Pharmacokinetics and tolerability of the maturation inhibitor GSK3640254 coadministered with darunavir/ritonavir and/or etravirine in healthy adults.

AIMS: This phase I study investigated potential drug-drug interactions of the maturation inhibitor GSK3640254 (GSK'254) with darunavir/ritonavir (DRV/RTV) and/or etravirine (ETR). METHODS: In this randomized, open-label, single-sequence, multiple-dose study, healthy participants received GSK'254 200 mg once daily alone or coadministered with DRV/RTV 600/100 mg twice daily (BID; n = 19), ETR 200 mg BID (n = 19) or DRV/RTV 600/100 mg + ETR 200 mg BID (n = 16) under fed conditions. Primary endpoints were steady-state area under the plasma concentration-time curve from time 0 to the end of the dosing interval (AUC0-τ ) and maximum observed concentration (Cmax ). Secondary endpoints included trough concentration (Cτ ), safety and tolerability. Pharmacokinetic parameters were calculated using standard noncompartmental analysis, and geometric least-squares mean ratios were derived from linear mixed-effects models. RESULTS: GSK'254 AUC0-τ (geometric least-squares mean ratio [90% confidence interval], 1.14 [1.00-1.29]), Cmax (1.07 [0.92-1.24]) and Cτ (1.17 [1.01-1.35]) were similar when administered alone and with DRV/RTV. Etravirine coadministration decreased GSK'254 AUC0-τ (0.53 [0.48-0.59]), Cmax (0.60 [0.53-0.68]) and Cτ (0.51 [0.39-0.66]). Similar reductions were not observed with GSK'254 + DRV/RTV + ETR (AUC0-τ , 0.94 [0.82-1.09]; Cmax , 0.89 [0.75-1.07]; Cτ , 1.02 [0.89-1.18]). GSK'254 had no meaningful effect on DRV/RTV or ETR concentrations. All reported adverse events (AEs) were grade 1; 3 led to withdrawal and resolved (rash, asymptomatic electrocardiogram T-wave inversion, periorbital oedema). Most common AEs were diarrhoea (n = 9) and headache (n = 7). No deaths or serious AEs occurred. CONCLUSION: GSK'254 pharmacokinetics was not meaningfully affected by DRV/RTV or DRV/RTV + ETR, but were reduced with only ETR; no new tolerability concerns were observed.

Open-label, drug-drug interaction study between the HIV-1 maturation inhibitor GSK3640254 and a metabolic probe cocktail in healthy participants.

AIMS: GSK3640254 (GSK'254) is an HIV-1 maturation inhibitor with pharmacokinetics (PK) supporting once-daily dosing. GSK'254 will be co-administered with cytochrome P450 enzyme substrates and drug transporters, including other antiretrovirals, in people living with HIV-1 (PLWH). METHODS: In this open-label study, healthy participants received a single dose of a cocktail of eight cytochrome P450 and transporter probe substrates on Day 1, followed by a 10-day washout before receiving GSK'254 200 mg once daily from Days 11 to 20 and a single dose of cocktail + GSK'254 200 mg on Day 21. Geometric least-squares mean ratios and 90% confidence intervals were obtained using linear mixed-effects models. Adverse events (AEs) were monitored. RESULTS: Of 20 participants enrolled, 19 completed the study. Plasma concentrations of all cocktail substrates were generally similar with or without GSK'254 co-administration. All 90% confidence intervals around geometric least-squares mean ratios for cocktail substrate PK parameters indicated no to weak interactions. Steady-state plasma GSK'254 concentrations were achieved by Day 17 and maintained through Day 21. Nine participants (45%) reported 17 AEs; most (88%) were grade 1. Two grade 2 treatment-related AEs (maculopapular rash [leading to withdrawal] and papular rash) were reported during GSK'254 administration alone. CONCLUSIONS: Co-administration of GSK'254 with a metabolic probe cocktail in healthy participants indicated very low risk of clinically relevant effect on PK of any substrates or associated metabolites. No new safety/tolerability concerns were identified. These results support ongoing phase IIb and planned phase III studies of GSK'254 in people living with HIV-1.

Phase IIa Proof-of-Concept Evaluation of the Antiviral Efficacy, Safety, Tolerability, and Pharmacokinetics of the Next-Generation Maturation Inhibitor GSK3640254.

