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The Journal of Antimicrobial... Jan 2021Doravirine is a recently licensed HIV-1 NNRTI with improved efficacy, pharmacokinetics and safety profile compared with efavirenz and limited cross-resistance with...
OBJECTIVES
Doravirine is a recently licensed HIV-1 NNRTI with improved efficacy, pharmacokinetics and safety profile compared with efavirenz and limited cross-resistance with rilpivirine and etravirine. In this in vitro study, cross-resistance to doravirine was analysed in a representative panel of NNRTI-resistant clones.
METHODS
In vitro phenotypic susceptibility to doravirine was assessed in 10 clinically derived infectious clones with intermediate- to high-level resistance to rilpivirine, etravirine, efavirenz and nevirapine, and in NL4-3 site-directed mutants harbouring K103N, Y181C, M230L or K103N/Y181C NNRTI mutations.
RESULTS
Although none of the infectious clones harboured any of the major doravirine resistance-associated mutations (RAMs) included in the IAS-USA reference list, doravirine fold change (FC) values were comparable to or higher than those calculated for other NNRTIs, particularly etravirine and rilpivirine. As expected, single NNRTI mutations K103N and Y181C did not impair doravirine susceptibility (FC 1.4 and 1.8, respectively), while reduced activity was observed with the single M230L or double K103N/Y181C mutations (FC 7.6 and 4.9, respectively). Median FC values increased significantly with increasing numbers of NNRTI RAMs (P = 0.005) and were >10 in 4/4 and 1/4 clones harbouring four and three NNRTI RAMs, respectively. FC values correlated well with predicted susceptibility as inferred by Stanford HIV Drug Resistance Database (HIVdb) and ANRS algorithms (both P < 0.001).
CONCLUSIONS
Substantial cross-resistance to doravirine was detected in NNRTI-resistant viruses harbouring complex mutational patterns, even in the absence of major IAS-USA doravirine RAMs. Therefore, based on the simple IAS-USA reference list, doravirine resistance may be underestimated in viruses harbouring multiple NNRTI mutations.
Topics: Anti-HIV Agents; Clone Cells; Drug Resistance, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Mutation; Nitriles; Pyridones; Pyrimidines; Reverse Transcriptase Inhibitors; Triazoles
PubMed: 32974670
DOI: 10.1093/jac/dkaa401 -
European Journal of Pharmaceutics and... Nov 2019Existing HIV therapy using oral antiretrovirals (ARVs) can result in pill fatigue and sub-optimal adherence. Microneedle array patches (MAPs) offer non-invasive,...
INTRODUCTION
Existing HIV therapy using oral antiretrovirals (ARVs) can result in pill fatigue and sub-optimal adherence. Microneedle array patches (MAPs) offer non-invasive, blood-free and painless drug delivery, and may improve patient adherence. The objective of this study was to develop a novel physiologically-based pharmacokinetic (PBPK) model to simulate the systemic pharmacokinetics of cabotegravir and rilpivirine MAPs using the intradermal route.
METHODS
The developed PBPK models were qualified against observed pharmacokinetic data after intramuscular (IM) and intradermal administration of long-acting nanoformulated rilpivirine to rats, and for IM administration of both drugs to healthy adults. Qualified models were then utilised to estimate suitable MAP characteristics (e.g. nanoformulation dose and release rates) and inform dosing strategies to maintain plasma concentrations above target trough concentrations for the designated dosing interval.
RESULTS
PBPK models simulated q4-weekly loading and maintenance doses of 360 mg and 180 mg for long-acting formulated cabotegravir between the release rates of 1 × 10-3 × 10h and 1 × 10-1.5 × 10h respectively, for a 70 kg adult. Estimated patch size was 60 cm for a 360 mg dose of cabotegravir. For q4-weekly dosing, rilpivirine required a 1080 mg loading dose and a 540 mg maintenance dose with release rates of 1.5 × 10-2.5 × 10h and 5 × 10-1 × 10h, respectively. Weekly dosing was also evaluated to assess the potential application from a smaller patch size. The ability to self-administer via a patch that is only left in place for a short duration makes longer durations less important than for some other long-acting approaches. Weekly cabotegravir required 60 mg between release rates 7 × 10-9 × 10h and rilpivirine required 270 mg and 180 mg respectively between release rates of 7 × 10-9 × 10h.
