-
Antiviral Therapy Dec 2023Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function for the treatment of heavily treatment-experienced people...
BACKGROUND
Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function for the treatment of heavily treatment-experienced people with HIV (PWH) harbouring multidrug resistance in combination with an optimized background regimen (OBR). Here, we describe in vitro analysis of the interplay between entry inhibitors (EI; enfuvirtide, fostemsavir, ibalizumab, and maraviroc) susceptibility and LEN susceptibility in samples from 72 participants in the phase 2/3 CAPELLA study, as well as the emergence of resistance in CAPELLA through 52 weeks.
METHODS
The phenotypic susceptibility to EIs of screening samples from participants was analysed using entry assays, and susceptibility to LEN was generated. Genotypic and phenotypic resistance to LEN was evaluated for subjects with virological failure through Week 52.
RESULTS
Overall, viruses with resistance to EIs showed no cross-resistance to LEN, with a mean fold change from wild type close to 1.0. Of the 22 participants analysed for resistance through Week 52, 9 participants (13%) had emergence of capsid resistance mutation(s) while the remaining 13 participants (18%) had no change in the capsid sequence.
CONCLUSION
The sequence from EI-resistant isolates did not affect LEN susceptibility. The lack of cross-resistance to LEN across ARV-resistant isolates supports the use of LEN in PWH regardless of their treatment history. During the second half-year period of the CAPELLA Study, development of LEN resistance was rare and was overall associated with functional LEN monotherapy due to either nonadherence or resistance-driven non-susceptibility to OBR.
Topics: Humans; HIV Infections; Anti-HIV Agents; HIV Fusion Inhibitors; Maraviroc; HIV-1; Drug Resistance, Viral
PubMed: 38085652
DOI: 10.1177/13596535231220754 -
Continuum (Minneapolis, Minn.) Oct 2018Widespread use of antiretroviral therapy (ART) has led to near-normal life expectancy in people with human immunodeficiency virus (HIV) infection. However, neurologic... (Review)
Review
PURPOSE OF REVIEW
Widespread use of antiretroviral therapy (ART) has led to near-normal life expectancy in people with human immunodeficiency virus (HIV) infection. However, neurologic complications of HIV remain common; can affect any part of the neuraxis; and are due to direct effects of the virus, immunosuppression because of untreated HIV infection, aberrant immune responses in the setting of ART initiation, and ART toxicities.
RECENT FINDINGS
HIV-associated neurocognitive disorder (HAND) remains one of the most common neurologic complications of HIV encountered today, but milder forms predominate in people on ART. No specific treatments for HAND exist, but small trials and epidemiologic evidence suggest paroxetine, intranasal insulin, and maraviroc may have utility in its treatment; further trials of these agents are ongoing. Widespread ART use has decreased the incidence of central nervous system opportunistic infections, but prognosis often remains poor in those who develop opportunistic infections. High-titer positive serum cryptococcal antigen is strongly predictive of cryptococcal meningitis and provides a tool to enhance diagnosis in areas with limited resources. HIV is an independent risk factor for stroke, and accelerated aging associated with HIV infection results in neurologic diseases of older age occurring at much younger ages in individuals infected with HIV. Ongoing HIV replication in the CSF despite peripheral virologic suppression may contribute to the development of HAND and may not improve despite adjusting the ART regimen to increase central nervous system penetrance.
SUMMARY
Neurologists are likely to encounter patients infected with HIV in clinical practice. This article reviews the presentation, diagnosis, and management of the most common neurologic conditions associated with HIV infection and ART.
Topics: Adult; Disease Management; Female; HIV Infections; Humans; Magnetic Resonance Imaging; Nervous System Diseases
PubMed: 30273245
DOI: 10.1212/CON.0000000000000647 -
Vaccines May 2023Vesicular stomatitis virus (VSV) remains an attractive platform for a potential HIV-1 vaccine but hurdles remain, such as selection of a highly immunogenic HIV-1...
