- Drug-Drug Interactions of Glecaprevir and Pibrentasvir Coadministered with Human Immunodeficiency Virus Antiretrovirals. [Journal Article]J Infect Dis 2019JI
- CONCLUSIONS: Atazanavir is contraindicated with glecaprevir/pibrentasvir and use of boosted protease inhibitors or efavirenz is not recommended. No clinically significant interactions were observed with other studied antiretrovirals.
- Use of contemporary protease inhibitors and risk of incident chronic kidney disease in HIV-positive persons; the D:A:D Study. [Journal Article]J Infect Dis 2019JI
- CONCLUSIONS: While DRV/r use was not significantly associated with CKD an increasing incidence with longer ATV/r use was confirmed.
- Dolutegravir based antiretroviral therapy compared to other combined antiretroviral regimens for the treatment of HIV-infected naive patients: A systematic review and meta-analysis. [Journal Article]PLoS One 2019; 14(9):e0222229Plos
- CONCLUSIONS: Starting treatment in naive patients with dolutegravir containing ART has an increased likelihood of achieving viral suppression in the comparison with non-dolutegravir containing ART. The average benefit is particularly evident in those with high baseline viral load.
- Antiretroviral therapy and vaginally administered contraceptive hormones: a three-arm, pharmacokinetic study. [Journal Article]Lancet HIV 2019; 6(9):e601-e612LH
- CONCLUSIONS: Hormone exposure was significantly lower when an intravaginal ring contraceptive was combined with efavirenz-based ART. Further studies designed to examine pharmacodynamic endpoints, such as ovulation, when intravaginal ring hormones are combined with efavirenz are warranted.
- Anti-HIV and anti-HCV drugs inhibit p-glycoprotein efflux activity in Caco-2 cells and precision-cut rat and human intestinal slices. [Journal Article]Antimicrob Agents Chemother 2019AA
- P-glycoprotein (ABCB1), an ATP-binding-cassette efflux transporter, limits intestinal absorption of its substrates and is a common site of drug-drug interactions (DDIs). ABCB1 has been suggested to interact with many antivirals used to treat human immunodeficiency virus (HIV) and/or chronic hepatitis C virus (HCV) infections. Using bi-directional transport experiments in Caco-2 cells and a recent…
P-glycoprotein (ABCB1), an ATP-binding-cassette efflux transporter, limits intestinal absorption of its substrates and is a common site of drug-drug interactions (DDIs). ABCB1 has been suggested to interact with many antivirals used to treat human immunodeficiency virus (HIV) and/or chronic hepatitis C virus (HCV) infections. Using bi-directional transport experiments in Caco-2 cells and a recently established ex vivo model of accumulation in precision cut intestinal slices (PCIS) prepared from rat ileum or human jejunum, we evaluated the potential of anti-HIV and anti-HCV antivirals to inhibit intestinal ABCB1. Lopinavir, ritonavir, saquinavir, atazanavir, maraviroc, ledipasvir, and daclatasvir inhibited the efflux of a model ABCB1 substrate, rhodamine123 (RHD123), in Caco-2 cells and rat-derived PCIS. Lopinavir, ritonavir, saquinavir, and atazanavir also significantly inhibited RHD123 efflux in human-derived PCIS, while possible inter-individual variability was observed in the inhibition of intestinal ABCB1 by maraviroc, ledipasvir, and daclatasvir. Abacavir, zidovudine, tenofovir disoproxil fumarate, etravirine, and rilpivirine did not inhibit intestinal ABCB1. In conclusion, using recently established ex vivo methods for measuring drug accumulation in rat- and human-derived PCIS, we have demonstrated that some antivirals have a high potential for DDIs on intestinal ABCB1. Our data help clarify the molecular mechanisms responsible for reported increases in the bioavailability of ABCB1 substrates including antivirals and drugs prescribed to treat co-morbidity. These results could help guide the selection of combination pharmacotherapies and/or suitable dosing schemes for patients infected with HIV and/or HCV.
- Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-experienced, virologically suppressed patients with HIV-1: subgroup analyses of the phase 3 EMERALD study. [Journal Article]AIDS Res Ther 2019; 16(1):23AR
- CONCLUSIONS: For treatment-experienced, virologically suppressed patients, switching to D/C/F/TAF was highly effective and safe, regardless of demographic characteristics, prior treatment experience, or pre-switch bPI. Trial registration ClinicalTrials.gov Identifier: NCT02269917. Registered 21 October 2014. https://clinicaltrials.gov/ct2/show/NCT02269917.
- Atazanavir urolithiasis without recent intake of atazanavir. [Journal Article]Ann Biol Clin (Paris) 2019; 77(4):459-460AB
- Kinetic and thermodynamic characterisation of HIV-protease inhibitors against E35D↑G↑S mutant in the South African HIV-1 subtype C protease. [Journal Article]J Enzyme Inhib Med Chem 2019; 34(1):1451-1456JE
- Herein, we report the effect of nine FDA approved protease inhibitor drugs against a new HIV-1 subtype C mutant protease, E35D↑G↑S. The mutant has five mutations, E35D, two insertions, position 36 (G and S), and D60E. Kinetics, inhibition constants, vitality, Gibbs free binding energies are reported. The variant showed a decreased affinity for substrate and low catalytic efficiency compared to th…
Herein, we report the effect of nine FDA approved protease inhibitor drugs against a new HIV-1 subtype C mutant protease, E35D↑G↑S. The mutant has five mutations, E35D, two insertions, position 36 (G and S), and D60E. Kinetics, inhibition constants, vitality, Gibbs free binding energies are reported. The variant showed a decreased affinity for substrate and low catalytic efficiency compared to the wild type. There was a significant decrease in the binding of seven FDA approved protease inhibitors against the mutant (p < .0001). Amprenavir and ritonavir showed the least decrease, but still significant reduced activity in comparison to the wildtype (4 and 5 folds, respectively, p = .0021 and .003, respectively). Nelfinavir and atazanavir were the worst inhibitors against the variant as seen from the IC50, with values of 1401 ± 3.0 and 685 ± 3.0 nM, respectively. Thermodynamics data showed less favourable Gibbs free binding energies for the protease inhibitors to the mutant.
- Delayed-onset effect of clofarabine in the treatment of an adult patient with acute myeloid leukemia. [Journal Article]Am J Health Syst Pharm 2019; 76(6):349-352AJ
- CONCLUSIONS: A 44-year-old African-American man with pancytopenia was transferred to an academic medical center for evaluation. His medical history included bipolar depression, gynecomastia, and HIV infection (diagnosed 5 years prior) for which he was being treated with atazanavir, emtricitabine-tenofovir, and ritonavir. He was diagnosed with AML with 60% myeloblasts found during bone marrow biopsy. He had primary refractory disease after induction chemotherapy treatment. His disease was refractory to subsequent therapy with high-dose cytarabine and then etoposide and mitoxantrone. The patient then underwent treatment with granulocyte-colony stimulating factor-primed clofarabine and cytarabine (G-CLAC). At blood count recovery, he was diagnosed with refractory disease, with 17% blasts in peripheral blood and was subsequently discharged home on hospice 38 days after G-CLAC and 19 days after the last dose of filgrastim. He arrived at the outpatient clinic 79 days after G-CLAC chemotherapy with significantly improved blood counts. Two weeks later, a bone marrow biopsy confirmed complete remission with incomplete hematologic recovery.A patient with relapsed AML achieved a delayed response to clofarabine at least 38 days after treatment.
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- Assessing the lymphoid tissue bioavailability of antiretrovirals in human primary lymphoid endothelial cells and in mice. [Journal Article]J Antimicrob Chemother 2019JA
- CONCLUSIONS: ARVs displayed distinct HLEC penetration patterns. PK studies of representative ARVs in LT of mice were concordant with HLEC bioavailability. These findings support further development of this approach and its translational predictability in humans.