and CD4/CD8 ratio, under BIC-STR. Patients with viremia < 50 cp/mL increased in all groups. In the overall population, previous ART with TAF and nadir CD4 cell count favored immunological recovery. In the ART-experienced group, time in therapy with BIC-STR was associated with HIV-RNA undetectability. In the older group, previous opportunistic infection and advanced age were associated with lower CD4 count. CONCLUSIONS: BIC-STR was demonstrated, in real-life, to be a valid option for a switch, such as initial ART.

Neurosteroid modulation of the presynaptic NMDA receptors regulating hippocampal noradrenaline release in normal rats and those exposed prenatally to diazepam.

Prenatal exposure to diazepam (DZ), a positive allosteric modulator of the gamma-aminobutyric acid(A) (GABA(A)) receptor complex, exerts profound effects that become more evident during puberty and in many cases are sex-specific, suggesting that such exposure interferes with the activity of steroid hormones. Apart from their well known effects on the genome, the reduced metabolites of many steroid hormones also interact directly with membrane receptors, including those for N-methyl-D-aspartate (NMDA). In this study, we compared the effects of several neurosteroids on NMDA receptors from normal rats and those exposed in utero to DZ (1.25mg/kg per day) from the 14th through the 20th day of gestation. In superfused rat hippocampal synaptosomes, activation of the NMDA receptor stimulates the basal release of [3H]noradrenaline ([3H]NA), which was used in our study as an index of receptor function. [3H]NA release was evoked in a concentration-dependent manner by NMDA (100 microM) plus glycine (GLY). The maximal increase (68.23+/-3.86%) with respect to basal release was achieved with a GLY concentration of 10 microM, and the EC(50) for GLY was 0.1 microM. Release stimulated by 100 microM NMDA + 0.1 microM GLY was not modified by any of the neurosteroids tested, with the exception of pregnenolone sulfate (PREG-S), which produced a 78.57+/-3.94% reduction in release at the maximal concentration used (0.3 microM). In synaptosomes from animals exposed in utero to DZ, the inhibitory effect of PREG-S was reduced by 46.55+/-2.33%. Given the important roles played by NMDA receptors in physiological and pathological processes within the central nervous system (CNS), characterization of NMDA receptor modulation is an important objective. The fact that this modulation can be altered by exposure in utero to DZ indicates that the behavioral abnormalities observed in exposed animals might be partially attributed to an altered sensitivity of NMDA receptors to the modulatory effects of neurosteroids.

Prenatal diazepam exposure functionally alters the GABA(A) receptor that modulates [3H]noradrenaline release from rat hippocampal synaptosomes.

In rats, exposure to diazepam (DZ) during the last week of gestation is associated with behavioral alterations (in some cases sexually dimorphic) that appear when the animals reach adulthood. This study was conducted to evaluate the effects of prenatal DZ exposure on the function of the gamma-aminobutyric (GABA)(A) receptor complex. The method used - perfusion of rat hippocampal nerve terminals labeled with [3H]noradrenaline (NA) - allowed us to evaluate the effects of DZ on a specific native GABA(A) receptor subtype which is located on hippocampal noradrenergic nerve endings and mediates the release of NA. Muscimol stimulated synaptosomal release of [3H]NA in a concentration-dependent manner; maximal stimulation (50%) was achieved with a concentration of 30 microM, and the ED(50) was 1.7 microM. The effect of muscimol was potentiated by the positive allosteric modulators DZ and 3alpha-pregnan-5alpha-ol-20-one (3alpha,5alpha-P; allopregnanolone), which displayed similar maximal effects and affinities. In the presence of DZ (0.1 microM), muscimol stimulated the release of [3H]NA with an ED(50) of 0.5 microM; in the presence of 3alpha,5alpha-P (0.1 microM), the ED(50) of muscimol was 0.3 microM. Prenatal DZ exposure did not modify the concentration-effect curve for muscimol, but it did abolish the potentiating effects of DZ and 3alpha,5alpha-P. These findings demonstrate that prenatal exposure to DZ produces functional modifications of the GABA(A) receptor subtype we investigated. This effect may be related to the relative contributions of the various protein subunits that compose the GABA(A) receptor complex. Exposure to DZ while the GABA(A) receptors are developing might influence the expression of these subunits, giving rise to a receptor that can be activated by muscimol but is not susceptible to allosteric modulation by DZ or 3alpha,5alpha-P.