BACKGROUND: GSK3640254 (GSK'254) is a next-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor with pharmacokinetics (PK) supporting once-daily therapy. METHODS: This phase IIa double-blind (sponsor-unblinded), randomized, placebo-controlled, adaptive study evaluated antiviral effect, safety, tolerability, and PK of once-daily GSK'254 monotherapy administered with food (moderate-fat meal) in HIV-1-positive, treatment-naive adults. In part 1, participants received GSK'254 10 or 200 mg for 10 days. In part 2, participants received GSK'254 40, 80, or 140 mg for 7 days, modified from 10 days by a protocol amendment to decrease potential for resistance-associated mutations (RAMs). The primary endpoint was maximum change from baseline in HIV-1 RNA. RESULTS: Maximum changes in HIV-1 RNA of -0.4, -1.2, -1.0, -1.5, and -2.0 log10 occurred with GSK'254 10, 40, 80, 140, and 200 mg, respectively. Regardless of dosing duration, doses ≥40 mg resulted in ≥1-log10 declines in HIV-1 RNA. Plasma PK was generally dose proportional to 140 mg but non-proportional between 140 and 200 mg. Four participants in the 200-mg group developed RAMs on day 11 in part 1, 1 with phenotypic resistance. No RAMs occurred in part 2. Adverse events (AEs) were reported by 22 (65%) participants; headache was the most common (n = 4). Two non-drug-related serious AEs occurred. All AEs were of mild-to-moderate intensity, except for 2 grade 3 non-drug-related AEs in 1 participant. CONCLUSIONS: This monotherapy study established a dose-antiviral response relationship for GSK'254. No safety or tolerability concerns were noted. These results supported dose selection for the ongoing phase IIb study (ClinicalTrials.gov: NCT04493216). CLINICAL TRIALS REGISTRATION: NCT03784079.

Lack of pharmacokinetic interaction between the HIV-1 maturation inhibitor GSK3640254 and combination oral contraceptives in healthy women.

AIMS: GSK3640254 is a next-generation maturation inhibitor likely to be coadministered with combined oral contraceptives in HIV-positive women. METHODS: This phase I, open-label, 1-way study assessed pharmacokinetic and pharmacodynamic interactions of GSK3640254 200 mg and ethinyl oestradiol 0.03 mg/levonorgestrel 0.15 mg once daily in healthy female participants who received ethinyl oestradiol/levonorgestrel for 10 days with a moderate-fat meal after which GSK3640254 was added from Days 11 to 21. Primary endpoints were area under the plasma concentration-time curve to the end of the dosing interval (AUC0-t ), maximum observed concentration (Cmax ) and plasma concentration at the end of the dosing interval (Cτ ) for ethinyl oestradiol and levonorgestrel. Serum follicle-stimulating hormone, luteinizing hormone and progesterone concentrations were determined. Adverse events were monitored. RESULTS: Among 23 enrolled participants, 17 completed the study. Geometric least squares mean ratios (with vs. without GSK3640254) of AUC0-t , Cmax and Cτ were 0.974, 0.970 and 1.050 for ethinyl oestradiol and 1.069, 1.032 and 1.083 for levonorgestrel, respectively. Three participants had elevated progesterone levels, which occurred before GSK3640254 administration in 2 participants. No participants had elevated follicle-stimulating hormone or luteinizing hormone values. Fourteen participants (61%) reported adverse events. Four participants reported asymptomatic elevated transaminase levels meeting liver-stopping criteria; of these, 3 events occurred before GSK3640254 administration and led to study withdrawal. CONCLUSION: Ethinyl oestradiol/levonorgestrel plus GSK3640254 coadministration did not affect steady-state pharmacokinetics or pharmacodynamics of ethinyl oestradiol and levonorgestrel in healthy female participants. No major tolerability findings were reported. Elevated liver transaminase levels were probably due to ethinyl oestradiol/levonorgestrel.

A Phase I Evaluation of the Pharmacokinetics and Tolerability of the HIV-1 Maturation Inhibitor GSK3640254 and Tenofovir Alafenamide/Emtricitabine in Healthy Participants.

