188 results found
Meng J, Sweeney NP, Doreste B, et al., 2020, Restoration of Functional Full-Length Dystrophin After Intramuscular Transplantation of Foamy Virus-Transduced Myoblasts, HUMAN GENE THERAPY, Vol: 31, Pages: 241-252, ISSN: 1043-0342
Wang X, Nijman R, Camuzeaux S, et al., 2019, Plasma lipid profiles discriminate bacterial from viral infection in febrile children, Scientific Reports, Vol: 9, ISSN: 2045-2322
Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The ‘omics’ approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n=20) and confirmed viral infection (n=20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group..A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics.
Wang X, Cerrone M, Ferretti F, et al., 2019, Pharmacokinetics of dolutegravir 100 mg once-daily with rifampicin, International Journal of Antimicrobial Agents, Vol: 54, Pages: 202-206, ISSN: 0924-8579
BackgroundTuberculosis (TB) causes 25% of all deaths among HIV-infected individuals. Rifampicin (RIF) is a potent inducer of drug metabolising enzymes and drug transporters and co-administration with dolutegravir (DTG) reduces DTG exposure, which can be overcome by doubling the DTG dose to 50 mg twice-daily. We investigated the effect of RIF on the DTG exposure when dosed at 100 mg once-daily, which could provide an easier option than 50 mg twice-daily.MethodsWe conducted an open label, pharmacokinetic (PK) study. Healthy HIV-negative subjects received DTG 50 mg for seven days (PK1), DTG 100 mg for seven days (PK2), RIF only for 14 days, DTG 50 mg plus RIF for seven days (PK3), and DTG 100 mg plus RIF for seven days (PK4). Steady state full DTG PK profiles were evaluated.ResultsDTG geometric mean ratios (GMR) (90% confidence intervals, CI) of PK3/PK1 of 50 mg Cmax, AUC24h, and C24h were 0.65 (0.55-0.75), 0.44 (0.37-0.52), 0.15 (0.13-0.17). GMR (90% CI) of PK4/PK1 Cmax, AUC24h, and C24h were 1.09 (0.97-1.21), 0.74 (0.64-0.86), 0.24 (0.20-0.28). C24h median (range) of DTG 50 mg plus RIF and DTG 100 mg plus RIF were 251(129–706) ng/mL and 140 (73-426) ng/mL, respectively.ConclusionAlthough there were substantial reductions in DTG C24h when co-administered with RIF, concentrations of both DTG 50 mg and 100 mg once-daily with RIF were still above the protein binding-adjusted IC90 of 64 ng/mL. Further studies in HIV-TB co-infected individuals are warranted to confirm these results.Clinical trial registration number (NCT03199690)
Wang X, Nutland W, Brady M, et al., 2019, Quantification of tenofovir disoproxil fumarate and emtricitabine in generic pre-exposure prophylaxis tablets obtained from the internet, INTERNATIONAL JOURNAL OF STD & AIDS, Vol: 30, Pages: 765-768, ISSN: 0956-4624
Gossez M, Martin GE, Pace M, et al., 2019, Virological remission after antiretroviral therapy interruption in female African HIV seroconverters, AIDS, Vol: 33, Pages: 185-197, ISSN: 0269-9370
INTRODUCTION: There are few data on the frequency of virological remission in African individuals after treatment with antiretroviral therapy (ART) in primary HIV infection (PHI). METHODS: We studied participants (n = 82) from South Africa and Uganda in Short Pulse Antiretroviral Treatment at HIV-1 Seroconversion, the first trial of treatment interruption in African individuals with PHI randomized to deferred ART or 48 weeks of immediate ART. All were female and infected with non-B HIV subtypes, mainly C. We measured HIV DNA in CD4 T cells, CD4 cell count, plasma viral load (pVL), cell-associated HIV RNA and T-cell activation and exhaustion. We explored associations with clinical progression and time to pVL rebound after treatment interruption (n = 22). Data were compared with non-African Short Pulse Antiretroviral Treatment at HIV-1 Seroconversion participants. RESULTS: Pretherapy pVL and integrated HIV DNA were lower in Africans compared with non-Africans (median 4.16 vs. 4.72 log10 copies/ml and 3.07 vs. 3.61 log10 copies/million CD4 T cells, respectively; P < 0.001). Pre-ART HIV DNA in Africans was associated with clinical progression (P = 0.001, HR per log10 copies/million CD4 T cells increase (95% CI) 5.38 (1.95-14.79)) and time to pVL rebound (P = 0.034, HR per log10 copies/ml increase 4.33 (1.12-16.84)). After treatment interruption, Africans experienced longer duration of viral remission than non-Africans (P < 0.001; HR 3.90 (1.75-8.71). Five of 22 African participants (22.7%) maintained VL less than 400 copies/ml over a median of 188 weeks following treatment interruption. CONCLUSION: We find evidence of greater probability of virological remission following treatment interruption among African participants, although we are unable to differentiate between sex, ethnicity and viral subtype. The finding warrants further investigation.
