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HIV Medicine Jun 2024Long-acting injectable cabotegravir + rilpivirine (CAB + RPV LAI) was approved for use in virally suppressed adults in the England and Wales national health service...
INTRODUCTION
Long-acting injectable cabotegravir + rilpivirine (CAB + RPV LAI) was approved for use in virally suppressed adults in the England and Wales national health service in November 2021. We describe a service evaluation of delivery processes and outcomes in 12 clinics.
METHODS
Centres populated a database using information from local policies and clinical records. Services were asked to describe approval processes, clinic pathways, and adherence to national guidelines. Additional data were collected on reasons for regimen choice, treatment discontinuations, and management of viraemia.
RESULTS
In total, 518 adults from 12 clinics were approved for CAB + RPV LAI between February 2022 and December 2023. Of the 518 people approved for CAB + RPV LAI, 423 received at least one injection. Median duration on CAB + RPV was 7.5 months (interquartile range 3.7-11.3). In total, 97% of injections were administered within the ±7-day window. Virological failure occurred in 0.7%, and 6% discontinued CAB + RPV.
CONCLUSION
In this large UK-based cohort, robust approval processes and clinic protocols facilitated on-time injections and low rates of both discontinuation and virological failure.
PubMed: 38858222
DOI: 10.1111/hiv.13679 -
Journal of Separation Science Jul 2023The (E)-isomer of rilpivirine is an approved antiretroviral drug used to treat human immunodeficiency virus. A simple, fast, accurate, and precise analytical method is...
Simultaneous quantification of (E) and (Z) isomers of rilpivirine and four degradation products in bulk and tablets by reversed-phase ultra-high-performance liquid chromatography and confirmation of all by molecular weight.
The (E)-isomer of rilpivirine is an approved antiretroviral drug used to treat human immunodeficiency virus. A simple, fast, accurate, and precise analytical method is required to confirm the quality, purity, efficacy, and safety of drug substances and drug products containing rilpivirine. This research article offers a comprehensive ultra-high performance liquid chromatography method for the simultaneous separation and quantification of (E) and (Z) isomers of rilpivirine, including two amide impurities, one nitrile impurity, and one dimer impurity, in both bulk and tablet forms. After complete validation, the proposed reversed-phase ultra-high-performance liquid chromatography method has proven to be simple, fast, linear, accurate, and precise, with a lower limit of quantification and detection of 0.05 and 0.03 μg/ml, respectively, for all six analytes. Separation was achieved on a Waters Acquity ethylene bridged hybrid Shield RP18 (150 × 2.1 mm, 1.7 μm) column maintained at 35.0°C using a gradient elution of acetonitrile and 0.05% formic acid in 10 mM ammonium formate at a flow rate of 0.30 ml/min. A systematic forced degradation study on the undissolved rilpivirine revealed the formation of acid-base hydrolyzed amide impurities (Impurity-A and Impurity-B), oxidative nitrile impurities (Impurity-C), and Z-isomer and dimer impurities of rilpivirine (Impurity-D and Impurity-E) due to alkaline hydrolysis and photodegradation. The proposed method is primarily appropriate for applications requiring the precise determination of desired and undesired isomers of rilpivirine and its degradation products, such as those involving the safety, efficacy, and quality roles of rilpivirine in bulk and tablet forms. Additionally, the proposed ultra-high-performance liquid chromatography method in combination with a mass spectrometer and photo-diode array detector is helpful for the confirmation and correct identification of all analytes.
Topics: Humans; Rilpivirine; Chromatography, High Pressure Liquid; Molecular Weight; Mass Spectrometry; Tablets
PubMed: 37021513
DOI: 10.1002/jssc.202201067 -
Clinical Infectious Diseases : An... Jan 2024Obesity is increasingly prevalent among people with HIV (PWH) and can possibly result in suboptimal antiretroviral drug (ARV) exposure and response. However, this has...
Antiretroviral Drug Exposure and Response in Obese and Morbidly Obese People With Human Immunodeficiency Virus (HIV): A Study Combining Modelling and Swiss HIV Cohort Data.