Vesicular stomatitis virus (VSV) remains an attractive platform for a potential HIV-1 vaccine but hurdles remain, such as selection of a highly immunogenic HIV-1 Envelope (Env) with a maximal surface expression on recombinant rVSV particles. An HIV-1 Env chimera with the transmembrane domain (TM) and cytoplasmic tail (CT) of SIVMac239 results in high expression on the approved Ebola vaccine, rVSV-ZEBOV, also harboring the Ebola Virus (EBOV) glycoprotein (GP). Codon-optimized (CO) Env chimeras derived from a subtype A primary isolate (A74) are capable of entering a CD4+/CCR5+ cell line, inhibited by HIV-1 neutralizing antibodies PGT121, VRC01, and the drug, Maraviroc. The immunization of mice with the rVSV-ZEBOV carrying the CO A74 Env chimeras results in anti-Env antibody levels as well as neutralizing antibodies 200-fold higher than with the NL4-3 Env-based construct. The novel, functional, and immunogenic chimeras of CO A74 Env with the SIV_Env-TMCT within the rVSV-ZEBOV vaccine are now being tested in non-human primates.
PubMed: 37243081
DOI: 10.3390/vaccines11050977 -
AIDS Research and Human Retroviruses May 2023Most of the studies using the colorectal tissue explants challenge model have been conducted after one single dose and before reaching a steady state. We consider that...
Pharmacokinetics, the Immunological Impact, and the Effect on HIV Infectivity of Maraviroc, Raltegravir, and Lopinavir in Men Who Have Sex with Men Using Postexposure Prophylaxis.
Most of the studies using the colorectal tissue explants challenge model have been conducted after one single dose and before reaching a steady state. We consider that longer exposure as in 28-day postexposure prophylaxis (PEP) course and in an setting, such as after a sexual risk exposure to HIV could give us valuable information about these drugs. In a substudy we assessed pharmacokinetics, changes on immune system and rectal mucosal susceptibility to HIV-1 infection after taking maraviroc (MVC), raltegravir (RAL), and ritonavir-boosted lopinavir (LPV/r) PEP-based regimens in 30 men who have sex with men. Participants received 28 days of twice-daily MVC ( = 11), RAL ( = 10) or LPV/r ( = 9) all with tenofovir/emtricitabine (TDF/FTC) backbone. Blood, rectal fluid, and rectal tissue samples were collected at days 7, 28, and 90 after starting PEP. The samples obtained at day 90 were considered baseline. All studied antiretrovirals were quantifiable at 7 and 28 days in all tissues. Activation markers were increased in CD4 mucosal mononuclear cells (MMCs) after 28 days of MVC: CD38 + 68.5 versus 85.1, = .008 and CD38+DR +16.1 versus 26.7, = .008. Exposure to MVC at both endpoints (7 and 28 days) was associated with significant suppression of HIV-1 ( = .005 and = .028), but we did not observe this effect with RAL or LPV/r. Merging together changes in MMC in all arms, we found a positive correlation in the CD8 T cell lineage between the infectivity at day 7 and activation (CD38+ = 0.43, = .025, DR + = 0.547, = .003 and 38+DR+ = 0.526, = .05), senescence (CD57+CD28- = 0.479, = .012), naive cells (RA+CCR7+ = 0.484, = .01), and CCR5 expression ( = 0.593, = .001). We conclude that MVC in combination with TDF/FTC was associated with viral suppression in rectal explants and that overall HIV infectivity correlated with activation and senescence in CD8 MMCs.
Topics: Male; Humans; Maraviroc; Raltegravir Potassium; Lopinavir; HIV Infections; Anti-HIV Agents; Homosexuality, Male; Sexual and Gender Minorities; Emtricitabine; Ritonavir; Post-Exposure Prophylaxis
PubMed: 36416229
DOI: 10.1089/AID.2021.0232 -
Clinical Infectious Diseases : An... Nov 2015To describe the pharmacokinetics of maraviroc in human immunodeficiency virus (HIV)-infected women during pregnancy and post partum.
