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Therapeutic Advances in Infectious... 2023The treatment of human immunodeficiency virus (HIV) has greatly advanced over the past few decades from complex regimens, with high toxicities, multiple daily dosing,... (Review)
Review
The treatment of human immunodeficiency virus (HIV) has greatly advanced over the past few decades from complex regimens, with high toxicities, multiple daily dosing, and incomplete viral suppression to more simplified, highly effective, daily oral regimens. Although these advancements greatly improved access and tolerability, the need for daily antiretroviral (ARV) administration remained until recently. With long-acting (LA) injectable ARV options emerging, patients may choose how they want to receive treatment. By eliminating the barrier of daily medication adherence, LA injectable ARV formulations have the potential to not only improve health outcomes for the individual, but also the community by reducing HIV transmission. At the time of this writing cabotegravir/rilpivirine (LA-CAB/RPV) is the only LA injectable ARV regimen approved as a complete regimen for the treatment of HIV in adults and adolescents (⩾35 kg and ⩾12 years of age) who are virologically suppressed. However, additional studies of LA-CAB/RPV in expanded populations, and of other LA ARVs, are underway. The goal of this article was to summarize clinical data and review pertinent clinical considerations for the use of LA-CAB/RPV in the management of HIV.
PubMed: 36741193
DOI: 10.1177/20499361221149773 -
Frontiers in Pediatrics 2021Pregnancy-induced changes in plasma pharmacokinetics of many antiretrovirals (ARV) are well-established. Current knowledge about the extent of ARV exposure in lymphoid...
Pregnancy-induced changes in plasma pharmacokinetics of many antiretrovirals (ARV) are well-established. Current knowledge about the extent of ARV exposure in lymphoid tissues of pregnant women and within the fetal compartment is limited due to their inaccessibility. Subtherapeutic ARV concentrations in HIV reservoirs like lymphoid tissues during pregnancy may constitute a barrier to adequate virological suppression and increase the risk of mother-to-child transmission (MTCT). The present study describes the pharmacokinetics of three ARVs (efavirenz, dolutegravir, and rilpivirine) in lymphoid tissues and fetal plasma during pregnancy using materno-fetal physiologically-based pharmacokinetic models (m-f-PBPK). Lymphatic and fetal compartments were integrated into our previously validated adult PBPK model. Physiological and drug disposition processes were described using ordinary differential equations. For each drug, virtual pregnant women ( = 50 per simulation) received the standard dose during the third trimester. Essential pharmacokinetic parameters, including Cmax, Cmin, and AUC (0-24), were computed from the concentration-time data at steady state for lymph and fetal plasma. Models were qualified by comparison of predictions with published clinical data, the acceptance threshold being an absolute average fold-error (AAFE) within 2.0. AAFE for all model predictions was within 1.08-1.99 for all three drugs. Maternal lymph concentration 24 h after dose exceeded the reported minimum effective concentration (MEC) for efavirenz (11,514 vs. 800 ng/ml) and rilpivirine (118.8 vs. 50 ng/ml), but was substantially lower for dolutegravir (16.96 vs. 300 ng/ml). In addition, predicted maternal lymph-to-plasma AUC ratios vary considerably (6.431-efavirenz, 0.016-dolutegravir, 1.717-rilpivirine). Furthermore, fetal plasma-to-maternal plasma AUC ratios were 0.59 for efavirenz, 0.78 for dolutegravir, and 0.57 for rilpivirine. Compared with rilpivirine (0 h), longer dose forgiveness was observed for dolutegravir in fetal plasma (42 h), and for efavirenz in maternal lymph (12 h). The predicted low lymphoid tissue penetration of dolutegravir appears to be significantly offset by its extended dose forgiveness and adequate fetal compartment exposure. Hence, it is unlikely to be a predictor of maternal virological failure or MTCT risks. Predictions from our m-f-PBPK models align with recommendations of no dose adjustment despite moderate changes in exposure during pregnancy for these drugs. This is an important new application of PBPK modeling to evaluate the adequacy of drug exposure in otherwise inaccessible compartments.