GSK3640254 is a next-generation maturation inhibitor that would likely be combined with standard antiretroviral agents to form a regimen of ≥2 fully active classes. This phase I, open-label, 2-period, 1-way study assessed potential pharmacokinetic (PK) interactions between GSK3640254 and tenofovir alafenamide/emtricitabine (TAF/FTC; including the metabolite tenofovir [TFV]) in healthy volunteers. Eligible participants received TAF/FTC 25/200 mg once daily (QD) on days 1 through 21 with a moderate-fat meal; GSK3640254 200 mg QD was added on days 15 through 21. Geometric least-squares mean ratios (GMRs) and 90% confidence intervals (CIs) were derived using linear mixed-effect models. Adverse events (AEs) and laboratory, electrocardiogram, and vital sign parameters were monitored. Sixteen participants, all male, received treatment; one withdrew because of treatment-related grade 1 urticaria. After TAF/FTC + GSK3640254 coadministration, TAF steady-state area under the plasma concentration-time curve from time zero to the end of the dosing interval and maximum observed concentration were 11% and 13% lower than when TAF/FTC was administered alone, with GMRs (90% CI) of 0.886 (0.75 to 1.04) and 0.874 (0.68 to 1.12), respectively. Steady-state PK of TFV and FTC was similar when TAF/FTC was administered alone or with GSK3640254. No clinically significant trends in tolerability or safety were observed. GSK3640254 200 mg QD did not meaningfully affect the steady-state PK of TAF, TFV, or FTC in healthy participants under fed conditions and was not associated with major tolerability or safety findings. These data support the further investigation of GSK3640254 for coadministration with TAF/FTC for the treatment of HIV. (This study has been registered at ClinicalTrials.gov under identifier NCT03836729.).

Phase I evaluation of pharmacokinetics and tolerability of the HIV-1 maturation inhibitor GSK3640254 and dolutegravir in healthy adults.

AIMS: GSK3640254, a novel, next-generation maturation inhibitor effective against a range of HIV polymorphisms with no cross-resistance to current antiretroviral therapy, could potentially be coadministered with dolutegravir as a 2-drug regimen. In this phase I study, pharmacokinetics and tolerability of GSK3640254 plus dolutegravir were assessed. METHODS: Healthy participants received dolutegravir 50 mg once daily (QD) on Days 1-5 in period 1, GSK3640254 200 mg QD on Days 1-7 in period 2, and dolutegravir 50 mg plus GSK3640254 200 mg QD on Days 1-7 in period 3. All treatments were administered with a moderate-fat meal 30 minutes prior to dosing. Pharmacokinetics parameters were derived by noncompartmental methods, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were derived using linear mixed effects models. Adverse events, laboratory measurements, electrocardiography and vital signs were monitored. RESULTS: Sixteen participants completed the study. GMRs (90% CIs) for dolutegravir area under the plasma concentration-time curve from time 0 to the end of the dosing interval at steady state, maximum observed concentration and plasma concentration at the end of the dosing interval were 1.17 (1.118-1.233), 1.09 (1.044-1.138) and 1.24 (1.160-1.315), respectively. The GMRs (90% CIs) for GSK3640254 were 1.04 (0.992-1.094), 0.99 (0.923-1.065) and 0.10 (0.939-1.056), respectively. Dolutegravir plus GSK3640254 coadministration did not meaningfully alter steady-state exposure to dolutegravir or GSK3640254. No clinically significant trends in tolerability or safety were observed. CONCLUSION: Coadministration of GSK3640254 with dolutegravir did not result in clinically significant drug interaction and was well tolerated.

Multiple network-constrained regressions expand insights into influenza vaccination responses.

MOTIVATION: Systems immunology leverages recent technological advancements that enable broad profiling of the immune system to better understand the response to infection and vaccination, as well as the dysregulation that occurs in disease. An increasingly common approach to gain insights from these large-scale profiling experiments involves the application of statistical learning methods to predict disease states or the immune response to perturbations. However, the goal of many systems studies is not to maximize accuracy, but rather to gain biological insights. The predictors identified using current approaches can be biologically uninterpretable or present only one of many equally predictive models, leading to a narrow understanding of the underlying biology. RESULTS: Here we show that incorporating prior biological knowledge within a logistic modeling framework by using network-level constraints on transcriptional profiling data significantly improves interpretability. Moreover, incorporating different types of biological knowledge produces models that highlight distinct aspects of the underlying biology, while maintaining predictive accuracy. We propose a new framework, Logistic Multiple Network-constrained Regression (LogMiNeR), and apply it to understand the mechanisms underlying differential responses to influenza vaccination. Although standard logistic regression approaches were predictive, they were minimally interpretable. Incorporating prior knowledge using LogMiNeR led to models that were equally predictive yet highly interpretable. In this context, B cell-specific genes and mTOR signaling were associated with an effective vaccination response in young adults. Overall, our results demonstrate a new paradigm for analyzing high-dimensional immune profiling data in which multiple networks encoding prior knowledge are incorporated to improve model interpretability. AVAILABILITY AND IMPLEMENTATION: The R source code described in this article is publicly available at https://bitbucket.org/kleinstein/logminer . CONTACT: steven.kleinstein@yale.edu or stefan.avey@yale.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Model-Based Phase 3 Dose Selection for HIV-1 Attachment Inhibitor Prodrug BMS-663068 in HIV-1-Infected Patients: Population Pharmacokinetics/Pharmacodynamics of the Active Moiety, BMS-626529.

