- In vitro-in vivo correlation of the drug-drug interaction potential of antiretroviral HIV treatment regimens on CYP1A1 substrate riociguat. [Journal Article]Expert Opin Drug Metab Toxicol 2019EO
- CONCLUSIONS: Antiretroviral treatment containing the potent CYP1A1 inhibitor abacavir had the greatest impact on riociguat metabolic clearance. The impact of comedications containing only strong CYP3A4 inhibitors e.g. ritonavir was less pronounced, suggesting benefit of riociguat over PAH-targeting medications with contraindications for use with strong CYP3A4 inhibitors.
- Integrase strand transfer inhibitor (INSTI)-resistance mutations for the surveillance of transmitted HIV-1 drug resistance. [Journal Article]J Antimicrob Chemother 2019JA
- CONCLUSIONS: A set of 24 non-polymorphic INSTI-selected mutations is likely to be useful for quantifying INSTI-associated TDR. This list may require updating as more sequences become available from INSTI-experienced persons infected with HIV-1 non-subtype B viruses and/or receiving dolutegravir.
- Comparable in vitro activity of second-generation HIV-1 integrase strand transfer inhibitors (INSTIs) on HIV-1 clinical isolates with INSTI resistance mutations. [Journal Article]Antimicrob Agents Chemother 2019AA
- Second-generation HIV-1 integrase strand transfer inhibitors (INSTIs) dolutegravir (DTG), bictegravir (BIC) and cabotegravir (CAB) showed a high genetic barrier to resistance and limited cross-resistance with first generation INSTIs raltegravir (RAL) and elvitegravir (EVG). In this study, DTG, BIC and CAB demonstrated a comparable activity on a panel of INSTI resistant strains isolated from patie…
Second-generation HIV-1 integrase strand transfer inhibitors (INSTIs) dolutegravir (DTG), bictegravir (BIC) and cabotegravir (CAB) showed a high genetic barrier to resistance and limited cross-resistance with first generation INSTIs raltegravir (RAL) and elvitegravir (EVG). In this study, DTG, BIC and CAB demonstrated a comparable activity on a panel of INSTI resistant strains isolated from patients exposed to RAL, EVG and/or DTG, with a significantly reduced susceptibility only with the Q148H/K/R plus one-two additional INSTI mutations pathway.
- Food insecurity is associated with lower levels of antiretroviral drug concentrations in hair among a cohort of women living with HIV in the United States. [Journal Article]
- CONCLUSIONS: Food insecurity was associated with lower ART concentrations in hair, suggesting that food insecurity may be associated with sub-optimal ART adherence and/or drug absorption. Interventions that aim to improve ART adherence among WLHIV should consider and address the role of food insecurity.
- Weight Gain Following Initiation of Antiretroviral Therapy: Risk Factors in Randomized Comparative Clinical Trials. [Journal Article]
- CONCLUSIONS: Weight gain is ubiquitous in clinical trials of ART initiation, and is multifactorial in nature, with demographic factors, HIV-related factors, and the composition of ART regimens contributing. The mechanisms by which certain ART agents differentially contribute to weight gain are unknown.
- Analysis of Pharmacovigilance Databases for Dolutegravir Safety in Pregnancy. [Journal Article]
- CONCLUSIONS: Pharmacovigilance databases have many limitations, most importantly lack of a clear denominator for patients exposed to the drug of interest and duplicate cases that are difficult to identify. Given widespread use of new antiretroviral drugs worldwide and anticipated use of new drugs, prospective follow-up of pregnant women and birth surveillance studies such as Tsepamo are critically needed.Neural tube defects have been reported among infants born from women taking a wide range of antiretrovirals in 4 pharmacovigilance databases. Safety reports were inconsistent between databases and very hard to interpret.
- Dolutegravir/lamivudine (Dovato)--a two-drug complete regimen for HIV-1 infection. [Journal Article]Med Lett Drugs Ther 2019; 61(1579):134-136ML
- Acute myocarditis after switch to dolutegravir: a reminder of potential toxicity of integrase inhibitor-including HAART. [Journal Article]AIDS 2019; 33(13):2105-2107AIDS
- Antiretroviral-Mediated Microglial Activation Involves Dysregulated Autophagy and Lysosomal Dysfunction. [Journal Article]Cells 2019; 8(10)C
- In the era of combined antiretroviral therapy (cART), as infected individuals continue to have longer lifespans, there is also an increased prevalence of HIV-associated neurocognitive disorders (HAND). Inflammation is one of the underlying features of HAND, with the role of viral proteins and antiretroviral drugs implicated in this process. Microglia are extremely sensitive to a plethora of stimu…
In the era of combined antiretroviral therapy (cART), as infected individuals continue to have longer lifespans, there is also an increased prevalence of HIV-associated neurocognitive disorders (HAND). Inflammation is one of the underlying features of HAND, with the role of viral proteins and antiretroviral drugs implicated in this process. Microglia are extremely sensitive to a plethora of stimuli, including viral products and cART. The current study was undertaken to understand the molecular mechanism(s) underlying cART-mediated activation of microglia. Herein we chose a combination of three commonly used drugs, tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and dolutegravir (DTG). We demonstrated that exposure of microglia to this cART cocktail induced lysosomal membrane permeabilization (LMP), which subsequently resulted in impaired lysosomal functioning involving elevated pH and decreased cathepsin D (CTSD) activity. cART exposure of microglia resulted in increased formation of autophagosomes as demonstrated by a time-dependent increase of autophagy markers, with a concomitant defect in the fusion of the lysosomes with the autophagosome. Taken together, our findings suggest a novel mechanism by which cART impairs lysosomal functioning, resulting in dysregulated autophagy and increased neuroinflammation. Interventions aimed at lysosome protection could likely be envisioned as promising therapeutic targets for abrogating cART-mediated microglia activation, which in turn, could thus be considered as adjunctive therapeutics for the treatment of HAND pathogenesis.
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- No overall change in the rate of weight gain after switching to an integrase-inhibitor in virologically suppressed adults with HIV. [Journal Article]AIDS 2019AIDS
- CONCLUSIONS: We found no clear evidence of an overall increase in rate of weight gain following switch to INSTI in virologically-suppressed individuals.