PubMed: 34616699
DOI: 10.3389/fped.2021.734122 -
Microorganisms May 2023The human immunodeficiency virus (HIV) is a type of virus that targets the body's immune cells. HIV infection can be divided into three phases: acute HIV infection,... (Review)
Review
Efficacy and Safety of Two-Drug Regimens That Are Approved from 2018 to 2022 for the Treatment of Human Immunodeficiency Virus (HIV) Disease and Its Opportunistic Infections.
The human immunodeficiency virus (HIV) is a type of virus that targets the body's immune cells. HIV infection can be divided into three phases: acute HIV infection, chronic HIV infection, and acquired immunodeficiency syndrome (AIDS). HIV-infected people are immunosuppressed and at risk of developing opportunistic infections such as pneumonia, tuberculosis, candidiasis, toxoplasmosis, and Salmonella infection. The two types of HIV are known as HIV-1 and HIV-2. HIV-1 is the predominant and more common cause of AIDS worldwide, with an estimated 38 million people living with HIV-1 while an estimated 1 to 2 million people live with HIV-2. No effective cures are currently available for HIV infection. Current treatments emphasise the drug's safety and tolerability, as lifelong management is needed to manage HIV infection. The goal of this review is to study the efficacy and safety of newly approved drugs from 2018 to 2022 for the treatment of HIV by the United States Food and Drug Administration (US-FDA). The drugs included Cabotegravir and Rilpivirine, Fostemsavir, Doravirine, and Ibalizumab. From the review, switching to doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) was shown to be noninferior to the continuation of the previous regimen, efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) in virologically suppressed adults with HIV-1. However, DOR/3TC/TDF had shown a preferable safety profile with lower discontinuations due to adverse events (AEs), lower neuropsychiatric AEs, and a preferable lipid profile. Ibalizumab was also safe, well tolerated, and had been proven effective against multiple drug-resistant strains of viruses.
PubMed: 37374953
DOI: 10.3390/microorganisms11061451 -
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 -
British Journal of Clinical Pharmacology Dec 2020The purpose of this study was to assess the antiviral activity of the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination and to describe the...
Usefulness of therapeutic drug monitoring of rilpivirine and its relationship with virologic response and resistance in a cohort of naive and pretreated HIV-infected patients.
AIMS
The purpose of this study was to assess the antiviral activity of the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination and to describe the pharmacokinetics of rilpivirine and its association with resistance in clinical routine.
METHODS
A retrospective multicentre cohort study was performed in both naive and pretreated HIV patients receiving the once-daily rilpivirine/emtricitabine/tenofovir disoproxil fumarate regimen. Immuno-virologic and resistance data, and rilpivirine plasma trough concentrations were collected over the follow-up. Statistical analyses were performed to evaluate the relationship between rilpivirine pharmacokinetics and virological response. Receiver operating characteristic (ROC) curve analysis was performed to determine the best target rilpivirine trough concentration.
RESULTS
Overall, 379 patients were included. After a median follow-up of 28 months, 26% of patients discontinued mainly due to toxicity and the virological success rate was 65.7%. Virological failure occurred in 5% of patients. A significant proportion of patients with HIV-RNA > 40 copies/mL displayed rilpivirine plasma trough concentrations below the currently used 50 ng/mL efficacy threshold at both M6 (28%) and M12 (31%), in agreement with a significant lower median rilpivirine plasma trough concentration compared with patients virologically suppressed. Half of the patients with virologic failure who acquired rilpivirine resistance mutations had at least one suboptimal rilpivirine trough concentration. The optimal target for rilpivirine trough concentration was 70 ng/mL (sensitivity 75.4%; specificity 61.5%).
CONCLUSIONS
This study shows the impact of rilpivirine plasma trough concentration on both virological response and the emergence of rilpivirine mutations. Moreover, our results suggest that a higher target of rilpivirine trough concentration could be proposed in clinical practice.
