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The Journal of Antimicrobial... Dec 2023Integrase strand transfer inhibitors (INSTIs) are recommended as first-line ART for people living with HIV (PLWH) in most guidelines. The INSTI-resistance-associated... (Observational Study)
Observational Study
BACKGROUND
Integrase strand transfer inhibitors (INSTIs) are recommended as first-line ART for people living with HIV (PLWH) in most guidelines. The INSTI-resistance-associated mutation E157Q, a highly prevalent (2%-5%) polymorphism of the HIV-1 (human immunodeficiency virus type 1) integrase gene, has limited data on optimal first-line ART regimens. We assessed the virological outcomes of various first-line ART regimens in PLWH with E157Q in real-world settings.
METHODS
A multicentre retrospective observational study was conducted on PLWH who underwent integrase genotypic drug-resistance testing before ART initiation between 2008 and 2019 and were found to have E157Q. Viral suppression (<50 copies/mL) rate at 24 and 48 weeks, time to viral suppression and time to viral rebound (≥100 copies/mL) were compared among the first-line ART regimens.
RESULTS
E157Q was detected in 167 (4.1%) of 4043 ART-naïve PLWH. Among them, 144 had available clinical data after ART initiation with a median follow-up of 1888 days. Forty-five started protease inhibitors + 2 NRTIs (PI group), 33 started first-generation INSTI (raltegravir or elvitegravir/cobicistat) + 2 NRTIs (INSTI-1 group), 58 started once-daily second-generation INSTI (dolutegravir or bictegravir) + 2 NRTIs (INSTI-2 group) and eight started other regimens. In the multivariate analysis, the INSTI-2 group showed similar or favourable outcomes compared with the PI group for viral suppression rates, time to viral suppression and time to viral rebound. Two cases in the INSTI-1 group experienced virological failure.
CONCLUSIONS
The general guideline recommendation of second-generation INSTI-based first-line ART for most PLWH is also applicable to PLWH harbouring E157Q.
Topics: Humans; HIV-1; Retrospective Studies; HIV Infections; HIV Integrase Inhibitors; Raltegravir Potassium; HIV Integrase; Heterocyclic Compounds, 3-Ring; Drug Resistance, Viral
PubMed: 37856677
DOI: 10.1093/jac/dkad319 -
European Journal of Pharmaceutical... Dec 2022This work aimed to develop a physiologically based pharmacokinetic (PBPK) model for raltegravir accounting for UDP-glucuronosyltransferase (UGT) metabolism to assess the...
This work aimed to develop a physiologically based pharmacokinetic (PBPK) model for raltegravir accounting for UDP-glucuronosyltransferase (UGT) metabolism to assess the effect of UGT gene polymorphisms. Raltegravir elimination was evaluated using K and V values from human recombinant systems and UGT tissue scalar considering liver, kidney, and intestine. The predicted/observed ratios for raltegravir PK parameters were within a 2-fold error range in UGT1A1 poor and normal metabolizers, except in Asian UGT1A1 poor metabolizers. This PBPK modeling approach suggests that UGT1A3 is the main contributor to raltegravir's metabolism. UGT1A3 and UGT1A1 gene polymorphisms might have an additive effect on raltegravir's drug disposition and response. The final model accounting for hepatic, renal, and intestinal UGT metabolism, biliary clearance, and renal excretion improved model predictions compared with the previously published models. This PBPK model with the quantitative characterization of raltegravir elimination pathways can support dose adjustments in different clinical scenarios.
Topics: Humans; Raltegravir Potassium; Microsomes, Liver; Glucuronosyltransferase; Kinetics; Protein Isoforms
PubMed: 36265816
DOI: 10.1016/j.ejps.2022.106309 -
Brazilian Journal of Medical and... 2022Disruption of pulmonary endothelial permeability and associated barrier integrity increase the severity of acute respiratory distress syndrome (ARDS). This study...