OBJECTIVE
To describe the pharmacokinetics of maraviroc in human immunodeficiency virus (HIV)-infected women during pregnancy and post partum.
METHODS
HIV-infected pregnant women receiving maraviroc as part of clinical care had intensive steady-state 12-hour pharmacokinetic profiles performed during the third trimester and ≥2 weeks after delivery. Cord blood samples and matching maternal blood samples were taken at delivery. The data were collected in 2 studies: P1026 (United States) and PANNA (Europe). Pharmacokinetic parameters were calculated.
RESULTS
Eighteen women were included in the analysis. Most women (12; 67%) received 150 mg of maraviroc twice daily with a protease inhibitor, 2 (11%) received 300 mg twice daily without a protease inhibitor, and 4 (22%) had an alternative regimen. The geometric mean ratios for third-trimester versus postpartum maraviroc were 0.72 (90% confidence interval, .60-.88) for the area under the curve over a dosing interval (AUCtau) and 0.70 (0.58-0.85) for the maximum maraviroc concentration. Only 1 patient showed a trough concentration (Ctrough) below the suggested target of 50 ng/mL, both during pregnancy and post partum. The median ratio of maraviroc cord blood to maternal blood was 0.33 (range, 0.03-0.56). The viral load close to delivery was <50 copies/mL in 13 women (76%). All children were HIV negative at testing.
CONCLUSIONS
Overall maraviroc exposure during pregnancy was decreased, with a reduction in AUCtau and maximum concentration of about 30%. Ctrough was reduced by 15% but exceeded the minimum Ctrough target concentration. Therefore, the standard adult dose seems sufficient in pregnancy.
CLINICAL TRIALS REGISTRATION
NCT00825929 and NCT000422890.
Topics: Adult; Anti-HIV Agents; Blood Chemical Analysis; Cyclohexanes; Europe; Female; HIV Infections; Humans; Maraviroc; Pregnancy; Pregnancy Complications, Infectious; Triazoles; United States; Young Adult
PubMed: 26202768
DOI: 10.1093/cid/civ587 -
Haematologica Mar 2019Classic Hodgkin lymphoma tumor cells express a functional CCR5 receptor, and tumor tissues express high CCL5 levels, suggesting that CCL5-CCR5 signaling is involved in...
Classic Hodgkin lymphoma tumor cells express a functional CCR5 receptor, and tumor tissues express high CCL5 levels, suggesting that CCL5-CCR5 signaling is involved in tumor-microenvironment formation and tumor growth. Using the CCR5 antagonist, maraviroc, and a neutralizing anti-CCL5 antibody, we found that CCL5 secreted by classic Hodgkin lymphoma cells recruited mesenchymal stromal cells and monocytes. The "education" of mesenchymal stromal cells by tumor cell-conditioned medium enhanced mesenchymal stromal cells' proliferation and CCL5 secretion. In turn, educated mesenchymal stromal cell-conditioned medium increased the clonogenic growth of tumor cells and monocyte migration, but these effects were reduced by maraviroc. Monocyte education by tumor cell-conditioned medium induced their growth and reprogrammed them towards immunosuppressive tumor-associated macrophages that expressed IDO and PD-L1 and secreted IL-10, CCL17 and TGF-β. Educated monocyte-conditioned medium slowed the growth of phytohemagglutinin-activated lymphocytes. Maraviroc decreased tumor cell growth and synergized with doxorubicin and brentuximab vedotin. A three-dimensional heterospheroid assay showed that maraviroc counteracted both the formation and viability of heterospheroids generated by co-cultivation of tumor cells with mesenchymal stromal cells and monocytes. In mice bearing tumor cell xenografts, maraviroc reduced tumor growth by more than 50% and inhibited monocyte accumulation, without weight loss. Finally, in classic Hodgkin lymphoma human tumor tissues, CCL5 and CD68 expression correlated positively, and patients with high CCL5 levels had poor prognosis. In conclusion, since the present challenges are to find molecules counteracting the formation of the immunosuppressive tumor microenvironment or new, less toxic drug combinations, the repurposed drug maraviroc may represent a new opportunity for classic Hodgkin lym phoma treatment.
