-
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 -
Journal of Acquired Immune Deficiency... Oct 2013To address the need for nucleos(t)ide reverse transcriptase inhibitor (NRTI)-sparing regimens, we explored the virologic and pharmacokinetic characteristics of maraviroc...
OBJECTIVE
To address the need for nucleos(t)ide reverse transcriptase inhibitor (NRTI)-sparing regimens, we explored the virologic and pharmacokinetic characteristics of maraviroc plus ritonavir-boosted darunavir in a single-arm, open-label, 96-week study.
METHODS
Twenty-four antiretroviral-naive R5 HIV-1-infected participants received maraviroc 150 mg and darunavir/ritonavir (DRV/r) 800/100 mg (MVC/DRV/r) once daily. The primary outcome was virologic failure (VF) = confirmed viral load (VL) >50 copies per milliliter at week 24 in the modified intent-to-treat population. To determine viral dynamics, participant-specific first- and second-phase empirical Bayes estimates were compared with decay rates from efavirenz (EFV) plus lopinavir/ritonavir, lopinavir/ritonavir plus 2NRTIs, and EFV plus 2NRTIs. Maraviroc plasma concentrations were determined at weeks 2, 4, 12, 24, and 48.
RESULTS
Baseline median (Q1, Q3) CD4 count and VL were 455 (299, 607) cells per cubic millimeter and 4.62 (4.18, 4.80) log10 copies per milliliter, respectively. VF occurred in 3 of 24 participants {12.5% [95% confidence interval (CI): 2.7 to 32.4]} at week 24. One of these resuppressed, yielding a week 48 VF rate of 2/24 [8.3% (95% CI: 1.0 to 27.0)]. The week 48 failures were 2 of the 4 participants (50%) with baseline VL >100,000 copies per milliliter. Week 96 VF rate was 2/20 [10% (95% CI: 1.2 to 31.7)]. Phase 1 decay was faster with MVC/DRV/r than reported for ritonavir-boosted lopinavir plus 2NRTIs (P = 0.0063) and similar to EFV-based regimens. Individual maraviroc trough concentrations collected between 20 and 28 hours post dose (n = 59) was 13.7 to 130 ng/mL (Q1, 23.4 ng/mL; Q3, 46.5 ng/mL), and modeled steady-state concentration was 128 ng/mL.
CONCLUSIONS
MVC/DRV/r 150/800/100 mg once daily has potential for treatment-naive patients with R5 HIV-1.
Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Cyclohexanes; Darunavir; Drug Therapy, Combination; Female; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Maraviroc; Pilot Projects; RNA Stability; RNA, Viral; Ritonavir; Sulfonamides; Treatment Outcome; Triazoles; Viral Load
PubMed: 23797691
DOI: 10.1097/QAI.0b013e3182a03d95 -
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 -
The Journal of Antimicrobial... Feb 2022Tenofovir disoproxil fumarate-containing pre-exposure prophylaxis (PrEP) has been associated with decreases in bone mineral density (BMD), but the bone effects of other... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Tenofovir disoproxil fumarate-containing pre-exposure prophylaxis (PrEP) has been associated with decreases in bone mineral density (BMD), but the bone effects of other non-tenofovir disoproxil fumarate candidate PrEP regimens are not well described.
METHODS
The HPTN 069/ACTG A5305 study randomized 406 US cisgender men and transgender women, and 188 cisgender women at risk for HIV infection to one of four double-blinded regimens: (i) maraviroc; (ii) maraviroc + emtricitabine; (iii) maraviroc + tenofovir disoproxil fumarate; or (iv) tenofovir disoproxil fumarate + emtricitabine. BMD was measured in a subset of participants at the lumbar spine (LS) and hip by dual-energy X-ray absorptiometry (DXA) at baseline and 48 weeks. Percentage change in LS and hip BMD was compared between the tenofovir disoproxil fumarate- and non-tenofovir disoproxil fumarate-containing arms by Wilcoxon rank-sum tests and multiple linear regression adjusting for sex, race and baseline BMI.
