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Medicina (Kaunas, Lithuania) May 2023The multidrug-resistant (MDR) human immunodeficiency virus 1 (HIV-1) infection is an unmet medical need. HIV-1 capsid plays an important role at different stages of the... (Review)
Review
Highlights on the Development, Related Patents, and Prospects of Lenacapavir: The First-in-Class HIV-1 Capsid Inhibitor for the Treatment of Multi-Drug-Resistant HIV-1 Infection.
The multidrug-resistant (MDR) human immunodeficiency virus 1 (HIV-1) infection is an unmet medical need. HIV-1 capsid plays an important role at different stages of the HIV-1 replication cycle and is an attractive drug target for developing therapies against MDR HIV-1 infection. Lenacapavir (LEN) is the first-in-class HIV-1 capsid inhibitor approved by the USFDA, EMA, and Health Canada for treating MDR HIV-1 infection. This article highlights the development, pharmaceutical aspects, clinical studies, patent literature, and future directions on LEN-based therapies. The literature for this review was collected from PubMed, authentic websites (USFDA, EMA, Health Canada, Gilead, and NIH), and the free patent database (Espacenet, USPTO, and Patent scope). LEN has been developed by Gilead and is marketed as Sunlenca (tablet and subcutaneous injection). The long-acting and patient-compliant LEN demonstrated a low level of drug-related mutations, is active against MDR HIV-1 infection, and does not reveal cross-resistance to other anti-HIV drugs. LEN is also an excellent drug for patients having difficult or limited access to healthcare facilities. The literature has established additive/synergistic effects of combining LEN with rilpivirine, cabotegravir, islatravir, bictegravir, and tenofovir. HIV-1 infection may be accompanied by opportunistic infections such as tuberculosis (TB). The associated diseases make HIV treatment complex and warrant drug interaction studies (drug-drug, drug-food, and drug-disease interaction). Many inventions on different aspects of LEN have been claimed in patent literature. However, there is a great scope for developing more inventions related to the drug combination of LEN with anti-HIV/anti-TB drugs in a single dosage form, new formulations, and methods of treating HIV and TB co-infection. Additional research may provide more LEN-based treatments with favorable pharmacokinetic parameters for MDR HIV-1 infections and associated opportunistic infections such as TB.
Topics: Humans; HIV-1; Anti-HIV Agents; Capsid; Antitubercular Agents; HIV Infections; Tuberculosis; Opportunistic Infections; Tuberculosis, Multidrug-Resistant
PubMed: 37374245
DOI: 10.3390/medicina59061041 -
Proceedings of the National Academy of... Jul 2022Structures trapping a variety of functional and conformational states of HIV-1 reverse transcriptase (RT) have been determined by X-ray crystallography. These structures...
Structures trapping a variety of functional and conformational states of HIV-1 reverse transcriptase (RT) have been determined by X-ray crystallography. These structures have played important roles in explaining the mechanisms of catalysis, inhibition, and drug resistance and in driving drug design. However, structures of several desired complexes of RT could not be obtained even after many crystallization or crystal soaking experiments. The ternary complexes of doravirine and rilpivirine with RT/DNA are such examples. Structural study of HIV-1 RT by single-particle cryo-electron microscopy (cryo-EM) has been challenging due to the enzyme's relatively smaller size and higher flexibility. We optimized a protocol for rapid structure determination of RT complexes by cryo-EM and determined six structures of wild-type and E138K/M184I mutant RT/DNA in complexes with the nonnucleoside inhibitors rilpivirine, doravirine, and nevirapine. RT/DNA/rilpivirine and RT/DNA/doravirine complexes have structural differences between them and differ from the typical conformation of nonnucleoside RT inhibitor (NNRTI)-bound RT/double-stranded DNA (dsDNA), RT/RNA-DNA, and RT/dsRNA complexes; the primer grip in RT/DNA/doravirine and the YMDD motif in RT/DNA/rilpivirine have large shifts. The DNA primer 3'-end in the doravirine-bound structure is positioned at the active site, but the complex is in a nonproductive state. In the mutant RT/DNA/rilpivirine structure, I184 is stacked with the DNA such that their relative positioning can influence rilpivirine in the pocket. Simultaneously, E138K mutation opens the NNRTI-binding pocket entrance, potentially contributing to a faster rate of rilpivirine dissociation by E138K/M184I mutant RT, as reported by an earlier kinetic study. These structural differences have implications for understanding molecular mechanisms of drug resistance and for drug design.