BMS-663068 is an oral prodrug of the HIV-1 attachment inhibitor BMS-626529, which prevents viral attachment to host CD4(+) T cells by binding to HIV-1 gp120. To guide dose selection for the phase 3 program, pharmacokinetic/pharmacodynamic modeling was performed using data from two phase 2 studies with HIV-1-infected subjects (n = 244). BMS-626529 population pharmacokinetics were described by a two-compartment model with first-order elimination from the central compartment, zero-order release of prodrug from the extended-release formulation into a hypothetical absorption compartment, and first-order absorption into the central compartment. The covariates of BMS-663068 formulation type, lean body mass, baseline CD8(+) T-cell percentage, and ritonavir coadministration were found to be significant contributors to intersubject variability. Exposure-response analyses showed a relationship between the loge-transformed concentration at the end of a dosing interval (Ctau) normalized for the protein binding-adjusted BMS-626529 half-maximal (50%) inhibitory concentration (PBAIC50) and the change in the HIV-1 RNA level from the baseline level after 7 days of BMS-663068 monotherapy. The probability of achieving a decline in HIV-1 RNA level of >0.5 or >1.0 log10 copies/ml as a function of the loge-transformed PBAIC50-adjusted Ctau after 7 days of monotherapy was 99 to 100% and 57 to 73%, respectively, for proposed BMS-663068 doses of 400 mg twice daily (BID), 600 mg BID (not studied in the phase 2b study), 800 mg BID, 600 mg once daily (QD), and 1,200 mg QD. On the basis of a slight advantage in efficacy of BID dosing over QD dosing, similar responses for the 600- and 800-mg BID doses, and prior clinical observations, BMS-663068 at 600 mg BID was predicted to have the optimal benefit-risk profile and selected for further clinical investigation. (The phase 2a proof-of-concept study AI438006 and the phase 2b study AI438011 are registered at ClinicalTrials.gov under numbers NCT01009814 and NCT01384734, respectively.).

Increased Levels of Macrophage Inflammatory Proteins Result in Resistance to R5-Tropic HIV-1 in a Subset of Elite Controllers.

UNLABELLED: Elite controllers (ECs) are a rare group of HIV seropositive individuals who are able to control viral replication without antiretroviral therapy. The mechanisms responsible for this phenotype, however, have not been fully elucidated. In this study, we examined CD4(+) T cell resistance to HIV in a cohort of elite controllers and explored transcriptional signatures associated with cellular resistance. We demonstrate that a subgroup of elite controllers possess CD4(+) T cells that are specifically resistant to R5-tropic HIV while remaining fully susceptible to X4-tropic and vesicular stomatitis virus G (VSV-G)-pseudotyped viruses. Transcriptome analysis revealed 17 genes that were differentially regulated in resistant elite controllers relative to healthy controls. Notably, the genes encoding macrophage inflammatory protein 1α (MIP-1α), CCL3 and CCL3L1, were found to be upregulated. The MIP-1α, MIP-1ß, and RANTES chemokines are natural ligands of CCR5 and are known to interfere with HIV replication. For three elite controllers, we observed increased production of MIP-1α and/or MIP-1ß at the protein level. The supernatant from resistant EC cells contained MIP-1α and MIP-1ß and was sufficient to confer R5-tropic resistance to susceptible CD4(+) T cells. Additionally, this effect was reversed by using inhibitory anti-MIP antibodies. These results suggest that the T cells of these particular elite controllers may be naturally resistant to HIV infection by blocking R5-tropic viral entry. IMPORTANCE: HIV is a pandemic health problem, and the majority of seropositive individuals will eventually progress to AIDS unless antiretroviral therapy (ART) is administered. However, rare patients, termed elite controllers, have a natural ability to control HIV infection in the absence of ART, but the mechanisms by which they achieve this phenotype have not been fully explored. This paper identifies one mechanism that may contribute to this natural resistance: some elite controllers have CD4(+) T cells that produce high levels of MIP chemokines, which block R5-tropic HIV entry. This mechanism could potentially be exploited to achieve a therapeutic effect in other HIV-seropositive individuals.