Topics: Adult; Aged; Anti-HIV Agents; Cohort Studies; Drug Monitoring; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Retrospective Studies; Rilpivirine; Tenofovir; Viral Load; Young Adult
PubMed: 32374049
DOI: 10.1111/bcp.14344 -
Acta Pharmaceutica Sinica. B Jun 2020Human immunodeficiency virus (HIV) is the primary infectious agent of acquired immunodeficiency syndrome (AIDS), and non-nucleoside reverse transcriptase inhibitors... (Review)
Review
Human immunodeficiency virus (HIV) is the primary infectious agent of acquired immunodeficiency syndrome (AIDS), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are the cornerstone of HIV treatment. In the last 20 years, our medicinal chemistry group has made great strides in developing several distinct novel NNRTIs, including 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), thio-dihydro-alkoxy-benzyl-oxopyrimidine (-DABO), diaryltriazine (DATA), diarylpyrimidine (DAPY) analogues, and their hybrid derivatives. Application of integrated modern medicinal strategies, including structure-based drug design, fragment-based optimization, scaffold/fragment hopping, molecular/fragment hybridization, and bioisosterism, led to the development of several highly potent analogues for further evaluations. In this paper, we review the development of NNRTIs in the last two decades using the above optimization strategies, including their structure-activity relationships, molecular modeling, and their binding modes with HIV-1 reverse transcriptase (RT). Future directions and perspectives on the design and associated challenges are also discussed.
PubMed: 32642405
DOI: 10.1016/j.apsb.2019.11.010 -
Saudi Journal of Biological Sciences Feb 2021Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) is a well-characterized therapeutic target which is a key player driving...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) is a well-characterized therapeutic target which is a key player driving the viral replication and transcription machinery. The recent elucidation of the experimental structure of SARS-CoV-2 RdRp enzyme complexed with triphosphate form of Remdesivir (RTP) has opened an avenue for structure-based identification of potent inhibitors. Given the high mortality rate of the coronavirus disease 2019 (COVID-19) and lack of effective therapeutics against it, an alternative for safe and speedy drug discovery needs to be sought after. One promising strategy could be to explore the possibility for repurposing the Food and Drug Administration (FDA) approved antiviral drugs and antiviral phytocompounds. In the present study, a set of FDA approved antiviral drugs and antiviral phytocompounds were screened for their ability to bind within the RdRp enzyme active pocket. The top 3 hits among the FDA approved drugs were Paritaprevir (D33), Rilpivirine (D19) and Simeprevir (D31) which scored binding energies between -8.08 kcal/mol and -10.46 kcal/mol. Emetine (P5), 7,4-di-O-galloyltricetifavan (P28) and Oleanolic acid (P17) were the top three phytocompounds hits and exhibited binding energies ranging from -7.81 kcal/mol to -8.17 kcal/mol. These drugs and phytocompounds were able to establish hydrogen bonds with the catalytic residues-Asp760 and Asp761 and hydrophobic interactions with neighbouring residues. Further, the physicochemical properties of the molecules were evaluated. These identified potential inhibitors warrant further experimental investigations before their acceptance as drug candidates for the treatment of the disease.
PubMed: 33281478
DOI: 10.1016/j.sjbs.2020.11.078 -
Infection & Chemotherapy Dec 2021Current oral antiretroviral agents provide highly effective treatment for patients infected with human immunodeficiency virus (HIV), and can be used as pre-exposure... (Review)
Review
Current oral antiretroviral agents provide highly effective treatment for patients infected with human immunodeficiency virus (HIV), and can be used as pre-exposure prophylaxis (PrEP) to prevent new HIV infections. Several single-tablet regimens with excellent antiviral efficacy have dramatically improved the quality of life of patients who can adhere to daily oral therapy. However, there is increasing demand on long-acting injectable antiretroviral agents for patients who cannot take oral agents or feel fatigue related to daily pill burden. Monthly long-acting (LA) cabotegravir (CAB) combined with rilpivirine (RPV) has recently been listed as optimizing agent for maintenance of HIV suppression in treatment-experienced patients whose viral load is undetectable for 3 to 6 months. Novel agents with different mechanism of action and long half-life extending dosing interval are being tested in phase 2 and 3 clinical trials. This review summarizes the data of efficacies and safety profiles of LA CAB with RPV regimen, and also new long-acting injectable antiretroviral agents in pipeline.
PubMed: 34979604
DOI: 10.3947/ic.2021.0136 -
AIDS Research and Human Retroviruses Jan 2020We investigated the use of a system with an ingestible sensor (Proteus Digital Health Feedback system) coencapsulated with antiretrovirals (ARVs) to measure real-time...
