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International Journal of STD & AIDS Apr 2016Raltegravir was the first licensed integrase inhibitor. Real-life experience is informative and complements trial data. We therefore evaluated raltegravir use in adults... (Observational Study)
Observational Study
Raltegravir was the first licensed integrase inhibitor. Real-life experience is informative and complements trial data. We therefore evaluated raltegravir use in adults in a large HIV treatment centre. From pharmacy and departmental HIV database records, we identified all adults taking ≥1 dose of raltegravir from first availability to the end of November 2012. Data were collected using a standardised case report form. Two hundred and fifteen individuals provided 502 patient-years (median 2.6 years/person) of raltegravir use. Of 215 individuals, 166 (77%) were male, median age 43 years; 189 (88%) were antiretroviral therapy (ART)-experienced and 26 (12%) ART-naive, with median baseline CD4 counts of 324 and 54 cells/µL, respectively. Of ten individuals using once-daily raltegravir, four, with good adherence remained virologically suppressed after a median 28 months, four stopped against medical advice, one stopped to simplify and one failed virologically. In hepatitis co-infection, 35 individuals (92 patient-years) took raltegravir without evidence of hepatotoxicity. Six women started raltegravir during pregnancy for intensification (5/6) or switch for tolerability without complications. Of ten individuals stopping raltegravir after virological failure, 2/4 with successful sequencing showed resistance. Raltegravir appears safe and effective, without evidence of toxicity above that in published trials, including in pregnancy and co-infections. Once-daily dosing seems effective where adherence is good.
Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Coinfection; Female; HIV Infections; HIV Integrase Inhibitors; HIV-1; Hepatitis, Viral, Human; Humans; Life Change Events; Male; Pregnancy; Raltegravir Potassium; Retrospective Studies; Treatment Outcome; Viral Load
PubMed: 25931236
DOI: 10.1177/0956462415584485 -
AIDS Reviews 2018Integrase strand transfer inhibitors (INSTIs) are a newer class of antiretroviral treatment for HIV-infected patient. INSTIs currently available for use are raltegravir,... (Review)
Review
Integrase strand transfer inhibitors (INSTIs) are a newer class of antiretroviral treatment for HIV-infected patient. INSTIs currently available for use are raltegravir, elvitegravir, dolutegravir (DTG), and bictegravir. Clinical studies using INSTIs have demonstrated an 80-90% efficiency in treating HIV-positive antiretroviral therapy - naive patients. They are recommended by internatioal guidelines as the preferred agents for the first-line regimen. INSTIs have also been demonstrated as safe and tolerable. In clinical trials, the rate of adverse events (AEs) such as neuropsychiatric AEs (NPSAEs) leading to discontinuation is very low. However, recent published cohort studies show growing concerns on DTG induced NPSAEs. In this paper, we will review available evidence about DTG - NPSAEs and analyze whether the backbone (abacavir or tenofovir) matters as well as discussing the possible mechanism behind this toxicity.
Topics: Amides; Dideoxynucleosides; HIV Integrase Inhibitors; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; Humans; Neuropsychiatry; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium
PubMed: 29628511
DOI: No ID Found -
Expert Review of Anti-infective Therapy Aug 2008Raltegravir (formerly known as MK-0518; Isentress) is the first in a new class of integrase inhibitors approved for the use in treatment-experienced adult patients who... (Review)
Review
Raltegravir (formerly known as MK-0518; Isentress) is the first in a new class of integrase inhibitors approved for the use in treatment-experienced adult patients who have evidence of viral replication and HIV strains resistant to multiple antiretroviral agents. It is dosed twice daily with or without food. Raltegravir is a novel antiretroviral that has been shown to be well tolerated. It has demonstrated potent efficacy in the virologic suppression of HIV-1 RNA levels up to 48 weeks in two controlled studies that were conducted in clinically advanced, three-class antiretroviral, treatment-experienced adults.
Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; HIV Infections; Humans; Pyrrolidinones; Raltegravir Potassium
PubMed: 18662108
DOI: 10.1586/14787210.6.4.419 -
The Journal of Antimicrobial... May 2016Liver transplantation (LTx) is considered a safe procedure in selected HIV-infected patients. In this clinical setting raltegravir is the antiretroviral of choice due to...