Topics: Anti-HIV Agents; Cryoelectron Microscopy; Drug Resistance, Viral; HIV Reverse Transcriptase; HIV-1; Mutation; Nitriles; Protein Conformation; Pyridones; Pyrimidines; Reverse Transcriptase Inhibitors; Rilpivirine; Triazoles
PubMed: 35858448
DOI: 10.1073/pnas.2203660119 -
Drugs in Context 2022The logistical management of an injectable therapy for the treatment of HIV can be expensive, time consuming, frustrating and riddled with barriers. In this Commentary,...
The logistical management of an injectable therapy for the treatment of HIV can be expensive, time consuming, frustrating and riddled with barriers. In this Commentary, we describe our experiences to date with acquiring, storing, handling, administering and billing for long-acting cabotegravir and rilpivirine through four scenarios, each of which have presented their own unique obstacles and learning curves. At the time of writing, we have successfully transitioned four patients from the CUSTOMIZE trial to long-acting cabotegravir and rilpivirine. In doing so, we encountered a variety of barriers to acquiring, handling and administering the medication for both insured and uninsured patients; it is expensive, on a limited number of insurance formularies, and often requires a prior authorization from the provider. Cold-chain handling of the injectable therapy, along with individual patient characteristics, present barriers to management and administration of this therapy. Whilst a seemingly very attractive option for the treatment of HIV-1 infection in adults, long-acting cabotegravir and rilpivirine present a variety of challenges to pharmacists, providers and clinic staff on how to obtain it for and administer it to the patient. We plan to continue documenting our experiences, progress and successes, or lack thereof, in order to fine-tune our process and share with others.
PubMed: 35310300
DOI: 10.7573/dic.2021-9-2 -
Topics in Antiviral Medicine May 2023Several innovative methods were presented at the 2023 Conference on Retroviruses and Opportunistic Infections (CROI) targeting different aspects of the HIV care... (Clinical Trial)
Clinical Trial
Several innovative methods were presented at the 2023 Conference on Retroviruses and Opportunistic Infections (CROI) targeting different aspects of the HIV care continuum to improve testing, linkage to care, and viral suppression. Some of these approaches were directed at more vulnerable groups, such as pregnant women, adolescents, and individuals who inject drugs. In contrast was the devastating impact of the COVID-19 pandemic, with negative outcomes on HIV viral load suppression and retention in care. Data were presented on hepatitis B virus (HBV) suppression showing that tenofovir alafenamide (TAF)/emtricitabine (FTC)/bictegravir (BIC) may be superior to tenofovir disoproxil fumarate/FTC plus dolutegravir in suppressing HBV in HIV/HBV-coinfected individuals. A pilot study examining a 4-week trial of direct-acting antiviral therapy to treat hepatitis C in recently infected individuals showed lower rates of sustained virologic response at 12 weeks than longer courses. Additional data were presented on the use of long-acting cabotegravir/rilpivirine, comparing this regimen with oral TAF/FTC/BIC and the use of long-acting cabotegravir/rilpivirine in those with viremia. Data were presented on a novel strategy of lenacapavir with 2 broadly neutralizing antibodies given every 6 months as maintenance antiretroviral therapy (ART). Data were presented on improving HIV care outcomes in adolescents, interventions to prevent mother-to-child transmission, and HIV reservoirs in children and adolescents. Data were also presented on interactions between ART and hormonal contraception, as well as ART-related weight gain and impact on pregnancy. A study examining BIC pharmacokinetics in pregnancy was presented, as well as retrospective data on outcomes of adolescents receiving TAF/FTC/BIC.
Topics: Adolescent; Female; Humans; Pregnancy; Anti-HIV Agents; Anti-Retroviral Agents; COVID-19; Emtricitabine; Hepatitis C, Chronic; Infectious Disease Transmission, Vertical; Pandemics; Pilot Projects; Retrospective Studies; Retroviridae Infections; Rilpivirine
PubMed: 37315511
DOI: No ID Found -
AIDS (London, England) May 2023Baseline rilpivirine drug resistance mutations (DRMs) are a risk factor for virological failure in patients treated with long-acting cabotegravir and rilpivirine...
Baseline rilpivirine drug resistance mutations (DRMs) are a risk factor for virological failure in patients treated with long-acting cabotegravir and rilpivirine (CAB/RPV LA). We investigated rilpivirine cross-resistance in treatment-naive and experienced patients in South Africa. One in 10 treatment-naive patients and 74.5% of patients failing treatment presented with rilpivirine DRMs. Our data suggest targeted genotyping may be required for patients initiating CAB/RPV LA, which significantly complicates the currently used public health approach.