Disruption of pulmonary endothelial permeability and associated barrier integrity increase the severity of acute respiratory distress syndrome (ARDS). This study investigated the potential ability of the human immunodeficiency virus-1 (HIV-1) integrase inhibitor raltegravir to protect against acute lung injury (ALI) and the underlying mechanisms. Accordingly, the impact of raltegravir treatment on an in vitro lipopolysaccharide (LPS)-stimulated human pulmonary microvascular endothelial cell (HPMEC) model of ALI and an in vivo LPS-induced two-hit ALI rat model was examined. In the rat model system, raltegravir treatment alleviated ALI-associated histopathological changes, reduced microvascular permeability, decreased Evans blue dye extravasation, suppressed the expression of inflammatory proteins including HMGB1, TLR4, p-NF-κB, NLRP3, and MPO, and promoted the upregulation of protective proteins including claudin 18.1, VE-cadherin, and aquaporin 5 as measured via western blotting. Immunohistochemical staining further confirmed the ability of raltegravir treatment to reverse LPS-induced pulmonary changes in NLRP3, claudin 18.1, and aquaporin 5 expression. Furthermore, in vitro analyses of HPMECs reaffirmed the ability of raltegravir to attenuate LPS-induced declines in VE-cadherin and claudin 18.1 expression while simultaneously inhibiting NLRP3 activation and reducing the expression of HMGB1, TLR4, and NF-kB, thus decreasing overall vascular permeability. Overall, our findings suggested that raltegravir may represent a viable approach to treating experimental ALI that functions by maintaining pulmonary microvascular integrity.
Topics: Animals; Humans; Rats; Acute Lung Injury; Aquaporin 5; Claudins; HMGB1 Protein; Lipopolysaccharides; Lung; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Raltegravir Potassium; Signal Transduction; Toll-Like Receptor 4
PubMed: 36350972
DOI: 10.1590/1414-431X2022e12268 -
International Journal of STD & AIDS Mar 2023Limited data is available on raltegravir (RAL) pharmacokinetics during pregnancy and the value of therapeutic drug monitoring (TDM) in pregnancy is unknown. This study...
BACKGROUND
Limited data is available on raltegravir (RAL) pharmacokinetics during pregnancy and the value of therapeutic drug monitoring (TDM) in pregnancy is unknown. This study aims to describe RAL trough plasma concentrations (C) during pregnancy and review the impact of RAL TDM on outcomes.
METHODS
Women from the prospective mother-infant HIV cohort of Mother and Children's Infectious Diseases Center who received RAL during their pregnancy between 2011-2020 were included. TDM reports were reviewed and C values estimated when possible, using historical RAL half-lives.
RESULTS
We included 76 pregnant women of which 47 underwent TDM. We observed a significant association between virological response and C (-value .034) with an increase of 0.1 mg/L corresponding to a 2.96 reduction in the risk of having a detectable viral load. The results indicated that in pregnant women a RAL C threshold of 0.04 mg/L has a higher specificity (75%) as compared to our current C target value of 0.02 mg/L (25%) and an acceptable sensitivity (77%). No significant differences were observed between C at each trimester. When comparing pregnancies with and without TDM, no statistically significant differences were observed in the virologic response during pregnancy and at delivery, or with the need for triple antiretroviral prophylaxis in newborns.
CONCLUSIONS
An association between RAL C and viral load was observed and achieving a RAL C of 0.04 mg/L or greater is a predictor of virologic response in pregnant women. The impact of TDM in pregnancy, however, could not be demonstrated.
Topics: Child; Female; Humans; Infant, Newborn; Pregnancy; Raltegravir Potassium; HIV Infections; Prospective Studies; Drug Monitoring; Pregnancy Complications, Infectious; Viral Load; Anti-HIV Agents
PubMed: 36529684
DOI: 10.1177/09564624221144489 -
HIV Medicine Nov 2023Our objectives were to investigate the characteristics of people living with HIV who presented with new or recurrent symptoms in the context of re-emergence of...
OBJECTIVES
Our objectives were to investigate the characteristics of people living with HIV who presented with new or recurrent symptoms in the context of re-emergence of cerebrospinal fluid HIV RNA escape after antiretroviral therapy (ART) modification (termed relapse of CSF HIV RNA escape).
METHODS
People living with HIV-1 with known CSF HIV RNA escape were identified, with clinical and laboratory data obtained from records in a tertiary centre. CSF HIV RNA escape was defined as quantifiable CSF HIV RNA in the presence of unquantifiable plasma HIV-RNA or CSF HIV RNA greater than plasma HIV RNA in cases where plasma HIV-RNA was quantifiable. Relapse was defined as a re-emergence of CSF HIV RNA escape with new symptoms after ART therapy intensification post-initial CSF HIV RNA escape.