OBJECTIVES
Liver transplantation (LTx) is considered a safe procedure in selected HIV-infected patients. In this clinical setting raltegravir is the antiretroviral of choice due to its optimal tolerability and its negligible interactions with immunosuppressive drugs. We aimed at providing data on the pharmacokinetics of raltegravir in LTx recipients, on which the available information is inconclusive.
METHODS
In this retrospective multicentre study we characterized the pharmacokinetics of raltegravir in a consecutive series of HIV-infected LTx recipients referred to our laboratory for therapeutic drug monitoring (TDM) and compared the obtained profiles with those collected from a control group of HIV-infected patients.
RESULTS
Seventeen HIV-infected LTx patients were considered. LTx recipients had significantly higher raltegravir AUC0-12 compared with the control group of HIV-infected patients [14 314 (11 627-19 998) versus 8795 (5218-12 954) ng·h/mL; P < 0.01]. Two LTx patients experienced moderate increments in serum transaminases, nausea and vomiting that improved after raltegravir dose reduction.
CONCLUSIONS
High raltegravir exposure and acceptable safety profile were observed in HIV-infected LTx recipients. Our results highlight that some patients may obtain an advantage from TDM-guided raltegravir dose adjustments with potential benefits in terms of drug tolerability.
Topics: Adult; Anti-HIV Agents; Drug Interactions; Female; HIV Infections; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Nausea; Plasma; Raltegravir Potassium; Retrospective Studies; Transaminases; Transplant Recipients
PubMed: 26755497
DOI: 10.1093/jac/dkv466 -
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 -
Journal of the Pediatric Infectious... Apr 2021We present the first published case of raltegravir-associated drug-reaction with eosinophilia and systemic symptoms (DRESS) syndrome in a child without characteristic...
Raltegravir-associated Drug-Reaction With Eosinophilia and Systemic Symptoms Syndrome in a Pediatric Patient Without Characteristic Human Leukocyte Antigen B*57:01 or B*53:01 alleles.
We present the first published case of raltegravir-associated drug-reaction with eosinophilia and systemic symptoms (DRESS) syndrome in a child without characteristic human leukocyte antigen haplotypes HLA-B*57:01 or HLA-B*53:01. A 4-year-old African American female with perinatally acquired human immunodeficiency virus infection was hospitalized for DRESS after starting a raltegravir-based antiretroviral regimen.
Topics: Alleles; Child; Child, Preschool; Drug Hypersensitivity Syndrome; Eosinophilia; Female; HLA Antigens; HLA-B Antigens; Humans; Pharmaceutical Preparations; Raltegravir Potassium
PubMed: 32766769
DOI: 10.1093/jpids/piaa089 -
AIDS Research and Human Retroviruses Jul 2017Nucleoside reverse transcriptase inhibitor (NRTI)- and protease inhibitor (PI)-sparing antiretroviral regimens may be useful in selected human immune deficiency virus... (Observational Study)
Observational Study
Nucleoside reverse transcriptase inhibitor (NRTI)- and protease inhibitor (PI)-sparing antiretroviral regimens may be useful in selected human immune deficiency virus (HIV)-infected patients with resistance or intolerance to these drug classes. This was an observational prospective study of patients on suppressive antiretroviral therapy containing two NRTIs plus one ritonavir-boosted PI who switched to a dual regimen containing raltegravir plus etravirine. Patients were required not to have prior virological failure to raltegravir and to have efficacy of etravirine shown through the genotypic resistance assay in case of prior non-nucleoside reverse transcriptase inhibitor (NNRTI) virological failure. As a whole, 38 patients were enrolled. The mean duration of current regimen was 4.3 years, and the reason for simplification was toxicity in 29 patients and resistance to NRTIs in 9 patients. After switching, the percentage of patients with HIV RNA <20 copies/ml at week 48 was 81.6% in the intent-to-treat-exposed analysis. The switch led to a significant reduction in the mean serum triglyceride levels (-81.2 mg/dl), in the mean total cholesterol levels (-44.3 mg/dl), and in the prevalence of tubular proteinuria (-30.2%), with a significant increase in the mean phosphoremia (+0.52 mg/dl) and in both mean lumbar and femoral neck bone mineral density (+6.5% and +4.7%, respectively). Two patients (5.2%) had virological failure due to suboptimal adherence, and five subjects (13.1%) discontinued treatment due to adverse events. In our study, simplification to the dual-therapy raltegravir plus etravirine was associated with a good efficacy and tolerability, in addition to a favorable effect on kidney, bone, and serum lipids.