Prolonged proinflammatory cytokine production in monocytes modulated by interleukin 10 after influenza vaccination in older adults.

We evaluated in vivo innate immune responses in monocyte populations from 67 young (aged 21-30 years) and older (aged ≥65 years) adults before and after influenza vaccination. CD14(+)CD16(+) inflammatory monocytes were induced after vaccination in both young and older adults. In classical CD14(+)CD16(-) and inflammatory monocytes, production of tumor necrosis factor α and interleukin 6, as measured by intracellular staining, was strongly induced after vaccination. Cytokine production was strongly associated with influenza vaccine antibody response; the highest levels were found as late as day 28 after vaccination in young subjects and were substantially diminished in older subjects. Notably, levels of the anti-inflammatory cytokine interleukin 10 (IL-10) were markedly elevated in monocytes from older subjects before and after vaccination. In purified monocytes, we found age-associated elevation in phosphorylated signal transducer and activator of transcription-3, and decreased serine 359 phosphorylation of the negative IL-10 regulator dual-specificity phosphatase 1. These findings for the first time implicate dysregulated IL-10 production in impaired vaccine responses in older adults.

Effects of the HIV-1 maturation inhibitor GSK3640254 on QT interval in healthy participants.

GSK3640254 (GSK'254) is a novel HIV-1 maturation inhibitor with pharmacokinetics supporting once-daily (QD) therapy for HIV-1 treatment. This thorough QT/corrected QT (QTc) study evaluated the effect of GSK'254 on cardiac repolarization. In this two-part, randomized study, healthy participants received GSK'254 or placebo QD for 7 days (part 1) to determine safety and pharmacokinetics of a 500-mg supratherapeutic dose. Four sequential treatment periods composed the main QTc study (part 2): GSK'254 100 mg, GSK'254 500 mg, placebo QD for 7 days, or placebo QD for 6 days with a 400-mg moxifloxacin dose on Day 7 (all with a moderate-fat meal). Concentration-QTc analyses modeled the relationship between GSK'254 plasma concentrations and placebo-adjusted change from baseline in QT interval corrected with Fridericia's formula (ΔΔQTcF). Of 50 participants enrolled, 48 completed the study (part 1, 8/8; part 2, 40/42). Least-squares (LS) mean change from baseline in QTcF for GSK'254 100 mg followed the placebo pattern across time points (maximum LS mean ΔΔQTcF, 1.7 ms); the upper bound of the 90% CI remained <10 ms. Maximum LS mean ΔΔQTcF for GSK'254 500 mg exceeded the 10-ms threshold: 10.6 ms (90% CI 7.75-13.38). Neither GSK'254 dose had clinically relevant effects on heart rate or cardiac conduction. By concentration-QTc analysis, no effect on ΔΔQTcF >10 ms is expected up to GSK'254 concentrations of ~3070 ng mL-1 . No clinically relevant effects on cardiac parameters were seen in healthy participants with GSK'254 at the 100-mg dose.

Relative Bioavailability and Food Effect of GSK3640254 Tablet and Capsule Formulations in Healthy Participants.

GSK3640254 is a next-generation maturation inhibitor with demonstrated potency across HIV-1 subtypes and a high barrier to emergent resistance. This phase I, 2-part, randomized, open-label study (ClinicalTrials.gov identifier, NCT04263142) in healthy participants assessed the relative bioavailability of a single dose of GSK3640254 200 mg in tablet and capsule formulations (part 1) and the effect of food on the pharmacokinetic profile of the tablet formulation (part 2). Overall, 39 participants were randomized to treatment (part 1, n = 18; part 2, n = 21). All participants in part 1 completed the study; 2 participants in part 2 withdrew before study completion (adverse event, n = 1; physician decision, n = 1). In part 1, plasma exposures of the GSK3640254 tablet formulation were not meaningfully different from those of the capsule formulation when administered in the presence of a moderate-fat meal. In part 2, GSK3640254 plasma exposures increased by ≈3- to 4-fold under high- and moderate-fat conditions, respectively, compared with fasted conditions. No major safety or tolerability findings were observed. The highest incidence of adverse events (24%) was reported under high-fat conditions. Taken together, these data support the use of the tablet formulation coadministered with food in the clinical development of GSK3640254 for treatment of HIV-1.

Metabolomic and transcriptomic signatures of influenza vaccine response in healthy young and older adults.

