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A switch strategy to investigate whether a dual therapy with Ritonavir-boosted (RTV) Darunavir (DRV) + Dolutegravir (DTG) over 48 weeks is non-inferior to a continuous standard of care therapy with RTV-boosted DRV in combination with 2 Nucleosidic Reverse Transcriptase Inhibitors (NRTIs) in HIV patients, who are on a stable antiretroviral therapy (ART) with RTV-boosted DRV in combination with 2 NRTIs.
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Background: Dolutegravir (DTG) combined with boosted darunavir may be a promising NRTI sparing and/or salvage strategy for the treatment of HIV-1 infection. In patients undergoing drug monitoring, DTG trough concentrations doubled when switching from darunavir/ritonavir (DRV/r) to DRV/cobicistat (c), in contrast to a 38% decrease with darunavir/ritonavir (DRV/r) twice daily. However, no formal interaction studies between DTG and DRV/c have been published. Methods: This phase 1, open label, 57 day, cross over, pharmacokinetic (PK) study, enrolled healthy volunteers aged 18-65years, who were randomized to: i) group 1: DTG 50mg on days 1-14 followed by a 7 day wash out period, DTG+DRV/c 50mg+800/150mg on days 22-35 (co-administration period), which was followed by a 7 day wash out, and finally DRV/c 800/150mg on days 43-56 or ii) group 2: DRV/c 800/150mg on days 1-14 followed by a 7 day wash out period, DTG 50mg+DRV/c 800/150mg on days 22-35 (co-administration period), which was followed by a 7 day wash out and finally DTG 50mg on days 43-56. All doses were administered once daily. Each group underwent intensive PK sampling (0-24 hr post-dose) on days 14, 35 and 56 and DTG/DRV/c concentrations were measured by validated LC-MS methods. Results: To date, 13 healthy volunteers have been screened, 12 baselined and 9 have completed all PK phases (1 subject withdrew for personal reasons and 2 are ongoing). Median age (range) was 31yrs (24-55), 1 was male, 4 self-reported as white and 5 as black African/Caribbean. DTG geometric mean ratios (GMR, DTG+DRV/c versus DTG alone) and 90% confidence intervals (CI) Cmax, AUC, C24h were 0.89 (0.79-1.02), 0.84 (0.73-0.96), 0.81 (0.66-0.98). DRV GMR (DRV/c+DTG versus DRV/c alone, 90%CI) of DRV Cmax, AUC, C24h were 0.79 (0.71-0.89), 0.87 (0.78-0.96), 0.82 (0.67-1.00), and of C Cmax, AUC, C24h were 0.86 (0.77-0.96), 0.88 (0.78-1.00) 0.98 (0.74-1.28), No grade 3 or 4 adverse events or laboratory abnormalities were observed. Conclusion: Concentrations of DTG during co-administration with DRV/c decreased by <20% and those of DRV with DTG by <21%, suggesting this combination can be prescribed safely in the treatment of HIV-1, including in patients harbouring resistance that benefit from optimal antiretroviral exposures.
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Darunavir/ritonavir is indicated in combination with other antiretroviral drugs for the treatment of HIV-1 infection in pre-treated adult patients. In hepatitis B or C co-infected patients, the virological response rate to darunavir/ritonavir appeared to be unaffected and, except for increased liver enzymes, the incidence of adverse events was not higher than in patients without co-infection. Drug-induced hepatitis has been reported in 0.5% of patients receiving combination therapy with darunavir/ritonavir. Patients with pre-existing liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events. Therefore AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, (HVB/HCV) like it is recommended in all patients receiving boosted PIS. Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir are similar in patients with normal liver function, mild hepatic impairment (Child-Pugh Class A), and moderate hepatic impairment (Child-Pugh Class B). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated. No dose adjustment is required in patients with mild or moderate hepatic impairment. There are no data on the use of darunavir in patients with severe hepatic impairment and consequently this drug is not recommended in this group of patients.
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This study will evaluate the pharmacokinetic properties of Rilpivirine and Darunavir when used in combination with Levonorgestrel
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This study will assess and characterize the variability observed in the response to darunavir therapy, an antiretroviral medication used against the Human Immunodeficiency Virus (HIV). More specifically, it aims to quantify variations in the drug\'s blood concentrations and determine the sources of such variability, both genetic and non-genetic. In light of this information, current dosage guidelines will then be reviewed.
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