Cerrone M, Wang X, Neary M, et al., 2019, Pharmacokinetics of efavirenz 400 mg once daily coadministered with isoniazid and rifampicin in human immunodeficiency virus-infected individuals, Clinical Infectious Diseases, Vol: 68, Pages: 446-452, ISSN: 1058-4838
Background: The World Health Organization recommends efavirenz 400 mg (EFV400) as first-line antiretroviral therapy, with a disclaimer that no data with anti-tuberculosis (TB) treatment exist. Many people living with human immunodeficiency virus (PLWH) require TB treatment with isoniazid (INH) and rifampicin (RIF), which affect cytochrome P450 and antiretroviral exposure. Methods: PLWH receiving tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/EFV 600 mg with a viral load (VL) <50 copies/mL switched to TDF/FTC/EFV400. Genetic polymorphisms and pharmacokinetic (PK) parameters of EFV400 without (PK1) and with INH/RIF following 4 (PK2) and 12 (PK3) weeks of coadministration were evaluated. Results: Twenty-six PLWH were enrolled; 22 completed PK2. All maintained VL <50 copies/mL throughout the study. Geometric mean ratio (GMR) PK2/PK1 of EFV400 maximum plasma concentration (Cmax), area under the curve (AUC), and concentration at 24 hours postdose (C24h) were 0.91 (90% confidence interval [CI], .83-.99), 0.91 (90% CI, .79-1.05), and 0.85 (90% CI, .72-.99), respectively. GMRs (90% CI) of PK3/PK2 and PK3/PK1 Cmax, AUC, and C24h were 0.95 (.86-1.05) and 0.92 (.83-1.01), 0.88 (.75-1.03) and 0.84 (.75-.93), and 0.84 (.72-.99) and 0.75 (.62-.92), respectively. Eleven of 22 participants carried polymorphisms in the CYP2B6 gene associated with slow EFV metabolism. Conclusions: INH/RIF coadministration was associated with limited changes in EFV400 AUC (<25%), and EFV400 concentrations were maintained within ranges of those measured in PLWH in the ENCORE-1 study, irrespective of CYP2B6 genotype. The coadministration of EFV400 with anti-TB treatment can be considered and this is being confirmed in PLWH with TB. Clinical Trials Registration: NCT02832778.
Kaboggoza JP, Wang X, Neary M, et al., 2019, A Lower Dose of Efavirenz Can Be Coadministered With Rifampicin and Isoniazid in Tuberculosis Patients, OPEN FORUM INFECTIOUS DISEASES, Vol: 6, ISSN: 2328-8957
Elliot ER, Wang X, Singh S, et al., 2019, Increased dolutegravir peak concentrations in people living with HIV aged 60 and over and analysis of sleep quality and cognition, Clinical Infectious Diseases, Vol: 68, Pages: 87-95, ISSN: 1058-4838
Background: Demographic data show an increasingly aging HIV population worldwide. Recent concerns over dolutegravir-related neuropsychiatric toxicity have emerged, particularly amongst older HIV patients. We describe the pharmacokinetics (PK) of dolutegravir (DTG) 50mg once daily in people living with HIV (PLWH) aged 60 and older. Additionally, to address the call for prospective neuropsychiatric toxicodynamic data, we evaluate changes in sleep quality and cognitive function after switching to abacavir (ABC)/lamivudine (3TC)/DTG, over 6 months in this population. Methods: PLWH aged≥60years with HIV-RNA<50copies/mL on any non-DTG based antiretroviral combination were switched to ABC/3TC/DTG. On day 28, 24-hour PK sampling was undertaken. Steady-state PK parameters were compared to a published historical control population aged≤50years. Six validated sleep questionnaires and neurocognitive (Cogstate®) testing were administered pre-switch and over 180 days (NCT02509195). Results: Forty-three participants were enrolled; 40 completed the PK phase. Overall, five discontinued (two due adverse events, both sleep related, 4.6%). DTG maximum concentration (Cmax) was significantly higher in patients≥60 versus controls (GM 4246ng/mL versus 3402ng/mL, p=0.005). In those who completed day 180 (n=38), sleep impairment was higher at day 28 (PSQI median global score 5.0 versus 6.0 p=0.02) but not at day 90 or 180. Insomnia, daytime function, fatigue test scores did not change statistically over time. Conclusion: DTG Cmax was significantly higher in older PLWH. Our data provides clinicians with key information on the safety of prescribing DTG in older PLWH.