BACKGROUND
Obesity is increasingly prevalent among people with HIV (PWH) and can possibly result in suboptimal antiretroviral drug (ARV) exposure and response. However, this has not been thoroughly evaluated given that obese PWH are underrepresented in clinical trials. We performed virtual trials using physiologically based pharmacokinetic (PBPK) modelling combined with observed clinical data to provide ARV dosing guidance in obese individuals.
METHODS
Each trial included a cohort of virtual adults with a body mass index (BMI) between 18.5 and 60 kg/m2. Therapeutic drug-monitoring data from the Swiss HIV Cohort Study (SHCS) were used to verify the predictive performance of the model. Subsequently, the model was applied to predict the pharmacokinetics of ARVs for different obesity classes. The association between ARV plasma concentrations and virological response was investigated in obese and nonobese individuals.
RESULTS
The PBPK model predicted an average reduction in ARV exposure of ∼20% and trough concentrations of ∼6% in obese (BMI ≥30 kg/m2) compared with nonobese (BMI: 18.5-25 kg/m2) individuals, consistent with observed clinical data. Etravirine and rilpivirine were the most impacted, especially in individuals with BMI >40 kg/m2 whose trough concentrations were below the clinical target threshold. Obese PWH in the SHCS did not have a higher rate of unsuppressed viral load than nonobese PWH.
CONCLUSIONS
The concentrations of ARVs are modestly reduced in obese individuals, with no negative impact on the virological response. Our data provide reassurance that standard doses of ARVs are suitable in obese PWH, including those who gained substantial weight with some of the first-line ARVs.
Topics: Adult; Humans; HIV; Obesity, Morbid; Cohort Studies; Switzerland; HIV Infections; Anti-Retroviral Agents
PubMed: 37602428
DOI: 10.1093/cid/ciad495 -
The Lancet. Infectious Diseases May 2024
PubMed: 38821072
DOI: 10.1016/S1473-3099(24)00296-2 -
Research Square Nov 2023Despite the scale-up of antiretroviral therapy (ART) in South Africa, HIV-1 incidence remains high. The anticipated use of potent integrase strand transfer inhibitors...
Despite the scale-up of antiretroviral therapy (ART) in South Africa, HIV-1 incidence remains high. The anticipated use of potent integrase strand transfer inhibitors and long-acting injectables aims to enhance viral suppression at the population level and diminish transmission. Nevertheless, pre-existing drug resistance could impede the efficacy of long-acting injectable ART combinations, such as rilpivirine (an NNRTI) and cabotegravir (an INSTI). Consequently, a thorough understanding of transmission networks and geospatial distributions is vital for tailored interventions, including pre-exposure prophylaxis with long-acting injectables. However, empirical data on background resistance and transmission networks remain limited. In a community-based study in rural KwaZulu-Natal (2018-2019), prior to the widespread use of integrase inhibitor-based first-line ART, we performed HIV testing with reflex HIV-1 RNA viral load quantification on 18,025 participants. From this cohort, 6,096 (33.9%) tested positive for HIV via ELISA, with 1,323 (21.7%) exhibiting detectable viral loads (> 40 copies/mL). Of those with detectable viral loads, 62.1% were ART-naïve, and the majority of the treated were on an efavirenz + cytosine analogue + tenofovir regimen. Deep sequencing analysis, with a variant abundance threshold of 20%, revealed NRTI resistance mutations such as M184V in 2% of ART-naïve and 32% of treated individuals. Tenofovir resistance mutations K65R and K70E were found in 12% and 5% of ART-experienced individuals, respectively, and in less than 1% of ART-naïve individuals. Integrase inhibitor resistance mutations were notably infrequent (< 1%). Prevalence of pre-treatment drug resistance to NNRTIs was 10%, predominantly consisting of the K103N mutation. Among those with viraemic ART, NNRTI resistance was 50%, with rilpivirine-associated mutations observed in 9% of treated and 6% of untreated individuals. Cluster analysis revealed that 20% (205/1,050) of those sequenced were part of a cluster. We identified 171 groups with at least two linked participants; three quarters of clusters had only two individuals, and a quarter had 3-6 individuals. Integrating phylogenetic with geospatial analyses, we revealed a complex transmission network with significant clustering in specific regions, notably peripheral and rural areas. These findings derived from population scale genomic analyses are encouraging in terms of the limited resistance to DTG, but indicate that transitioning to long-acting cabotegravir + rilpivirine for transmission reduction should be accompanied by prior screening for rilpivirine resistance. Whole HIV-1 genome sequencing allowed identification of significant proportions of clusters with multiple individuals, and geospatial analyses suggesting decentralised networks can inform targeting public health interventions to effectively curb HIV-1 transmission.