Topics: Humans; Rilpivirine; Anti-HIV Agents; Developing Countries; HIV Infections; HIV-1; Pyridones; Anti-Retroviral Agents
PubMed: 36779485
DOI: 10.1097/QAD.0000000000003505 -
Drugs Apr 2020Long-acting antiretroviral therapy holds the promise of new options for human immunodeficiency virus (HIV) treatment beyond the current paradigm of daily oral pills. Of... (Review)
Review
Long-acting antiretroviral therapy holds the promise of new options for human immunodeficiency virus (HIV) treatment beyond the current paradigm of daily oral pills. Of particular interest is their potential role in addressing challenges with adherence to oral therapy and treatment fatigue. Similar to other conditions where long-acting formulations have proven effective such as contraception and mental health, long-acting antiretroviral therapy could provide additional treatment choices to people with HIV. This review provides an outline of the current landscape of long-acting antiretroviral therapy for HIV treatment, both approved and under development, including cabotegravir, rilpivirine, leronlimab, islatravir, albuvirtide, GS-6207, and broadly neutralizaing antibodies. However, there are a number of research gaps for long-acting antiretroviral therapy including issues regarding resistance and understudied populations, and this review highlights some of the challenges that will need to be addressed for clinical implementation of these novel treatment modalities.
Topics: Anti-Retroviral Agents; Drug Resistance, Viral; HIV Infections; Humans
PubMed: 32180205
DOI: 10.1007/s40265-020-01284-1 -
The Journal of Antimicrobial... Mar 2020Long-acting (LA) formulations of cabotegravir, an HIV integrase inhibitor, and rilpivirine, an NNRTI, are in development as monthly or 2 monthly intramuscular (IM)...
BACKGROUND
Long-acting (LA) formulations of cabotegravir, an HIV integrase inhibitor, and rilpivirine, an NNRTI, are in development as monthly or 2 monthly intramuscular (IM) injections for maintenance of virological suppression.
OBJECTIVES
To evaluate cabotegravir and rilpivirine CSF distribution and HIV-1 RNA suppression in plasma and CSF in HIV-infected adults participating in a substudy of the Phase 2b LATTE-2 study (NCT02120352).
METHODS
Eighteen participants receiving cabotegravir LA 400 mg + rilpivirine LA 600 mg IM [every 4 weeks (Q4W), n = 3] or cabotegravir LA 600 mg + rilpivirine LA 900 mg IM [every 8 weeks (Q8W), n = 15] with plasma HIV-1 RNA <50 copies/mL enrolled. Paired steady-state CSF and plasma concentrations were evaluable in 16 participants obtained 7 (±3) days after an injection visit. HIV-1 RNA in CSF and plasma were assessed contemporaneously using commercial assays.
RESULTS
Median total CSF concentrations in Q4W and Q8W groups, respectively, were 0.011 μg/mL and 0.013 μg/mL for cabotegravir (0.30% and 0.34% of the paired plasma concentrations) and 1.84 ng/mL and 1.67 ng/mL for rilpivirine (1.07% and 1.32% of paired plasma concentrations). Cabotegravir and rilpivirine total CSF concentrations exceeded their respective in vitro EC50 for WT HIV-1 (0.10 ng/mL and 0.27 ng/mL, respectively). All 16 participants had HIV-1 RNA <50 copies/mL in plasma and CSF, and 15 of 16 participants had HIV-1 RNA <2 copies/mL in CSF.
CONCLUSIONS
A dual regimen of cabotegravir LA and rilpivirine LA achieved therapeutic concentrations in the CSF resulting in effective virological control in CSF.
Topics: Adult; Anti-HIV Agents; HIV Infections; HIV-1; Humans; Pyridones; Rilpivirine
PubMed: 31873746
DOI: 10.1093/jac/dkz504 -
Clinical Infectious Diseases : An... Aug 2023There are conflicting data regarding baseline determinants of virological nonsuppression outcomes in persons with human immunodeficiency virus (HIV) starting...
Plasma Human Immunodeficiency Virus 1 RNA and CD4+ T-Cell Counts Are Determinants of Virological Nonsuppression Outcomes With Initial Integrase Inhibitor-Based Regimens: A Prospective RESPOND Cohort Study.
BACKGROUND
There are conflicting data regarding baseline determinants of virological nonsuppression outcomes in persons with human immunodeficiency virus (HIV) starting antiretroviral treatment (ART). We evaluated the impact of different baseline variables in the RESPOND cohort.
METHODS
We included treatment-naive participants aged ≥18 who initiated 3-drug ART, in 2014-2020. We assessed the odds of virological suppression (VS) at weeks 48 and 96 using logistic regression. Viral blips, low-level viremia (LLV), residual viremia (RV), and virological failure (VF) rates were assessed using Cox regression.