RESULTS
At baseline (n = 307), the median age was 33 years, 56% male and 43% black. At the hip, the median percentage change in BMD at 48 weeks was -1.05% in the tenofovir disoproxil fumarate arms and 0.0% in the non-tenofovir disoproxil fumarate arms (between group P = 0.001). No interaction by sex was observed. The median percentage change in LS BMD was not different between arms.
CONCLUSIONS
Tenofovir disoproxil fumarate-containing PrEP was associated with significantly greater bone loss compared with maraviroc ± emtricitabine PrEP at the hip, but not the LS. The BMD changes at the hip were similar in magnitude in men and women.
Topics: Adult; Anti-HIV Agents; Double-Blind Method; Emtricitabine; Female; HIV Infections; Humans; Male; Maraviroc; Tenofovir
PubMed: 34791296
DOI: 10.1093/jac/dkab400 -
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 -
Journal of Translational Medicine Jan 2011Since the discovery of CCR5 as a coreceptor for HIV entry, there has been interest in blockade of the receptor for treatment and prevention of HIV infection. Although... (Review)
Review
Since the discovery of CCR5 as a coreceptor for HIV entry, there has been interest in blockade of the receptor for treatment and prevention of HIV infection. Although several CCR5 antagonists have been evaluated in clinical trials, only maraviroc has been approved for clinical use in the treatment of HIV-infected patients. The efficacy, safety and resistance profile of CCR5 antagonists with a focus on maraviroc are reviewed here along with their usage in special and emerging clinical situations. Despite being approved for use since 2007, the optimal use of maraviroc has yet to be well-defined in HIV and potentially in other diseases. Maraviroc and other CCR5 antagonists have the potential for use in a variety of other clinical situations such as the prevention of HIV transmission, intensification of HIV treatment and prevention of rejection in organ transplantation. The use of CCR5 antagonists may be potentiated by other agents such as rapamycin which downregulate CCR5 receptors thus decreasing CCR5 density. There may even be a role for their use in combination with other entry inhibitors. However, clinical use of CCR5 antagonists may have negative consequences in diseases such as West Nile and Tick-borne encephalitis virus infections. In summary, CCR5 antagonists have great therapeutic potential in the treatment and prevention of HIV as well as future use in novel situations such as organ transplantation. Their optimal use either alone or in combination with other agents will be defined by further investigation.
Topics: Animals; Antiviral Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclohexanes; Disease Models, Animal; Encephalitis, Tick-Borne; Female; HIV Infections; HIV-1; Humans; Male; Maraviroc; Protein Binding; Triazoles; West Nile Fever
PubMed: 21284908
DOI: 10.1186/1479-5876-9-S1-S9 -
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 -
PloS One Oct 2010Maraviroc treatment for HIV-1 infected patients results in larger CD4(+) T cell rises than are attributable to its antiviral activity alone. We investigated whether this... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Maraviroc treatment for HIV-1 infected patients results in larger CD4(+) T cell rises than are attributable to its antiviral activity alone. We investigated whether this is due to modulation of T cell activation and inflammation.
METHODS AND FINDINGS
Thirty maraviroc-treated patients from the Maraviroc versus Efavirenz Regimens as Initial Therapy (MERIT) study were randomly selected from among those who had CCR5-tropic (R5) HIV on screening and achieved undetectable HIV RNA (<50 copies/mL) by Week 48. Efavirenz-treated controls were matched for baseline characteristics to the maraviroc-treated patients selected for this substudy. Changes in immune activation and inflammation markers were examined for associations with CD4(+) T cell changes. Maraviroc treatment tended to result in more rapid decreases in CD38 expression on CD4(+) T cells and in plasma D-dimer concentrations than did treatment with efavirenz. The proportion of patients with high-sensitivity C-reactive protein >2 µg/mL increased from 45% to 66% in the efavirenz arm, but remained constant in the maraviroc arm (P = 0.033). Decreases in CD38 expression on CD8(+) T cells were correlated with CD4(+) T cell rises for maraviroc treatment (r = -0.4, P = 0.048), but not for treatment with efavirenz.