RESULTS
Among 40 people living with HIV who presented with neurosymptomatic CSF HIV RNA, eight (20%) presented with a relapse of CSF HIV RNA escape. Symptoms on relapse included confusion (n = 2), cognitive decline (n = 2), cerebellar dysfunction (n = 2) and worsening of pre-existing seizures (n = 1). Prior to their relapse, three people underwent drug therapy modification, with two people stopping raltegravir intensification, and one person switched from tenofovir alafenamide, emtricitabine and raltegravir for a new regimen.
CONCLUSIONS
People with a relapse of CSF HIV RNA escape within this cohort presented with varied symptoms similar to their initial CSF HIV RNA escape. Clinicians should be vigilant of relapse of symptoms, particularly when simplifying ART regimens in people with CSF HIV RNA escape.
Topics: Humans; HIV Infections; Raltegravir Potassium; RNA, Viral; HIV Seropositivity; Anti-Retroviral Agents; Cerebrospinal Fluid; Viral Load
PubMed: 37487714
DOI: 10.1111/hiv.13527 -
AIDS Research and Human Retroviruses Jun 2023Integrase strand transfer inhibitors (INSTIs), including raltegravir (RAL), dolutegravir (DTG), elvitegravir (EVG), bictegravir (BIC), and cabotegravir (CAB), are... (Review)
Review
Integrase strand transfer inhibitors (INSTIs), including raltegravir (RAL), dolutegravir (DTG), elvitegravir (EVG), bictegravir (BIC), and cabotegravir (CAB), are increasingly used, given excellent data on their efficacy, effectiveness, and tolerability profile in adults, while data in children are accumulating. To review the most recent evidence on the efficacy, effectiveness, safety, and resistance of INSTIs in children, a quick narrative review of the available literature data was performed using the MEDLINE/PubMed and Scopus databases, including only English-language studies, published between 2009 and 2022. Six studies (259 children) on RAL use, 17 studies (3,448 children) on DTG, 2 studies (73 children) on EVG, and 1 study (102 children) on BIC were retrieved. Results on efficacy and effectiveness were close to those reported in adult studies, suggesting similarities between children and adult population. Resistance to RAL was detected in four studies, ranging between 5.0% to 35.3% of participants. In four studies resistance to DTG occurred in 12.4% to 22% of children. Adverse events to RAL have been uncommon reported. In studies on EVG, 8% to 74% of children developed uveitis, nausea, or abdominal pain. In DTG studies, the proportion of weight gain ranged from 10% to 87%, and neuropsychiatric effects ranged 1% to 16% of participants. One BIC study reported adverse events >10% of participants. The evidence supports high efficacy and low toxicity of INSTIs in pediatric and adolescent populations.
Topics: Adult; Child; Humans; Adolescent; HIV Infections; HIV Integrase Inhibitors; HIV-1; Raltegravir Potassium; Heterocyclic Compounds, 3-Ring; Oxazines; Heterocyclic Compounds, 4 or More Rings; Drug Resistance, Viral; Integrases; HIV Integrase
PubMed: 36352827
DOI: 10.1089/AID.2022.0039 -
The Journal of Antimicrobial... Oct 2021The second-generation integrase strand transfer inhibitor (INSTI) bictegravir is becoming accessible in low- and middle-income countries (LMICs), and another INSTI,...
OBJECTIVES
The second-generation integrase strand transfer inhibitor (INSTI) bictegravir is becoming accessible in low- and middle-income countries (LMICs), and another INSTI, cabotegravir, has recently been approved as a long-acting injectable. Data on bictegravir and cabotegravir susceptibility in raltegravir-experienced HIV-1 subtype A- and D-infected patients carrying drug resistance mutations (DRMs) remain very scarce in LMICs.
PATIENTS AND METHODS
HIV-1 integrase (IN)-recombinant viruses from eight patients failing raltegravir-based third-line therapy in Uganda were genotypically and phenotypically tested for susceptibility to bictegravir and cabotegravir. Ability of these viruses to integrate into human genomes was assessed in MT-4 cells.