DISCUSSION
This model estimated optimal dose and release rates for cabotegravir and rilpivirine MAPs. Our approach provides a computational platform to support rational development of intradermal administration strategies to tackle problems associated with chronic oral ARV administration.
Topics: Adolescent; Adult; Animals; Anti-Retroviral Agents; Drug Delivery Systems; Female; HIV Infections; Humans; Injections, Intradermal; Male; Middle Aged; Needles; Rats; Rilpivirine; Young Adult
PubMed: 31525446
DOI: 10.1016/j.ejpb.2019.09.011 -
Open Forum Infectious Diseases Feb 2024The interpretation of long-acting cabotegravir and rilpivirine concentrations is complicated by the lack of consensus on the threshold to consider. Building on...
The interpretation of long-acting cabotegravir and rilpivirine concentrations is complicated by the lack of consensus on the threshold to consider. Building on real-world therapeutic drug monitoring data and documented virologic failures, this article provides a reappraisal of the existing thresholds and guidance for the interpretation of cabotegravir and rilpivirine concentrations.
PubMed: 38379570
DOI: 10.1093/ofid/ofae023 -
Open Forum Infectious Diseases Apr 2022In the LATTE study, daily oral cabotegravir + rilpivirine demonstrated higher rates of efficacy than efavirenz + 2 nucleoside reverse-transcriptase inhibitors (NRTIs)...
BACKGROUND
In the LATTE study, daily oral cabotegravir + rilpivirine demonstrated higher rates of efficacy than efavirenz + 2 nucleoside reverse-transcriptase inhibitors (NRTIs) through Week 96 in antiretroviral therapy (ART)-naive adults with human immunodeficiency virus (HIV)-1. We present the results from 6 years of continued treatment with oral cabotegravir + rilpivirine.
METHODS
LATTE was a phase IIb, randomized, multicenter, partially blinded, dose-ranging study in ART-naive adults with HIV-1. After a 24-week induction phase with cabotegravir + 2 NRTIs, participants with HIV-1 ribonucleic acid (RNA) <50 copies/mL were randomized to receive cabotegravir (10, 30, or 60 mg) + rilpivirine (25 mg) in the maintenance phase through Week 96 and switched to cabotegravir 30 mg + rilpivirine 25 mg in the open-label phase through Week 312.
RESULTS
Of 160 participants who entered the maintenance phase, 111 completed the study at Week 312. At Week 312, 105 (66%) participants maintained HIV-1 RNA <50 copies/mL, 15 (9%) had HIV-1 RNA ≥50 copies/mL, and 40 (25%) had no virologic data. Eight participants met protocol-defined virologic failure criteria through Week 312, 2 of whom met protocol-defined virologic failure criteria after Week 144. Six participants developed treatment-emergent resistance to 1 or both agents during the study, 3 of whom developed integrase inhibitor resistance substitutions. Two participants (1%) reported drug-related serious adverse events. Few adverse events led to withdrawal during the open-label phase (n = 5, 3%).
CONCLUSIONS
Oral cabotegravir + rilpivirine demonstrated efficacy in the majority of participants and an acceptable safety profile through 6 years of treatment, demonstrating its durability as maintenance therapy for HIV-1.
PubMed: 35350172
DOI: 10.1093/ofid/ofac067 -
Journal of Mass Spectrometry : JMS Jun 2020The widespread use of highly active antiretroviral treatments has dramatically changed the prognosis of people living with HIV (PLWH). However, such treatments have to...
Development and validation of a multiplex UHPLC-MS/MS assay with stable isotopic internal standards for the monitoring of the plasma concentrations of the antiretroviral drugs bictegravir, cabotegravir, doravirine, and rilpivirine in people living with HIV.