We investigated the use of a system with an ingestible sensor (Proteus Digital Health Feedback system) coencapsulated with antiretrovirals (ARVs) to measure real-time adherence. To assess the safety and impact, if any, coencapsulation might have on ARV concentrations, we evaluated the pharmacokinetics of ARVs coencapsulated with an ingestible sensor for eight commonly used fixed-dose combination ARVs: emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF); FTC/tenofovir alafenamide (TAF); efavirenz (EFV)/FTC/TDF; abacavir (ABC)/lamivudine (3TC); dolutegravir (DTG)/ABC/3TC; rilpivirine (RPV)/TAF/FTC; elvitegravir (EVG)/cobicistat (COBI)/FTC/TAF; and bictegravir (BIC)/FTC/TAF. The steady-state apparent peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) were determined from plasma concentrations measured at predose, 1, 2, 4, and 6 h postdose, and compared with literature values. A total of 49 unique patients on stable regimens for at least 12 weeks with undetectable viral loads were recruited. Cmax and AUC values were not statistically significantly different from literature values for all of the formulations except the Cmax of FTC/TDF, Cmax of BIC, and the Cmax of RPV. In a subsequent evaluation of FTC/TDF and BIC/FTC/TAF using a crossover design, the geometric mean ratio (GMR) between the coencapsulated and the unencapsulated formulations for FTC/TDF were the following: FTC, 84.6% (90% confidence interval [CI] 66.6-107.4) for AUC and 77.5% (60.1-99.9) for Cmax. For tenofovir (TFV), the GMR was 96.2% (90% CI 89.2-103.8) for AUC and 87.3% (64.2-118.7) for Cmax. The GMR for BIC (from the BIC/FTC/TAF formulation) was 98.0% (90% CI 84.5-113.5) for AUC and 89.9% (84.5-95.7) for Cmax. The observed deviation in FTC/TDF (Truvada) may be due to participant characteristics, fasted/fed conditions, and/or random variation and may warrant further investigations with a larger sample size. These findings provide assurance for use of coencapsulated ARVs for future HIV treatment-adherence research.
Topics: Adult; Anti-HIV Agents; Biosensing Techniques; Cross-Over Studies; Drug Carriers; Drug Compounding; Drug Monitoring; Eating; Female; HIV Infections; Humans; Male; Medication Adherence; Middle Aged; Monitoring, Ambulatory; Viral Load
PubMed: 31516025
DOI: 10.1089/AID.2019.0202 -
Journal of Controlled Release :... Oct 2019Antiretroviral therapy requires lifelong daily dosing to attain viral suppression, restore immune function, and improve quality of life. As a treatment alternative,...
Antiretroviral therapy requires lifelong daily dosing to attain viral suppression, restore immune function, and improve quality of life. As a treatment alternative, long-acting (LA) antiretrovirals can sustain therapeutic drug concentrations in blood for prolonged time periods. The success of recent clinical trials for LA parenteral cabotegravir and rilpivirine highlight the emergence of these new therapeutic options. Further optimization can improve dosing frequency, lower injection volumes, and facilitate drug-tissue distributions. To this end, we report the synthesis of a library of RPV prodrugs designed to sustain drug plasma concentrations and improved tissue biodistribution. The lead prodrug M3RPV was nanoformulated into the stable LA injectable NM3RPV. NM3RPV treatment led to RPV plasma concentrations above the protein-adjusted 90% inhibitory concentration for 25 weeks with substantial tissue depots after a single intramuscular injection in BALB/cJ mice. NM3RPV elicited 13- and 26-fold increases in the RPV apparent half-life and mean residence time compared to native drug formulation. Taken together, proof-of-concept is provided that nanoformulated RPV prodrugs can extend the apparent drug half-life and improve tissue biodistribution. These results warrant further development for human use.
Topics: Animals; Anti-HIV Agents; Delayed-Action Preparations; HIV-1; Humans; Macaca mulatta; Macrophages; Male; Mice, Inbred BALB C; Nanoparticles; Prodrugs; Rilpivirine; Tissue Distribution
PubMed: 31491432
DOI: 10.1016/j.jconrel.2019.09.001