Seasonal influenza causes mild to severe respiratory infections and significant morbidity, especially in older adults. Transcriptomic analysis in populations across multiple flu seasons has provided insights into the molecular determinants of vaccine response. Still, the metabolic changes that underlie the immune response to influenza vaccination remain poorly characterized. We performed untargeted metabolomics to analyze plasma metabolites in a cohort of younger and older subjects before and after influenza vaccination to identify vaccine-induced molecular signatures. Metabolomic and transcriptomic data were combined to define networks of gene and metabolic signatures indicative of high and low antibody response in these individuals. We observed age-related differences in metabolic baselines and signatures of antibody response to influenza vaccination and the abundance of α-linolenic and linoleic acids, sterol esters, fatty-acylcarnitines, and triacylglycerol metabolism. We identified a metabolomic signature associated with age-dependent vaccine response, finding increased tryptophan and decreased polyunsaturated fatty acids (PUFAs) in young high responders (HRs), while fatty acid synthesis and cholesteryl esters accumulated in older HRs. Integrated metabolomic and transcriptomic analysis shows that depletion of PUFAs, which are building blocks for prostaglandins and other lipid immunomodulators, in young HR subjects at Day 28 is related to a robust immune response to influenza vaccination. Increased glycerophospholipid levels were associated with an inflammatory response in older HRs to flu vaccination. This multi-omics approach uncovered age-related molecular markers associated with influenza vaccine response and provides insight into vaccine-induced metabolic responses that may help guide development of more effective influenza vaccines.

Emergence of resistance to azithromycin-atovaquone in immunocompromised patients with Babesia microti infection.

BACKGROUND: Babesiosis is an emerging tickborne malaria-like infection principally caused by Babesia microti. This infection typically resolves either spontaneously or after administration of a 7-10-day course of azithromycin plus atovaquone or clindamycin plus quinine. Although certain highly immunocompromised patients may respond suboptimally to these drug regimens, unlike the situation with malaria there has been no reported evidence that the cause of treatment failure is infection with drug-resistant strains of B. microti. METHODS: Emergence of drug resistance in B. microti was defined as the development of a microbiologic relapse (recurrent parasitemia or a marked increase in parasitemia) in association with both clinical and laboratory abnormalities indicative of active babesiosis in a patient after 28 days of uninterrupted antibabesia drug therapy and while still receiving treatment. RESULTS: The clinical case histories of 3 highly immunocompromised patients who received a subcurative course of azithromycin-atovaquone associated with the eventual development of resistance to this drug regimen are described. One of the 3 patients died of complications related to babesiosis. CONCLUSIONS: B. microti may become resistant to azithromycin-atovaquone during the treatment of babesiosis with this combined drug regimen in highly immunocompromised patients. Although research is needed to determine the optimal therapy for highly immunocompromised patients with babesiosis, reducing the level of immunosuppression when possible would appear to be a desirable strategy.

Phase I evaluation of the safety, tolerability, and pharmacokinetics of GSK3640254, a next-generation HIV-1 maturation inhibitor.

Despite advances in HIV-1 management with antiretroviral therapy, drug resistance and toxicities with multidrug regimens can result in treatment failure. Hence, there is a continuing demand for antiretroviral agents (ARVs) with novel mechanisms of action. Maturation inhibitors inhibit HIV-1 replication via a unique mechanism of action and can be combined with other ARVs. Two phase I randomized clinical trials were conducted for a maturation inhibitor, GSK3640254, to determine safety, pharmacokinetics (NCT03231943), and relative bioavailability (NCT03575962) in healthy adults. The first trial was conducted in two parts. Part 1 was conducted in a two-cohort, interlocking, eight-period fashion in 20 participants with single ascending doses of GSK3640254 (1-700 mg) or placebo. In Part 2, 58 participants were randomized to receive GSK3640254 (n = 44) or placebo (n = 14). Four participants reported adverse events (AEs) leading to study discontinuation, with one adverse drug reaction (maculopapular rash). There was no relationship between frequency or severity of AEs and dose. Pharmacokinetic assessments showed that GSK3640254 was slowly absorbed, with time to maximum concentration (tmax) occurring between 3.5 and 4 hours and half-life of ~24 hours. In the relative bioavailability study of GSK3640254 mesylate salt vs bis-hydrochloride salt capsules in 14 healthy adults, the mesylate salt performed slightly better than the bis-hydrochloride formulation (12%-16% increase in area under the concentration-time curve and maximum concentration); tmax (5 hours) was similar between the formulations. Initial pharmacokinetic and safety data from these healthy-participant studies informed further development of GSK3640254 for once-daily dosing for the treatment of HIV-1 infection.