PubMed: 38076835
DOI: 10.21203/rs.3.rs-3640717/v1 -
The Journal of Antimicrobial... Aug 2023The NNRTI doravirine has been recently approved for the first-line treatment of HIV-infected patients, eliciting favourable responses against viruses bearing the K103N,...
OBJECTIVES
The NNRTI doravirine has been recently approved for the first-line treatment of HIV-infected patients, eliciting favourable responses against viruses bearing the K103N, Y181C and G190A mutations. This study used in vitro drug selections to elaborate the breadth of doravirine responses against viruses bearing NNRTI and NRTI resistance-associated mutations (RAMs).
METHODS
WT clinical isolates (n = 6) and viruses harbouring common NRTI and NNRTI RAMs (n = 6) were serially passaged in escalating concentrations of doravirine, doravirine/islatravir, doravirine/lamivudine and rilpivirine over 24 weeks. Genotypic analysis ascertained the appearance and accumulation of NNRTI RAMs. Phenotypic drug susceptibility assays assessed resistance conferred by acquired NNRTI RAMs.
RESULTS
For WT viruses, doravirine pressure led to the appearance of V108I or V106A/I/M RAMs after 8 weeks, conferring low-level (∼2-fold) resistance. After 24 weeks, the accumulation of three to six secondary RAMs, including F227L, M230L, L234I and/or Y318, resulted in high-level (>100-fold) resistance to doravirine. Notably, viruses with these doravirine RAMs remained susceptible to rilpivirine and efavirenz. This contrasted with rilpivirine where acquisition of E138K, L100I and/or K101E resulted in >50-fold cross-resistance to all NNRTIs. Doravirine selection of viruses bearing common NRTI and NNRTI RAMs showed delayed acquisition of RAMs compared with WT virus. Pairing doravirine with islatravir or lamivudine attenuated the development of NNRTI RAMs.
CONCLUSIONS
Doravirine showed favourable resistance profiles against viruses harbouring NRTI and NNRTI RAMs. The high barrier to resistance to doravirine coupled with the long intracellular half-life of islatravir may provide the opportunity for long-acting treatment options.
Topics: Humans; HIV-1; Anti-HIV Agents; HIV Infections; Lamivudine; Drug Resistance, Viral; Rilpivirine; HIV Seropositivity; Mutation; Reverse Transcriptase Inhibitors; HIV Reverse Transcriptase
PubMed: 37303226
DOI: 10.1093/jac/dkad184 -
Infectious Diseases and Therapy Aug 2023Current antiretroviral therapies (ARTs) have improved outcomes for people living with HIV. However, the requirement to adhere to lifelong daily oral dosing may be...
INTRODUCTION
Current antiretroviral therapies (ARTs) have improved outcomes for people living with HIV. However, the requirement to adhere to lifelong daily oral dosing may be challenging for some people living with HIV, leading to suboptimal adherence and therefore reduced treatment effectiveness. Treatment with long-acting (LA) ART may improve adherence and health-related quality of life. The objective of this study was to evaluate the cost-effectiveness of cabotegravir + rilpivirine (CAB+RPV) LA administered every 2 months (Q2M) compared with current ART administered as daily oral single-tablet regimens (STRs) from a Spanish National Healthcare System perspective.
METHODS
A hybrid decision-tree and Markov state-transition model was used with pooled data from three phase III/IIIb trials (FLAIR, ATLAS, and ATLAS-2M) over a lifetime horizon, with health states defined by viral load and CD4 cell count. Direct costs (in €) were taken from Spanish public sources from 2021 and several deterministic and probabilistic analyses were carried out. An annual 3% discount rate was applied to both costs and utilities.
