A phase IV randomised, open-label pilot study to evaluate switching from protease-inhibitor based regimen to Bictegravir/Emtricitabine/Tenofovir Alafenamide single tablet regimen in Integrase inhibitor-naïve, virologically suppressed HIV-1 infected adults harbouring drug resistance mutations (PIBIK study): study protocol for a randomised trial

Iwuji, Collins; Churchill, Duncan; Bremner, Stephen; Perry, Nicky; To, Ye Mong; Lambert, Debbie; Bruce, Chloe; Waters, Laura; Orkin, Chloe; Geretti, Anna María

doi:10.1186/s12879-020-05240-y

Cited by 6 publications

(3 citation statements)

References 31 publications

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“…BIC was approved in 2018 and it is only available in a three-drug combination (BIC/FTC/TAF) FDC tablet ( Biktarvy, 2019 ). The efficacy and safety of BIC/FTC/TAF compared to other core regimens using on HIV treatment naïve and Treatment-experienced patients or switching from other regimens to BIC/FTC/TAF were confirmed in multiple clinical trials ( Sax et al., 2017 ; Daar et al., 2018 ; Gallant et al., 2017 ; Iwuji et al., 2020 ). Because of the durable virology efficacy, BIC/FTC/TAF is recommended as an initial HIV therapy ( Panel on Antiretroviral G, 2020 ).…”

Section: Pharmacokineticsmentioning

confidence: 90%

Pharmacokinetic drug interactions of integrase strand transfer inhibitors

Bednarczyk

Catanzaro

et al. 2021

Current Research in Pharmacology and Drug Discovery

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The integrase strand transfer inhibitor (INSTI)-containing regimens are currently considered as the first-line treatment of human immunodeficiency virus (HIV) infection. Although possessing a common mechanism of action to inhibit HIV integrase irreversibly to stop HIV replication cycle, the INSTIs, including raltegravir, elvitegravir, dolutegravir, and bictegravir, differ in pharmacokinetic characteristics. While raltegravir undergoes biotransformation by the UDP-glucuronosyltransferases (UGTs), elvitegravir is primarily metabolized by cytochrome P450 (CYP) 3A4 and co-formulated with cobicistat to increase its plasma exposure. The metabolism pathways of dolutegravir and bictegravir are similar, both including CYP3A and UGT1A1, and both agents are substrates to different drug transporters. Because of their differences in metabolism, INSTIs interact with other medications differently through CYP enzymes and transporters as inducers or inhibitors. These drug interactions may become an important consideration in the long-term clinical use because the life expectancy of people with HIV (PWH) approaches to that of the general population. Also, common geriatric challenges such as multimorbidity and polypharmacy have been increasingly recognized in PWH. This review provides a summary of pharmacokinetic interactions with INSTIs and future perspectives in implications of INSTI drug interactions.

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Section: Pharmacokineticsmentioning

confidence: 90%

Pharmacokinetic drug interactions of integrase strand transfer inhibitors

Bednarczyk

Catanzaro

et al. 2021

Current Research in Pharmacology and Drug Discovery

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“…In general, patients receive a combination of two or three drugs, such as nucleoside reverse transcriptase inhibitors (lamivudine and abacavir), along with protease inhibitors (ritonavir and atazanavir) (18). Although, in 2020 international antiviral society-USA panel suggest that regimens of three drugs including 2 nucleoside reverse transcriptase inhibitor and an integrase inhibitor can be useful to suppress the viral replication (19), some of the developing nations continuously using the old regime of first line NRTIbased cocktail along with protease inhibitors (20)(21)(22). Chronic administration of multiple drugs may lead to CVD and heart failure in HIV patients through cellular and molecular modification in cardiomyocytes, which leads to modulation of pathological gene expression (5,23,24).…”

Section: Introductionmentioning

confidence: 99%

Antiretroviral Drugs Regulate Epigenetic Modification of Cardiac Cells Through Modulation of H3K9 and H3K27 Acetylation

Kashyap

Mukker

Gupta

et al. 2021

Front. Cardiovasc. Med.