Pandemic influenza H1N1 2009, innate immunity, and the impact of immunosenescence on influenza vaccine.

Seasonal and pandemic strains of influenza have widespread implications for the global economy and global health. This has been highlighted recently as the epidemiologic characteristics for hospitalization and mortality for pandemic influenza H1N1 2009 are now emerging. While treatment with neuraminidase inhibitors are effective for seasonal and pandemic influenza, prevention of morbidity and mortality through effective vaccines requires a rigorous process of research and development. Vulnerable populations such as older adults (i.e., > age 65 years) suffer the greatest impact from seasonal influenza yet do not have a consistent seroprotective response to seasonal influenza vaccines due to a combination of factors. This short narrative review will highlight the emerging epidemiologic characteristics of pandemic H1N1 2009 and focus on immunosenescence, innate immune system responses to influenza virus infection and vaccination, and influenza vaccine responsiveness as it relates to seasonal and H1N1 pandemic influenza vaccines.

Resistance profile of the HIV-1 maturation inhibitor GSK3532795 in vitro and in a clinical study.

GSK3532795 (formerly BMS955176) is a second-generation maturation inhibitor (MI) that progressed through a Phase 2b study for treatment of HIV-1 infection. Resistance development to GSK3532795 was evaluated through in vitro methods and was correlated with information obtained in a Phase 2a proof-of-concept study in HIV-1 infected participants. Both low and high concentrations of GSK3532795 were used for selections in vitro, and reduced susceptibility to GSK3532795 mapped specifically to amino acids near the capsid/ spacer peptide 1 (SP1) junction, the cleavage of which is blocked by MIs. Two key substitutions, A364V or V362I, were selected, the latter requiring secondary substitutions to reduce susceptibility to GSK3532795. Three main types of secondary substitutions were observed, none of which reduced GSK3532795 susceptibility in isolation. The first type was in the capsid C-terminal domain and downstream SP1 region (including (Gag numbering) R286K, A326T, T332S/N, I333V and V370A/M). The second, was an R41G substitution in viral protease that occurred with V362I. The third was seen in the capsid N-terminal domain, within the cyclophilin A binding domain (V218A/M, H219Q and G221E). H219Q increased viral replication capacity and reduced susceptibility of poorly growing viruses. In the Phase 2a study, a subset of these substitutions was also observed at baseline and some were selected following GSK35323795 treatment in HIV-1-infected participants.

Viral Drug Resistance Through 48 Weeks, in a Phase 2b, Randomized, Controlled Trial of the HIV-1 Attachment Inhibitor Prodrug, Fostemsavir.

BACKGROUND: Fostemsavir is a prodrug of temsavir, an attachment inhibitor that binds to HIV-1 gp120, blocking viral attachment to host CD4 T-cells. The phase 2b trial AI438011 investigated the safety, efficacy, and dose-response of fostemsavir vs ritonavir-boosted atazanavir (ATV/r) in treatment-experienced, HIV-1-infected subjects. METHODS: Two hundred fifty-one treatment-experienced subjects with baseline (BL) susceptibility to study drugs [temsavir half-maximal inhibitory concentration (IC50) <100 nM, PhenoSense Entry assay] received fostemsavir or ATV/r, each with tenofovir disoproxil fumarate + raltegravir. Subjects meeting resistance-testing criteria were assessed for emergent viral drug resistance. Changes in temsavir IC50 from BL was given a conservative technical cutoff (>3-fold increase). RESULTS: 66/200 fostemsavir and 14/51 ATV/r subjects had resistance testing performed; 44/66 and 9/14 were successfully tested using the PhenoSense GT assay. No subjects had emergent tenofovir disoproxil fumarate or ATV resistance. Six fostemsavir-treated subjects developed emergent raltegravir resistance. 29/66 fostemsavir-treated subjects had an evaluable phenotype using PhenoSense Entry (which tests for viral susceptibility to temsavir) and 13/29 exhibited >3-fold increase in temsavir IC50 from BL. gp120 population sequencing was successful in 11/13 subjects and 7 had emergent substitutions in gp120 associated with reduced temsavir susceptibility (S375, M426, or M434). However, 5/13 fostemsavir-treated subjects achieved subsequent suppression to <50 copies/mL before the week 48 database lock, regardless of key gp120 substitutions. CONCLUSIONS: Response rates remained similar across study arms regardless of BL nucleoside reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitor, and protease inhibitor resistance-associated mutations. Emergent changes in viral susceptibility occurred more frequently with fostemsavir compared with ATV/r. However, the full impact of temsavir IC50 changes and emergent HIV-1 gp120 substitutions, and thus appropriate clinical cutoffs, requires further study. Fostemsavir is being evaluated in a phase 3 trial in heavily treatment-experienced subjects.