RESULTS
HIV-1 IN-recombinant viruses harbouring single primary mutations (N155H or Y143R/S) or in combination with secondary INSTI mutations (T97A, M50I, L74IM, E157Q, G163R or V151I) were susceptible to both bictegravir and cabotegravir. However, combinations of primary INSTI-resistance mutations such as E138A/G140A/G163R/Q148R or E138K/G140A/S147G/Q148K led to decreased susceptibility to both cabotegravir (fold change in EC50 values from 429 to 1000×) and bictegravir (60 to 100×), exhibiting a high degree of cross-resistance. However, these same IN-recombinant viruses showed impaired integration capacity (14% to 48%) relative to the WT HIV-1 NL4-3 strain in the absence of drug.
CONCLUSIONS
Though not currently widely accessible in most LMICs, bictegravir and cabotegravir offer a valid alternative to HIV-infected individuals harbouring subtype A and D HIV-1 variants with reduced susceptibility to first-generation INSTIs but previous exposure to raltegravir may reduce efficacy, more so with cabotegravir.
Topics: Amides; Drug Resistance, Viral; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; HIV-1; Heterocyclic Compounds, 3-Ring; Humans; Mutation; Piperazines; Pyridones; Raltegravir Potassium
PubMed: 34453542
DOI: 10.1093/jac/dkab276 -
Journal of the International AIDS... Jun 2022ACTG A5288 was a strategy trial conducted in diverse populations from multiple continents of people living with HIV (PLWH) failing second-line protease inhibitor...
Third-line antiretroviral therapy, including raltegravir (RAL), darunavir (DRV/r) and/or etravirine (ETR), is well tolerated and achieves durable virologic suppression over 144 weeks in resource-limited settings: ACTG A5288 strategy trial.
INTRODUCTION
ACTG A5288 was a strategy trial conducted in diverse populations from multiple continents of people living with HIV (PLWH) failing second-line protease inhibitor (PI)-based antiretroviral therapy (ART) from 10 low- and middle-income countries (LMICs). Participants resistant to lopinavir (LPV) and/or multiple nucleotide reverse transcriptase inhibitors started on third-line regimens that included raltegravir (RAL), darunavir/ritonavir (DRV/r) and/or etravirine (ETR) according to their resistance profiles. At 48 weeks, 87% of these participants achieved HIV-1 RNA ≤200 copies/ml. We report here long-term outcomes over 144 weeks.
METHODS
Study participants were enrolled from 2013 to 2015, prior to the availability of dolutegravir in LMICs. "Extended Follow-up" of the study started after the last participant enrolled had reached 48 weeks and included participants still on antiretroviral (ARV) regimens containing RAL, DRV/r and/or ETR at that time. RAL, DRV/r and ETR were provided for an additional 96 weeks (giving total follow-up of ≥144 weeks), with HIV-1 RNA measured at 48 and 96 weeks and CD4 count at 96 weeks after entry into Extended Follow-up. Proportion of participants with HIV-1 RNA ≤200 copies/ml was estimated every 24 weeks, using imputation if necessary to handle the different measurement schedule in Extended Follow-up; mean CD4 count changes were estimated using loess regression.
RESULTS AND DISCUSSION
Of 257 participants (38% females), at study entry, median CD4 count was 179 cells/mm , and HIV-1 RNA was 4.6 log copies/ml. Median follow-up was 168 weeks (IQR: 156-204); 15 (6%) participants were lost to follow-up and 9 (4%) died. 27/246 (11%), 26/246 (11%) and 13/92 (14%) of participants who started RAL, DRV/r and ETR, respectively, discontinued these drugs; only three due to adverse events. 87%, 86%, 83% and 80% of the participants had HIV-1 RNA ≤200 copies/ml at weeks 48, 96, 144 and 168 (95% CI at week 168: 74-85%), respectively. Mean increase from study entry in CD4 count at week 168 was 265 cells/mm (95% CI 247-283).
CONCLUSIONS
Third-line regimens comprising of RAL, DRV/r and/or ETR were very well tolerated and had high rates of durable virologic suppression among PLWH in LMICs who were failing on second-line PI-based ART prior to the availability of dolutegravir.
Topics: Anti-HIV Agents; Anti-Retroviral Agents; Darunavir; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Nitriles; Pyrimidines; RNA; Raltegravir Potassium; Ritonavir; Viral Load
PubMed: 36039892
DOI: 10.1002/jia2.25905 -
Journal of Infection and Public Health Dec 2020Outbreak of COVID-19 has been recognized as a global health concern since it causes high rates of morbidity and mortality. No specific antiviral drugs are available for...
Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine against main protease and RNA-dependent RNA polymerase of SARS-CoV-2: A molecular docking and drug repurposing approach.