Topics: Animals; CCR5 Receptor Antagonists; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cells, Cultured; Cellular Reprogramming; Disease Models, Animal; Doxorubicin; Drug Synergism; Hodgkin Disease; Humans; Maraviroc; Mice; Models, Biological; Monocytes; Receptors, CCR5; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 30309853
DOI: 10.3324/haematol.2018.196725 -
Nature Reviews. Clinical Oncology Sep 2014Graft-versus-host disease (GVHD) represents the most serious and challenging complication of allogeneic haematopoietic stem-cell transplantation (HSCT). New insights on... (Review)
Review
Graft-versus-host disease (GVHD) represents the most serious and challenging complication of allogeneic haematopoietic stem-cell transplantation (HSCT). New insights on the role of regulatory T-cells, T cells, and antigen-presenting cells have led to an improved understanding of the pathophysiology of GVHD. However, little progress has been made since the introduction of calcineurin-inhibitor-based regimens in the mid-1980s. Despite standard prophylaxis with these regimens, GVHD still develops in approximately 40-60% of recipients. Thus, there is a need for developing newer approaches to mitigate GVHD, which may facilitate the use of allogeneic HSCT for the treatment of a wider range of haematological cancers. We discuss the rationale, clinical evidence, and outcomes of current (and widely employed) strategies for GVHD prophylaxis, namely calcineurin-inhibitor-based regimens (such as cyclosporine or tacrolimus) combined with methotrexate or mycophenolate mofetil. We assess the clinical evidence for emerging approaches in the prevention of GVHD, including therapies targeting T cells or B cells, the use of mesenchymal stem cells, chemo-cytokine antagonists (such as maraviroc, TNF-α inhibitor, IL-2 receptor antagonist, IL-6 inhibitor), and the use of novel molecular regulators that target multiple cell types simultaneously, including atorvastatin, bortezomib, and epigenetic modulators.
Topics: Antineoplastic Agents; B-Lymphocytes; Calcineurin Inhibitors; Cytokines; DNA Methylation; Genes, Transgenic, Suicide; Genetic Therapy; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Histone Deacetylase Inhibitors; Humans; Immunosuppressive Agents; Mesenchymal Stem Cells; Molecular Targeted Therapy; T-Lymphocytes; T-Lymphocytes, Regulatory; Transplantation, Homologous
PubMed: 24958183
DOI: 10.1038/nrclinonc.2014.102 -
The Pediatric Infectious Disease Journal Nov 2022Treatment and prophylaxis options for neonatal HIV are limited. This study aimed to develop a population pharmacokinetic model to characterize the disposition of...
BACKGROUND
Treatment and prophylaxis options for neonatal HIV are limited. This study aimed to develop a population pharmacokinetic model to characterize the disposition of maraviroc in neonates to inform dosing regimens and expand available options.
METHODS
Using maraviroc concentrations from neonates who received either a single dose or multiple doses of 8 mg/kg of maraviroc in the first 6 weeks of life, a population pharmacokinetic model was developed to determine the effects of age, sex, maternal efavirenz exposure and concomitant ARV therapy on maraviroc disposition. The final model was used in Monte Carlo simulations to generate expected exposures with recommended dosing regimens.
RESULTS
A total of 396 maraviroc concentrations, collected in the first 4 days of life, at 1 week, at 4 weeks and at 6 weeks, from 44 neonates were included in the analysis. After allometrically scaling for weight, age less than 4 days was associated with a 44% decreased apparent clearance compared with participants 7 days to 6 weeks of life. There were no differences identified in apparent clearance or volume of distribution from ages 7 days to 6 weeks, sex, maternal efavirenz exposure or concomitant nevirapine therapy. Monte Carlo simulations with FDA-approved weight band dosing resulted in the majority of simulated patients (84.3%) achieving an average concentration of ≥75 ng/mL.