The widespread use of highly active antiretroviral treatments has dramatically changed the prognosis of people living with HIV (PLWH). However, such treatments have to be taken lifelong raising issues regarding the maintenance of both therapeutic effectiveness and long-term tolerability. Recently approved or investigational antiretroviral drugs present considerable advantages, allowing once daily oral dosage along with activity against resistant variants (eg, bictegravir and doravirine) and also parenteral intramuscular administration that facilitates treatment adherence (eg, long-acting injectable formulations such as cabotegravir and rilpivirine). Still, there remains a risk of insufficient or exaggerated circulating exposure due to absorption issues, abnormal elimination, drug-drug interactions, and others. In this context, a multiplex ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) bioassay has been developed for the monitoring of plasma levels of bictegravir, cabotegravir, doravirine, and rilpivirine in PLWH. A simple and convenient protein precipitation was performed followed by direct injection of the supernatant into the UHPLC-MS/MS system. The four analytes were eluted in less than 3 minutes using a reversed-phase chromatography method coupled with triple quadrupole mass spectrometry detection. This bioassay was fully validated following international guidelines and achieved good performances in terms of trueness (94.7%-107.5%), repeatability (2.6%-11%), and intermediate precision (3.0%-11.2%) over the clinically relevant concentration ranges (from 30 to 9000 ng/mL for bictegravir, cabotegravir, and doravirine and from 10 to 1800 ng/mL for rilpivirine). This sensitive, accurate, and rapid UHPLC-MS/MS assay is currently applied in our laboratory for routine therapeutic drug monitoring of the oral drugs bictegravir and doravirine and is also intended to be applied for the monitoring of cabotegravir/rilpivirine levels in plasma from PLWH receiving once monthly or every 2-month intramuscular injection of these long-acting antiretroviral drugs.
Topics: Amides; Anti-Retroviral Agents; Chromatography, High Pressure Liquid; Drug Monitoring; HIV Infections; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; Humans; Limit of Detection; Linear Models; Piperazines; Pyridones; Reference Standards; Reproducibility of Results; Rilpivirine; Tandem Mass Spectrometry; Triazoles
PubMed: 32160389
DOI: 10.1002/jms.4506 -
Journal of Pharmaceutical and... May 2022The antiretroviral agents rilpivirine (RPV) and cabotegravir (CAB) are approved as a combined treatment regimen against human immunodeficiency virus (HIV). To fully...
The antiretroviral agents rilpivirine (RPV) and cabotegravir (CAB) are approved as a combined treatment regimen against human immunodeficiency virus (HIV). To fully understand the biodistribution of these agents and determine their concentration levels in various parts of the body, a simple, selective and sensitive bioanalytical method is essential. In the present study, a high performance liquid chromatography method with mass spectrometry detection (HPLC-MS) was developed for simultaneous detection and quantification of RPV and CAB in various biological matrices. These included plasma, skin, lymph nodes, vaginal tissue, liver, kidneys and spleen, harvested from female Sprague Dawley rats. The suitability of the developed method for each matrix was validated based on the guidelines of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) on bioanalytical method validation. Analytes were extracted from biological samples employing a simple one-step protein precipitation method using acetonitrile. Samples were analysed using an Apex Scientific Inertsil ODS-3 column (4.6 mm × 250 mm, 5 µm particle size), maintained at 40 °C, on a HPLC system coupled with a single quadrupole MS detector. RPV was detected at a mass-to-charge ratio (m/z) of 367.4 and CAB at 406.3. Separation was achieved using isocratic elution at 0.3 mL/min with a mixture of acetonitrile and 0.1% (v/v) trifluoroacetic acid in water (81:19, v/v) as the mobile phase. The run time was set at 13 min. The presented method was selective, sensitive, accurate and precise for detection and quantification of RPV and CAB in all matrices. The developed and validated bioanalytical method was successfully employed for in vivo samples with both drugs simultaneously.