BACKGROUND
Outbreak of COVID-19 has been recognized as a global health concern since it causes high rates of morbidity and mortality. No specific antiviral drugs are available for the treatment of COVID-19 till date. Drug repurposing strategy helps to find out the drugs for COVID-19 treatment from existing FDA approved antiviral drugs. In this study, FDA approved small molecule antiviral drugs were repurposed against the major viral proteins of SARS-CoV-2.
METHODS
The 3D structures of FDA approved small molecule antiviral drugs were retrieved from PubChem. Virtual screening was performed to find out the lead antiviral drug molecules against main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) using COVID-19 Docking Server. Furthermore, lead molecules were individually docked against protein targets using AutoDock 4.0.1 software and their drug-likeness and ADMET properties were evaluated.
RESULTS
Out of 65 FDA approved small molecule antiviral drugs screened, Raltegravir showed highest interaction energy value of -9 kcal/mol against Mpro of SARS-CoV-2 and Indinavir, Tipranavir, and Pibrentasvir exhibited a binding energy value of ≥-8 kcal/mol. Similarly Indinavir showed the highest binding energy of -11.5 kcal/mol against the target protein RdRp and Dolutegravir, Elbasvir, Tipranavir, Taltegravir, Grazoprevir, Daclatasvir, Glecaprevir, Ledipasvir, Pibrentasvir and Velpatasvir showed a binding energy value in range from -8 to -11.2 kcal/mol. The antiviral drugs Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine also exhibited good bioavailability and drug-likeness properties.
CONCLUSION
This study suggests that the screened small molecule antiviral drugs Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine could serve as potential drugs for the treatment of COVID-19 with further validation studies.
Topics: Antiviral Agents; Coronavirus Protease Inhibitors; Drug Repositioning; Heterocyclic Compounds, 3-Ring; Humans; Indinavir; Molecular Docking Simulation; Nitriles; Oxazines; Piperazines; Pyridines; Pyridones; Pyrimidines; Pyrones; RNA-Dependent RNA Polymerase; Raltegravir Potassium; SARS-CoV-2; Sulfonamides; COVID-19 Drug Treatment
PubMed: 33168456
DOI: 10.1016/j.jiph.2020.10.015 -
Clinical Infectious Diseases : An... Mar 2022The adipokines leptin and adiponectin, produced primarily by adipose tissue, have diverse endocrine and immunologic effects, and circulating levels reflect adipocyte... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The adipokines leptin and adiponectin, produced primarily by adipose tissue, have diverse endocrine and immunologic effects, and circulating levels reflect adipocyte lipid content, local inflammation, and tissue composition. We assessed relationships between changes in regional fat depots, leptin and adiponectin levels, and metabolic and inflammatory markers over 96 weeks in the AIDS Clinical Trials Group (ACTG) A5260s metabolic substudy of the A5257 randomized trial of tenofovir disoproxil fumarate/emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir, or raltegravir among treatment-naive persons with human immunodeficiency virus (PWH).
METHODS
Fat depots were measured using dual-energy absorptiometry and abdominal computed tomographic imaging at treatment initiation and 96 weeks later. Serum leptin and adiponectin, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hsCRP) were measured at the same timepoints. Multivariable regression models assessed relationships between fat depots, adipokines, HOMA-IR, and hsCRP at week 96.
RESULTS
Two hundred thirty-four participants maintained viral suppression through 96 weeks (90% male, 29% black, median age 36 years). Serum leptin increased over 96 weeks (mean change 22%) while adiponectin did not (mean change 1%), which did not differ by study arm. Greater trunk, limb, and abdominal subcutaneous and visceral fat were associated with higher HOMA-IR and hsCRP at 96 weeks, but serum leptin level was a stronger determinant of these endpoints using a mediation model approach. A similar mediating effect was not observed for adiponectin.
CONCLUSIONS
Higher circulating leptin is associated with greater HOMA-IR and hsCRP independent of fat depot size, suggesting that greater adipocyte lipid content may contribute to impaired glucose tolerance and systemic inflammation among PWH starting antiretroviral therapy.
Topics: Acquired Immunodeficiency Syndrome; Adipokines; Adult; Female; HIV Infections; Humans; Insulin Resistance; Male; Raltegravir Potassium; Weight Gain
PubMed: 34117756
DOI: 10.1093/cid/ciab542