CONCLUSIONS
While maraviroc apparent clearance is decreased in the first few days of life, the current FDA-approved maraviroc weight band dosing provides maraviroc exposures for neonates in the first 6 weeks of life, which were consistent with adult maraviroc exposure range. Maraviroc provides another antiretroviral treatment option for very young infants.
Topics: Adult; Alkynes; Benzoxazines; Cyclopropanes; HIV Infections; Humans; Infant; Infant, Newborn; Maraviroc; Nevirapine
PubMed: 35980827
DOI: 10.1097/INF.0000000000003665 -
Cellular and Molecular Life Sciences :... Dec 2019The chemokine system mediates acute inflammation by driving leukocyte migration to damaged or infected tissues. However, elevated expression of chemokines and their... (Review)
Review
The chemokine system mediates acute inflammation by driving leukocyte migration to damaged or infected tissues. However, elevated expression of chemokines and their receptors can contribute to chronic inflammation and malignancy. Thus, great effort has been taken to target these molecules. The first hint of the druggability of the chemokine system was derived from the role of chemokine receptors in HIV infection. CCR5 and CXCR4 function as essential co-receptors for HIV entry, with the former accounting for most new HIV infections worldwide. Not by chance, an anti-CCR5 compound, maraviroc, was the first FDA-approved chemokine receptor-targeting drug. CCR5, by directing leukocytes to sites of inflammation and regulating their activation, also represents an important player in the inflammatory response. This function is shared with CCR2 and its selective ligand CCL2, which constitute the primary chemokine axis driving the recruitment of monocytes/macrophages to inflammatory sites. Both receptors are indeed involved in the pathogenesis of several immune-mediated diseases, and dual CCR5/CCR2 targeting is emerging as a more efficacious strategy than targeting either receptor alone in the treatment of complex human disorders. In this review, we focus on the distinctive and complementary contributions of CCR5 and CCR2/CCL2 in HIV infection, multiple sclerosis, liver fibrosis and associated hepatocellular carcinoma. The emerging therapeutic approaches based on the inhibition of these chemokine axes are highlighted.
Topics: Carcinoma, Hepatocellular; Chemokine CCL2; Gene Targeting; HIV; HIV Infections; Humans; Inflammation; Liver Cirrhosis; Liver Neoplasms; Multiple Sclerosis; Receptors, CCR2; Receptors, CCR5
PubMed: 31377844
DOI: 10.1007/s00018-019-03255-6 -
Viruses Oct 2022With the aim of rationally devising a refined and potent HIV-1 blocker, the cDNA of CCL5 5p12 5m, an extremely potent CCR5 antagonist, was fused to that of C37, a...
With the aim of rationally devising a refined and potent HIV-1 blocker, the cDNA of CCL5 5p12 5m, an extremely potent CCR5 antagonist, was fused to that of C37, a gp41-targeted fusion inhibitor. The resulting CCL5 5p12 5m-C37 fusion protein was expressed in and proved to be capable of inhibiting R5 HIV-1 strains with low to sub-picomolar IC, maintaining its antagonism toward CCR5. In addition, CCL5 5p12 5m-C37 inhibits R5/X4 and X4 HIV-1 strains in the picomolar concentration range. The combination of CCL5 5p12 5m-C37 with tenofovir (TDF) exhibited a synergic effect, promoting this antiviral cocktail. Interestingly, a CCR5-targeted combination of maraviroc (MVC) with CCL5 5p12 5m-C37 led to a synergic effect that could be explained by an extensive engagement of different CCR5 conformational populations. Within the mechanism of HIV-1 entry, the CCL5 5p12 5m-C37 chimera may fit as a powerful blocker in several instances. In its possible consideration for systemic therapy or pre-exposure prophylaxis, this protein design represents an interesting lead in the combat of HIV-1 infection.
Topics: Humans; HIV-1; Receptors, CCR5; Escherichia coli; Maraviroc; HIV Infections; HIV Seropositivity; CCR5 Receptor Antagonists
PubMed: 36366513
DOI: 10.3390/v14112415