Topics: Animals; Anti-Retroviral Agents; Chromatography, High Pressure Liquid; Diketopiperazines; Female; Pharmaceutical Preparations; Pyridones; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Rilpivirine; Tandem Mass Spectrometry; Tissue Distribution
PubMed: 35259714
DOI: 10.1016/j.jpba.2022.114698 -
BMJ Open Dec 2022Current antiretroviral regimens have, for the most part, achieved optimal antiretroviral efficacy and tolerability, transforming HIV infection from a deadly disease into...
BACKGROUND
Current antiretroviral regimens have, for the most part, achieved optimal antiretroviral efficacy and tolerability, transforming HIV infection from a deadly disease into a manageable chronic condition. However, adherence to daily oral drug intake remains an issue, as it is the most important determinant for sustained viral suppression and prevention of the emergence of drug-resistant viral strains. The long-acting injection antiretroviral cabotegravir and rilpivirine combination, a novel drug delivery approach, is about to revolutionise the therapy for people living with HIV. In this protocol, we aim to generate a clinically useful summary of the interventions based on their efficacy.
METHODS AND ANALYSIS
We searched the literature for eligible studies published from inception up to 16 August 2022 through PubMed, EMBASE, Cochrane Library, Scopus and ClinicalTrials.gov. Two methodologically trained researchers will select the qualified studies for data extraction independently. Cochrane Risk of Bias tool will be used to assess the risk of bias in included studies. Statistical heterogeneity will be computed by Cochrane X and I tests. Sensitivity analysis will be conducted to evaluate the stability of the results. Publication biases will be evaluated by Begg's and Egger's tests. The quality of evidence will be assessed by the Grading of Recommendations Assessment, Development and Evaluation system. The RevMan V.5.3 and Stata V.14.0 software will be applied for statistical analyses.
ETHICS AND DISSEMINATION
Ethical approval will not be required for this systematic review because the data used are not linked to the individual patient. The results of this review will be disseminated by being published in a peer-reviewed journal.
PROSPERO REGISTRATION NUMBER
CRD42022310414.
Topics: Humans; Adult; Rilpivirine; HIV Infections; HIV-1; Pyridones; Anti-Retroviral Agents; Meta-Analysis as Topic; Systematic Reviews as Topic
PubMed: 36572503
DOI: 10.1136/bmjopen-2022-063089 -
Biomedica : Revista Del Instituto... May 2020Introduction: Satisfaction and knowledge among patients with HIV after switching from tenofovir to tenofovir/alafenamide remain unexplored. Given that both parameters...
Introduction: Satisfaction and knowledge among patients with HIV after switching from tenofovir to tenofovir/alafenamide remain unexplored. Given that both parameters are associated with better health outcomes it is relevant to measure them in patients during routine clinical practice. Objective: To evaluate the degree of knowledge and satisfaction in patients who had their antiretroviral regimen switched from rilpivirine (RPV)/emtricitabine (FTC)/TDF to RPV/FTC/TAF. Materials and methods: We conducted a prospective study in a third-level hospital between September, 2018, and November, 2018. We included patients who had previously been treated with RPV/FTC/TDF and collected their RPV/FTC/TAF treatment in the second visit. A 5-point Likert-type agreement/disagreement scale was used to assess satisfaction and knowledge regarding the medication switch. Results: We included 116 patients in the study of whom 75% were satisfied and 64% had a high-level of knowledge. Young patients were less satisfied with the way in which the change was explained (p=0.0487). Concerning the new medication, the patients were better informed about its renal (85% of them) and bone benefits (82%) than about its adverse effects on the lipid profile (40%). Conclusions: The patients were generally satisfied with the change in medication and well nformed about the dosage and advantages of TAF over TDF, but less well informed about the possible adverse effects of TAF.