CONCLUSIONS
Maraviroc-treated patients had earlier, modest decreases in certain markers of immune activation and inflammation, although in this small study, many of the differences were not statistically significant. Levels of high-sensitivity C-reactive protein remained constant in the maraviroc arm and increased in the efavirenz arm. Decreases in immune activation correlated with increased CD4(+) T cell gains.
TRIAL REGISTRATION
ClinicalTrials.gov NCT00098293.
Topics: Alkynes; Benzoxazines; CD4 Lymphocyte Count; Case-Control Studies; Cyclohexanes; Cyclopropanes; HIV Fusion Inhibitors; HIV Infections; Humans; Maraviroc; Receptors, CCR5; Reverse Transcriptase Inhibitors; Triazoles; Viral Load
PubMed: 20949133
DOI: 10.1371/journal.pone.0013188 -
PloS One 2019The study aimed to survey maraviroc use and assess effectiveness and durability of maraviroc-containing antiretroviral treatment (ART) in routine practice across Europe.
OBJECTIVES
The study aimed to survey maraviroc use and assess effectiveness and durability of maraviroc-containing antiretroviral treatment (ART) in routine practice across Europe.
METHODS
Data were retrieved from 26 cohorts in 8 countries comprising adults who started maraviroc in 2005-2016 and had ≥1 follow-up visit. Available V3 sequences were re-analysed centrally for tropism determination by geno2pheno[coreceptor]. Treatment failure (TF) was defined as either virological failure (viral load >50 copies/mL) or maraviroc discontinuation for any reason over 48 weeks. Predictors of TF were explored by logistic regression analysis. Time to maraviroc discontinuation was estimated by Kaplan-Meier survival analysis.
RESULTS
At maraviroc initiation (baseline), among 1,381 patients, 67.1% had experienced ≥3 ART classes and 45.6% had a viral load <50 copies/mL. Maraviroc was occasionally added to the existing regimen as a single agent (7.3%) but it was more commonly introduced alongside other new agents, and was often (70.4%) used with protease inhibitors. Accompanying drugs comprised 1 (40.2%), 2 (48.6%) or ≥3 (11.2%) ART classes. Among 1,273 patients with available tropism data, 17.6% showed non-R5 virus. Non-standard maraviroc use also comprised reported once daily dosing (20.0%) and a total daily dose of 150mg (12.1%). Over 48 weeks, 41.4% of patients met the definition of TF, although the 1-year estimated retention on maraviroc was 82.1% (95% confidence interval 79.9-84.2). Among 1,010 subjects on maraviroc at week 48, the viral load was >50 copies/mL in 19.9% and >200 copies/mL in 10.7%. Independent predictors of TF comprised a low nadir CD4 count, a detectable baseline viral load, previous PI experience, non-R5 tropism, having ≥3 active drugs in the accompanying regimen, and a more recent calendar year of maraviroc initiation.
CONCLUSIONS
This study reports on the largest observation cohort of patients who started maraviroc across 8 European countries. In this overall highly treatment-experienced population, with a small but appreciable subset that received maraviroc outside of standard treatment guidelines, maraviroc was safe and reasonably effective, with relatively low rates of discontinuation over 48 weeks and only 2 cases of serum transaminase elevations reported as reasons for discontinuation.
Topics: Adult; Anti-HIV Agents; Female; HIV Infections; HIV-1; Humans; Male; Maraviroc; Microbial Sensitivity Tests; Middle Aged; Public Health Surveillance; Treatment Failure; Treatment Outcome; Viral Load; Viral Tropism
PubMed: 31751385
DOI: 10.1371/journal.pone.0225381