Topics: Adult; Aged; Anti-HIV Agents; Female; HIV Infections; Humans; Maintenance Chemotherapy; Male; Middle Aged; Nitriles; Prospective Studies; Pyridazines; Pyrimidines; Raltegravir Potassium; Treatment Outcome
PubMed: 28088884
DOI: 10.1089/AID.2016.0291 -
The Journal of Pharmacy and Pharmacology Nov 2016Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for... (Clinical Trial)
Clinical Trial
OBJECTIVES
Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for once-daily regimen (QD) at a dose of 1200 mg is under development. The effect of calcium carbonate and magnesium/aluminium hydroxide antacids on the pharmacokinetics of a 1200 mg dose of raltegravir was assessed in this study.
METHODS
An open-label, four-period, four-treatment, fixed-sequence study in 20 HIV-infected patients was performed. Patients needed to be on raltegravir as part of a stable treatment regimen for HIV, and upon entry into the trial received 5 days of 1200 mg raltegravir as pretreatment, before they entered the four-period study: 1200 mg of raltegravir alone (period 1), calcium carbonate antacid as TUMS Ultra Strength (US) 1000 and 1200 mg raltegravir given concomitantly (Period 2), magnesium/aluminium hydroxide antacid as 20 ml MAALOX Maximum Strength substitute MS given 12 h after administration of 1200 mg raltegravir (period 3), and calcium carbonate antacid as TUMS US 1000 given 12 h after administration of 1200 mg raltegravir (period 4). Patients received their dose of 1200 mg QD raltegravir during the intervals between periods to re-establish steady state. AUC , C , C and T were calculated from the individual plasma concentrations of 1200 mg QD raltegravir after administration alone or with a calcium carbonate antacid or with a staggered dose of a calcium carbonate antacid or magnesium/aluminium hydroxide antacid. Adverse events, in addition to laboratory safety tests (haematology, serum chemistry and urinalysis), 12-lead electrocardiograms and vital signs were assessed.
KEY FINDINGS
All treatments were well tolerated in the study. Metal-cation antacids variably affected the pharmacokinetics of 1200 mg QD raltegravir. When calcium carbonate antacid was given with 1200 mg raltegravir concomitantly, the geometric mean ratio (GMR) and its associated 90% confidence interval (90% CI) for AUC , C and C were 0.28 (0.24, 0.32), 0.26 (0.21, 0.32) and 0.52 (0.45, 0.61), respectively. When calcium carbonate antacid and magnesium/aluminium hydroxide were given 12 h after raltegravir 1200 mg QD dosing, the GMR (90% CI) values for AUC and C were 0.90 (0.80, 1.03), 0.98 (0.81, 1.17), and 0.86 (0.73, 1.03), 0.86 (0.65, 1.15), respectively. However, significant reduction in the trough concentrations of raltegravir was observed: C 0.43 (0.36, 0.51) in the presence of calcium carbonate antacids and 0.42 (0.34, 0.52) in presence of magnesium/aluminium hydroxide, respectively.
CONCLUSIONS
Overall, the use of metal-cation antacids with 1200 mg QD raltegravir is not recommended.
Topics: Administration, Oral; Adult; Aluminum Hydroxide; Antacids; Area Under Curve; Calcium Carbonate; Drug Administration Schedule; Drug Combinations; Drug Interactions; Female; HIV Infections; HIV Integrase Inhibitors; Humans; Magnesium; Magnesium Hydroxide; Male; Metabolic Clearance Rate; Middle Aged; Polypharmacy; Raltegravir Potassium
PubMed: 27671833
DOI: 10.1111/jphp.12632 -
Infection, Genetics and Evolution :... Dec 2016Three integrase strand transfer inhibitors (INSTIs), raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG), have been approved by the FDA. Resistance against... (Review)
Review
Three integrase strand transfer inhibitors (INSTIs), raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG), have been approved by the FDA. Resistance against these three INSTIs have been reported and cross-resistance among them has been documented. Due to extensive and dynamic genetic diversity in different HIV-1 variants, significant differences in susceptibility to the INSTIs have been observed among HIV subtypes. This review summarizes what is known about this topic and discusses possible clinical implications.