Topics: Adenine; Adult; Alanine; Antiviral Agents; Drug Combinations; Drug Substitution; Emtricitabine; Female; HIV Infections; Health Knowledge, Attitudes, Practice; Humans; Male; Middle Aged; Patient Satisfaction; Prospective Studies; Rilpivirine; Tenofovir
PubMed: 32463615
DOI: 10.7705/biomedica.4989 -
Infectious Diseases and Therapy Dec 2023The first complete long-acting antiretroviral therapy (ART) regimen, cabotegravir + rilpivirine long-acting (CAB + RPV LA) injectable, was approved in the US for...
INTRODUCTION
The first complete long-acting antiretroviral therapy (ART) regimen, cabotegravir + rilpivirine long-acting (CAB + RPV LA) injectable, was approved in the US for HIV-1 treatment in individuals on a stable antiretroviral regimen with a viral load < 50 copies/mL, no treatment failure history, and no resistance to either cabotegravir or rilpivirine. We describe injection schedule adherence and virologic effectiveness of CAB + RPV LA in routine clinical care in the US.
METHODS
From the OPERA cohort, all adults with HIV who received their first CAB + RPV LA injection and ≥ 1 continuation injections between 21 January 2021 and 15 March 2022 were included. The injection target date was updated monthly and set to the same date of the month as the previous injection. Continuation injections administered within 7 days before or after the target date were considered on time, as per the label. Virologic undetectability (viral load < 50 copies/mL), suppression (viral load < 200 copies/mL), and confirmed virologic failure (2 consecutive viral loads ≥ 200 copies/mL or 1 viral load ≥ 200 copies/mL followed by discontinuation) were described among individuals with a viral load < 50 copies/mL at initiation and ≥ 1 follow-up viral load.
RESULTS
Among 321 individuals on CAB + RPV LA, 90% of the continuation injections were administered on time (within ± 7 days of the target date). Of the 237 individuals with a viral load < 50 copies/mL at initiation and ≥ 1 follow-up viral load, nearly all were undetectable (95%) or suppressed (99%) at their last viral load measurement, 96% maintained virologic suppression with all measured viral loads < 200 copies/mL, and four confirmed virologic failures were observed. Injection delays were infrequent, and did not affect virologic outcomes over the short term.
CONCLUSION
In this large US cohort, most monthly CAB + RPV LA injections were administered on time and high levels of virologic control were achieved. These results suggest that CAB + RPB LA injectable can be administered effectively during routine clinical care.
PubMed: 37966701
DOI: 10.1007/s40121-023-00890-2 -
Expert Opinion on Pharmacotherapy Mar 2020Antiretroviral therapy (ART) is recommended for all people who are living with HIV to suppress viral load and to stop the progression and transmission of HIV-1.... (Review)
Review
Antiretroviral therapy (ART) is recommended for all people who are living with HIV to suppress viral load and to stop the progression and transmission of HIV-1. Fixed-dose combinations of antiretrovirals largely reduce pill burden. The authors first provide an overview of the use of non-nucleoside reverse transcriptase inhibitor (NNRTI) based therapy in HIV care. They then summarize the properties of each drug in the fixed-dose combination of tenofovir alafenamide/emtricitabine/rilpivirine/(TAF/FTC/RPV). The efficacy and safety of each component and the combination as a whole are reviewed: FTC is non-inferior to lamivudine (3TC) at assessed dosages; TAF was non-inferior to tenofovir disoproxil fumarate (TDF); the viral efficacy of RPV is non-inferior with EFV at the assessed dosage; TAF/FTC/RPV is non-inferior in efficacy but shows less of a decline in bone mineral density and renal function compared to TDF/FTC/RPV. Finally, adverse effects and drug-drug interaction data with FTC/RPV/TAF are discussed. TAF/FTC/RPV can be used as an initial regimen for people living with HIV whose HIV RNA <100,000 copies/ml and CD4 cell count > 200 cells/mm when INSTI-based regimens are not a treatment option. Future antiretroviral therapy development may focus on dual therapy-based regimens containing RPV, particularly as long-acting formulations.
Topics: Adenine; Adult; Alanine; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Combinations; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Rilpivirine; Tenofovir; Viral Load
PubMed: 31957507
DOI: 10.1080/14656566.2020.1713096