RESULTS
Over the lifetime horizon, CAB+RPV LA Q2M was associated with an additional 0.27 quality-adjusted life years (QALYs) and slightly greater lifetime costs (€4003) versus daily oral ART, leading to an incremental cost-effectiveness ratio of €15,003/QALY, below the commonly accepted €30,000/QALY willingness-to-pay threshold in Spain. All scenario analyses showed consistent results, and the probabilistic sensitivity analysis showed cost-effectiveness compared with daily oral STRs in 62.4% of simulations, being dominant in 0.3%.
CONCLUSION
From the Spanish National Health System perspective, CAB+RPV LA Q2M is a cost-effective alternative compared with the current options of daily oral STR regimens for HIV treatment.
CLINICAL TRIALS REGISTRATION
ATLAS, NCT02951052; ATLAS-2M, NCT03299049; FLAIR, NCT02938520.
PubMed: 37452174
DOI: 10.1007/s40121-023-00840-y -
Antimicrobial Agents and Chemotherapy Jan 2024Cabotegravir + rilpivirine administered via intramuscular gluteal injections is the first complete long-acting (LA) regimen approved for maintaining HIV-1 virologic...
Cabotegravir + rilpivirine administered via intramuscular gluteal injections is the first complete long-acting (LA) regimen approved for maintaining HIV-1 virologic suppression. The (lateral) thigh muscle could be a potential alternative site of administration in circumstances such as injection site fatigue, intolerability, or contraindication for gluteal administration. Cabotegravir and rilpivirine pharmacokinetics and participant tolerability were evaluated following single intramuscular injections to the lateral thigh. Healthy adult participants received 4 weeks of daily oral cabotegravir (30 mg) and rilpivirine (25 mg), followed by a 10- to 14-day washout and single 3 mL intramuscular injections of cabotegravir LA 600 mg and rilpivirine LA 900 mg to the lateral thigh. Safety, tolerability, and pharmacokinetics were evaluated through 52 weeks post injection. Pharmacokinetic parameters were estimated using non-compartmental analysis. Fifteen participants (female at birth, = 6) enrolled. Median age was 33 years. Median weight was 93.6 kg. Median body mass index was 31.4 kg/m. One participant withdrew due to pregnancy after oral dosing before receiving an injection. Plasma concentrations at Weeks 4 and 8 were 15.4- and 5.3-fold above the protein-adjusted 90% inhibitory concentration for cabotegravir and 4.7- and 2.4-fold for rilpivirine, respectively. The most common injection site reactions were pain [28/28 (100%)], induration [15/28 (54%)], and swelling [12/28 (42%)]; 94% were Grade 1 or 2. Cabotegravir and rilpivirine plasma pharmacokinetic profiles observed in this study support further evaluation of thigh administration in target populations of people living with HIV-1. Tolerability of cabotegravir + rilpivirine LA intramuscular lateral thigh injections was similar to gluteal administration.
Topics: Adult; Infant, Newborn; Humans; Female; Rilpivirine; Injections, Intramuscular; Anti-HIV Agents; Quadriceps Muscle; Thigh; HIV Infections; Pyridones; Anti-Retroviral Agents; HIV-1
PubMed: 38038460
DOI: 10.1128/aac.00781-23 -
Journal of Medical Virology Oct 2023Real-life comparisons of dolutegravir/rilpivirine (DTG/RPV) and DTG/lamivudine (3TC) regimens in people living with human immunodeficiency virus (PLWHIV) who switched...
Efficacy and tolerability of dolutegravir/lamivudine versus dolutegravir/rilpivirine in switching from a three-drug regimen based on nonnucleoside reverse transcriptase inhibitors: A retrospective cohort study.