Topics: Drug Resistance, Viral; HIV Infections; HIV Integrase Inhibitors; HIV-1; Heterocyclic Compounds, 3-Ring; Humans; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium
PubMed: 27353185
DOI: 10.1016/j.meegid.2016.06.047 -
Pharmacotherapy Apr 2019The ANRS163-ETRAL study showed that etravirine 200 mg/raltegravir 400 mg twice-daily dual therapy was highly effective in the treatment of human immunodeficiency virus... (Clinical Trial)
Clinical Trial
Lack of a Clinically Significant Pharmacokinetic Interaction between Etravirine and Raltegravir Using an Original Approach Based on Drug Metabolism, Protein Binding, and Penetration in Seminal Fluid: A Pharmacokinetic Substudy of the ANRS-163 ETRAL Study.
STUDY OBJECTIVE
The ANRS163-ETRAL study showed that etravirine 200 mg/raltegravir 400 mg twice-daily dual therapy was highly effective in the treatment of human immunodeficiency virus (HIV)-infected patients older than 45 years, with virologic and therapeutic success rates at week 48 of 99.4% and 94.5%, respectively. The objective of this study was to determine whether a clinically significant pharmacokinetic interaction between etravirine and raltegravir exists by assessing steady-state total and unbound etravirine, raltegravir, and inactive raltegravir-glucuronide concentrations 12 hours after last intake (C ) in blood plasma (BP) and seminal plasma (SP).
DESIGN
Pharmacokinetic analysis of data from the ANRS163-ETRAL study.
PATIENTS
One hundred forty-six HIV-1-infected patients (of the 165 patients included in the ANRS-163 ETRAL study) who were receiving etravirine 200 mg and raltegravir 400 mg twice daily.
MEASUREMENTS AND MAIN RESULTS
Blood was collected from all 146 patients at weeks 2-4, 12, 24, and 48, and semen was collected from 21 patients at week 48. The extent of BP and SP protein binding was determined by using ultrafiltration assay. Total and unbound etravirine, raltegravir, and raltegravir-glucuronide C were determined by ultra high performance liquid chromatography coupled with tandem mass spectrometry and interpreted by using the in vitro calculated protein-bound 95% inhibitory concentration (PBIC ) for wild-type (WT) HIV: etravirine (116 ng/ml) and raltegravir (15 ng/ml). Median (interquartile range [IQR]) total BP etravirine C (536 ng/ml [376-719]) and raltegravir (278 ng/ml [97-690]) were adequate in 99% and 96% of patients, respectively. Median (IQR) SP:BP C ratio and BP unbound fraction were etravirine 0.3 (0.2-0.5) and < 1%, respectively, raltegravir 1.8 (1.3-3.3) and 12%, respectively, and raltegravir-glucuronide 12.0 (6.5-17.7) and > 99%, respectively. The BP raltegravir metabolic ratio (raltegravir glucuronide:raltegravir ratio) was 1.7, suggesting only weak induction of raltegravir glucuronidation by etravirine. Only three patients had etravirine and raltegravir C < PBIC simultaneously.
CONCLUSION
No clinically significant pharmacokinetic interaction between etravirine and raltegravir was detected. Total etravirine and raltegravir BP concentrations were adequate in most patients, favoring virologic efficacy and confirming good treatment adherence (> 95%), despite twice-daily administration. The long half-life of etravirine and higher unbound fraction SP of raltegravir (57%) ensured adequate concentrations of dual therapy in genital compartments. Our results indicate that etravirine and raltegravir have good, complementary pharmacokinetic profiles, suggesting that they could be used in a dual-treatment strategy.
Topics: Anti-HIV Agents; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nitriles; Protein Binding; Pyridazines; Pyrimidines; Raltegravir Potassium; Semen
PubMed: 30815916
DOI: 10.1002/phar.2242