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Antiretroviral therapy (ART) has significantly reduced the rate of mortality in HIV infected population, but people living with HIV (PLWH) show higher rates of cardiovascular disease (CVD). However, the effect of antiretroviral (ARV) drug treatment on cardiac cells is not clear. In this study, we explored the effect of ARV drugs in cardiomyocyte epigenetic remodeling. Primary cardiomyocytes were treated with a combination of four ARV drugs (ritonavir, abacavir, atazanavir, and lamivudine), and epigenetic changes were examined. Our data suggest that ARV drugs treatment significantly reduces acetylation at H3K9 and H3K27 and promotes methylation at H3K9 and H3K27, which are histone marks for gene expression activation and gene repression, respectively. Besides, ARV drugs treatment causes pathological changes in the cell through increased production of reactive oxygen species (ROS) and cellular hypertrophy. Further, the expression of chromatin remodeling enzymes was monitored in cardiomyocytes treated with ARV drugs using PCR array. The PCR array data indicated that the expression of epigenetic enzymes was differentially regulated in the ARV drugs treated cardiomyocytes. Consistent with the PCR array result, SIRT1, SUV39H1, and EZH2 protein expression was significantly upregulated in ARV drugs treated cardiomyocytes. Furthermore, gene expression analysis of the heart tissue from HIV+ patients showed that the expression of SIRT1, SUV39H1, and EZH2 was up-regulated in patients with a history of ART. Additionally, we found that expression of SIRT1 can protect cardiomyocytes in presence of ARV drugs through reduction of cellular ROS and cellular hypertrophy. Our results reveal that ARV drugs modulate the epigenetic histone markers involved in gene expression, and play a critical role in histone deacetylation at H3K9 and H3K27 during cellular stress. This study may lead to development of novel therapeutic strategies for the treatment of CVD in PLWH.

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“…According to a recent recommendation of the International Antiviral Society-USA panel, a cocktail of three drugs, including two nucleoside reverse transcriptase inhibitors and an integrase inhibitor, can be used to suppress viral replication [ 10 ]. However, some underdeveloped countries still use the old regime of drugs, including NRTIs and protease inhibitors, as a first-line drug for the treatment of HIV [ 11 , 12 , 13 ]. Although, ART improves the life expectancy of PLWH, the development of CVD in HIV patients is responsible for a higher mortality rate.…”

Section: Introductionmentioning

confidence: 99%

HOPX Plays a Critical Role in Antiretroviral Drugs Induced Epigenetic Modification and Cardiac Hypertrophy

Kashyap

Rabbani

Lima

et al. 2021

Cells

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People living with HIV (PLWH) have to take an antiretroviral therapy (ART) for life and show noncommunicable illnesses such as chronic inflammation, immune activation, and multiorgan dysregulation. Recent studies suggest that long-term use of ART induces comorbid conditions and is one of the leading causes of heart failure in PLWH. However, the molecular mechanism of antiretroviral drugs (ARVs) induced heart failure is unclear. To determine the mechanism of ARVs induced cardiac dysfunction, we performed global transcriptomic profiling of ARVs treated neonatal rat ventricular cardiomyocytes in culture. Differentially expressed genes were identified by RNA-sequencing. Our data show that ARVs treatment causes upregulation of several biological functions associated with cardiotoxicity, hypertrophy, and heart failure. Global gene expression data were validated in cardiac tissue isolated from HIV patients having a history of ART. Interestingly, we found that homeodomain-only protein homeobox (HOPX) expression was significantly increased in cardiomyocytes treated with ARVs and in the heart tissue of HIV patients. Furthermore, we found that HOPX plays a crucial role in ARVs mediated cellular hypertrophy. Mechanistically, we found that HOPX plays a critical role in epigenetic regulation, through deacetylation of histone, while the HDAC inhibitor, Trichostatin A, can restore the acetylation level of histone 3 in the presence of ARVs.

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Cited by 6 publications

References 31 publications

Pharmacokinetic drug interactions of integrase strand transfer inhibitors

Pharmacokinetic drug interactions of integrase strand transfer inhibitors

Antiretroviral Drugs Regulate Epigenetic Modification of Cardiac Cells Through Modulation of H3K9 and H3K27 Acetylation

HOPX Plays a Critical Role in Antiretroviral Drugs Induced Epigenetic Modification and Cardiac Hypertrophy

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