Real-life comparisons of dolutegravir/rilpivirine (DTG/RPV) and DTG/lamivudine (3TC) regimens in people living with human immunodeficiency virus (PLWHIV) who switched from a standard three-drug regimen based on nonnucleoside reverse transcriptase inhibitors (NNRTIs) are missing. This study aimed to compare DTG/3TC and DTG/RPV in virologically suppressed patients (HIV-RNA < 50 copies/mL) coming from any NNRTI-based regimen in terms of discontinuation due to virologic failure (VF) discontinuation rates due to all causes, and adverse events. As a secondary outcome, we evaluated the difference in creatinine, total cholesterol, CD4, and triglycerides from baseline to weeks 48 after the switch. Of the 415 PLWHs included in the study, 278 (66.9%) switched to DTG/3TC, and 137 (33.1%) switched to DTG/RPV. Overall, 48 PLWHs (11.6%) discontinued the treatment:38 with DTG/3TC and 10 with DTG/RPV with similar discontinuation rates: 5.01 × 100 py (95% confidence interval [CI] 3.64-6.94) and 4.66 × 100 py (95% CI 2.51-8.67), respectively. The most common reason for discontinuation was toxicity (26 patients, 22/278 [7.9%] in the DTG/3TC group and 4/137 [2.9%] in the DTG/RPV group), mainly neurologic toxicity (never above grade 2). We found no differences in discontinuation rates due to treatment adverse events. Two study participants experienced virological failure in the DTG/3TC arm. We observed no significant difference in CD4 cell counts, lipid parameters, or renal function between the two groups at 48 weeks. This study demonstrated that, in clinical practice, a two-drug regimen with DTG/3TC or DTG/RPV is characterized by a low discontinuation rate and VF in virologically suppressed PLWHs switched from an NNRTI-based three antiretroviral drugs regimen.
Topics: Humans; Lamivudine; Reverse Transcriptase Inhibitors; Anti-HIV Agents; HIV Infections; Retrospective Studies; Rilpivirine; Heterocyclic Compounds, 3-Ring
PubMed: 37805832
DOI: 10.1002/jmv.29149 -
British Journal of Clinical Pharmacology Jul 2023SWORD-1 and SWORD-2 phase 3 studies concluded that switching virologically suppressed participants with HIV-1 from their current three- or four-drug antiretroviral... (Randomized Controlled Trial)
Randomized Controlled Trial
AIM
SWORD-1 and SWORD-2 phase 3 studies concluded that switching virologically suppressed participants with HIV-1 from their current three- or four-drug antiretroviral regimen (CAR) to the two-drug regimen of once-daily dolutegravir (DTG, 50 mg) and rilpivirine (RPV, 25 mg) was safe, well tolerated and noninferior for maintaining HIV-1 suppression at week 48 and highly efficacious to week 148. A secondary objective was to characterize drug exposure and exposure-efficacy/safety relationships.
METHODS
Adults with plasma HIV-1 RNA <50 copies/mL were randomized to switch to once-daily DTG + RPV on day 1 or to continue CAR for 52 weeks before switching. Trough plasma concentrations (C0) of DTG and RPV, the proportion of participants with HIV-1 RNA <50 copies/mL and adverse events to week 100 were summarized and subjected to exposure-response analyses in the overall population, in the subset of participants who switched from CAR containing enzyme-inducing drugs and by age category (≥50 and <50 years). The relationship between C0avg (individual average C0 across visits) and efficacy/safety was investigated.
RESULTS
Although week 2 DTG and RPV C0 were lower in participants switching from enzyme-inducing antiretroviral drugs, C0 and C0avg stayed above in vitro antiviral protein binding-adjusted IC90 and to week 100 with viral suppression >89%. DTG or RPV C0avg showed no relationship with virologic failures or safety. Participants ≥50 years had similar C0avg and safety response to younger participants.
CONCLUSION
No clinically relevant relationship between DTG or RPV exposures and virologic or safety response was observed, confirming the DTG + RPV switch for participants as a safe and effective treatment.
Topics: Adult; Humans; Middle Aged; Anti-HIV Agents; HIV Infections; Rilpivirine; Oxazines; Pyridones; Heterocyclic Compounds, 3-Ring; Anti-Retroviral Agents; Treatment Outcome; RNA; Viral Load
PubMed: 36740580
DOI: 10.1111/bcp.15683