RESULTS
Of 4310 eligible participants, 72% started integrase strand transfer inhibitor (INSTI)-based regimens. At 48 and 96 weeks, 91.0% and 93.3% achieved VS, respectively. At 48 weeks, Kaplan-Meier estimates of rates were 9.6% for viral blips, 2.1% for LLV, 22.2% for RV, and 2.1% for VF. Baseline HIV-1 RNA levels >100 000 copies/mL and CD4+ T-cell counts ≤200/µL were negatively associated with VS at weeks 48 (adjusted odds ratio, 0.51 [95% confidence interval, .39-.68] and .40 [.27-.58], respectively) and 96 and with significantly higher rates of blips, LLV, and RV. CD4+ T-cell counts ≤200/µL were associated with higher risk of VF (adjusted hazard ratio, 3.12 [95% confidence interval, 2.02-4.83]). Results were consistent in those starting INSTIs versus other regimens and those starting dolutegravir versus other INSTIs.
CONCLUSIONS
Initial high HIV-1 RNA and low CD4+ T-cell counts are associated with lower rates of VS at 48 and 96 weeks and higher rates of viral blips, LLV, and RV. Low baseline CD4+ T-cell counts are associated with higher VF rates. These associations remain with INSTI-based and specifically with dolutegravir-based regimens. These findings suggest that the impact of these baseline determinants is independent of the ART regimen initiated.
Topics: Humans; CD4-Positive T-Lymphocytes; Cohort Studies; HIV Infections; HIV Integrase Inhibitors; HIV-1; Prospective Studies; Viral Load; Viremia; RNA, Viral
PubMed: 37052343
DOI: 10.1093/cid/ciad219 -
Biomaterials Feb 2020Antiretroviral therapy (ART) has improved the quality and duration of life for people living with human immunodeficiency virus (HIV) infection. However, limitations in...
Antiretroviral therapy (ART) has improved the quality and duration of life for people living with human immunodeficiency virus (HIV) infection. However, limitations in drug efficacy, emergence of viral mutations and the paucity of cell-tissue targeting remain. We posit that to maximize ART potency and therapeutic outcomes newer drug formulations that reach HIV cellular reservoirs need be created. In a step towards achieving this goal we harnessed the aggregation-induced emission (AIE) property of the non-nucleoside reverse transcriptase inhibitor rilpivirine (RPV) and used it as a platform for drug cell and subcellular tracking. RPV nanocrystals were created with endogenous AIE properties enabling the visualization of intracellular particles in cell and tissue-based assays. The intact drug crystals were easily detected in CD4 T cells and macrophages, the natural viral target cells, by flow cytometry and ultraperformance liquid chromatography tandem mass spectrometry. We conclude that AIE can be harnessed to monitor cell biodistribution of selective antiretroviral drug nanocrystals.
Topics: Anti-HIV Agents; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Nanoparticles; Reverse Transcriptase Inhibitors; Rilpivirine; Tissue Distribution
PubMed: 31865227
DOI: 10.1016/j.biomaterials.2019.119669 -
Biomedicine & Pharmacotherapy =... Nov 2023Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease (CLD) worldwide and inflammation is key to its progression/resolution. As we...
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease (CLD) worldwide and inflammation is key to its progression/resolution. As we have previously described that rilpivirine (RPV) is hepatoprotective in murine models of CLD, here we determine the molecular mechanisms involved, focusing on its anti-inflammatory and immunomodulating properties. They were evaluated in vitro (human hepatic cell lines of the major hepatic cell types), in vivo (liver samples from a murine nutritional model of NAFLD) and ex vivo (peripheral blood mononuclear cells -PBMC- from patients with CLD). Transcriptomic analysis of liver samples from NAFLD mice showed RPV down-regulated biological processes associated with the inflammatory response (NF-κB/IκB signaling and mitogen-activated protein kinase -MAPK- activity) and leukocyte chemotaxis and migration. We observed a decrease in Adgre1 and Ccr2 expression and in the number of CCR2 + cells in the periportal areas of RPV-treated NAFLD mice. This RPV-induced effect on the CCL2/CCR2 axis was confirmed in vitro. A similar result was also obtained with CXCL10/IP10, one of the main chemokines in the liver. RPV also diminished activation of MAP kinases p38 and JNK. In addition, RPV inhibited the NLRP3 inflammasome pathway in vitro, decreasing NLRP3 protein expression, caspase-1 activation and IL-1β gene expression. RPV was also proven anti-inflammatory in PBMC from patients with CLD treated ex vivo. In conclusion, beyond its well-described role in antiretroviral therapy, RPV manifests anti-inflammatory and immunoregulatory effects, a finding that could be of great relevance for the search of novel targets or repositioning strategies for CLD.
Topics: Humans; Animals; Mice; Non-alcoholic Fatty Liver Disease; Leukocytes, Mononuclear; Rilpivirine; Liver; Anti-Inflammatory Agents; NLR Family, Pyrin Domain-Containing 3 Protein; NF-kappa B
PubMed: 37738799
DOI: 10.1016/j.biopha.2023.115537