Safety, efficacy, and dose response of the maturation inhibitor GSK3532795 (formerly known as BMS-955176) plus tenofovir/emtricitabine once daily in treatment-naive HIV-1-infected adults: Week 24 primary analysis from a randomized Phase IIb trial.

GSK3532795 (formerly known as BMS-955176) is a second-generation maturation inhibitor targeting a specific Gag cleavage site between capsid p24 and spacer peptide 1 of HIV-1. Study 205891 (previously AI468038) investigated the efficacy, safety, and dose response of GSK3532795 in treatment-naive, HIV-1-infected participants. Study 205891 (NCT02415595) was a Phase IIb, randomized, active-controlled, double-blind, international trial. Participants were randomized 1:1:1:1 to one of three GSK3532795 arms at doses 60 mg, 120 mg or 180 mg once daily (QD), or to efavirenz (EFV) at 600 mg QD, each in combination with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) (300/200 mg QD). Primary endpoint was proportion of participants with plasma HIV-1 RNA <40 copies/mL at Week 24. Between May 2015 and May 2016, 206 participants received treatment. At Week 24, 76-83% participants receiving GSK3532795 and 77% receiving EFV achieved HIV-1 RNA <40 copies/mL. Fifteen participants receiving GSK3532795 and one receiving EFV met resistance testing criteria; 10/15 receiving GSK3532795 had emergent substitutions at reverse transcriptase positions M184, and one at position K65, while the participant receiving EFV did not have any nucleoside reverse transcriptase inhibitor (NRTI)/non-NRTI mutations. EFV, relative to GSK3532795, had more serious adverse events (9% versus 5%) and adverse events leading to discontinuation (17% versus 5%). However, 3-4-fold higher rates of gastrointestinal adverse events were observed with GSK3532795 relative to EFV. GSK3532795 combined with TDF/FTC is efficacious with 24 weeks of therapy. However, GSK3532795 showed a higher rate of gastrointestinal intolerability and treatment-emergent resistance to the NRTI backbone relative to EFV. Trial registration: ClinicalTrials.gov NCT02415595.

Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in antiretroviral-experienced subjects: week 48 analysis of AI438011, a Phase IIb, randomized controlled trial.

BACKGROUND: Fostemsavir is a prodrug of temsavir, an attachment inhibitor that binds directly to HIV-1 gp120, blocking initial viral attachment and entry into host CD4+ T-cells. Efficacy, safety and dose-response data of fostemsavir in treatment-experienced, HIV-1-infected subjects, through week 48, are reported. METHODS: AI438011 is an ongoing Phase IIb, randomized, active-controlled trial (NCT01384734). Subjects were randomized 1:1:1:1:1 into five arms: fostemsavir (400 mg twice daily, 800 mg twice daily, 600 mg once daily or 1,200 mg once daily) and a reference arm (ritonavir-boosted atazanavir [ATV/r] 300/100 mg once daily), each with a backbone of raltegravir 400 mg twice daily plus tenofovir disoproxil fumarate 300 mg once daily. RESULTS: In total, 251 subjects were treated. Through week 48, the proportion of fostemsavir subjects with HIV-1 RNA <50 copies/ml was 61-82% and 77-95% (modified intent-to-treat [mITT] and observed analysis, respectively); 71% and 88% for ATV/r subjects (mITT and observed). Observed virological response rates were 74-100% versus 96% (fostemsavir versus ATV/r) in subjects with baseline viral load <100,000 copies/ml and 60-91% versus 71% when baseline viral load was ≥100,000 copies/ml. Across fostemsavir arms, median CD4+ T-cell count increases from baseline were 145-186 cells/µl and 142 cells/µl for the ATV/r arm. Fostemsavir doses were generally well tolerated and no fostemsavir-related adverse events led to discontinuation. CONCLUSIONS: Through week 48, fostemsavir continued to be well tolerated and showed similar efficacy to ATV/r. These results support the ongoing Phase III trial in heavily treatment-experienced adults with limited therapeutic options (≤2 classes of active antiretrovirals remaining). ClinicalTrials.gov identifier: NCT01384734.