Wang X, Boffito M, Dickinson L, et al., 2018, Plasma NRTI exposure and associations with serum alanine aminotransferase in people living with HIV, Publisher: JOHN WILEY & SONS LTD
Wang X, Nutland W, Brady M, et al., 2018, Generic tenofovir disoproxil fumarate and emtricitabine tablets obtained from the internet: are they what they say they are?, Publisher: JOHN WILEY & SONS LTD
Lamorde M, Wang X, Neary M, et al., 2018, Pharmacokinetics, pharmacodynamics, and pharmacogenetics of Efavirenz 400 mg once daily during pregnancy and post-partum, Clinical Infectious Diseases, Vol: 67, Pages: 785-790, ISSN: 1058-4838
BackgroundA clinical trial showed that efavirenz 400 mg once daily (EFV400) is as effective as the standard adult dose. World Health Organization recommends EFV400 as an alternative first-line agent, but data are lacking in the third trimester of pregnancy (TT). We investigated the pharmacokinetics, efficacy, and CYP2B6 pharmacogenetics in HIV-infected women (WLWH) on EFV400 during TT and post-partum (PP).MethodsAn open-label 2-center study (United Kingdom, Uganda) was conducted in WLWH receiving antiretroviral regimens containing efavirenz 600 mg, who had their efavirenz dose reduced to EFV400. Weekly therapeutic drug monitoring (TDM), steady-state pharmacokinetic profiles (TT and PP), safety, virological efficacy, and CYP2B6 polymorphisms at positions 516 (C > T) and 938 (T > C) were evaluated.ResultsTwenty-five WLWH of African origin were enrolled. All had viral loads <50 copies/mL at baseline, which were maintained throughout the study. No infant was HIV infected. No WLWH were withdrawn due to low EFV400 TDM results. Geometric mean ratios (TT/PP; 90% confidence interval) for EFV400 maximum observed plasma concentration, area under the curve, and plasma concentration measured 24 hours after the observed dose were 0.97 (.85–1.10), 0.87 (.76–.99), and 0.77 (.65–.91), respectively. Five of 25 WLWH were slow metabolizers.ConclusionsAlthough EFV400 pharmacokinetic parameters were slightly lower for TT compared with PP values, efavirenz concentrations exceeded cutoff levels established by the study and those measured in antiretroviral-naive patients receiving EFV400 in ENCORE1. All subjects maintained a viral load <50 copies/mL, suggesting that EFV400 can be used in pregnant WLWH.
Khurshid S, Govada L, Wills G, et al., 2018, Chlamydia protein Pgp3 studied at high resolution in a new crystal form, IUCrJ, Vol: 5, Pages: 439-448, ISSN: 2052-2525
The protein Pgp3 is implicated in the sexually transmitted disease chlamydia and comprises an extended complex arrangement of a C terminal domain (CTD) and an N terminal domain (NTD), each linked by a triple helix coiled coil (THCC). We report the X-ray crystal structure of Pgp3 from a LGV1 strain at the highest X-ray diffraction resolution obtained to date for the full protein. The protein was crystallised using a high KBr salt concentration, which resulted in a new crystal form with relatively low solvent content diffracting to a resolution of 1.98 Å. We describe the 3D structure of this new crystal form, compare it with other crystal forms, describe the KBr salt binding sites and the relevance to chlamydia isolates from around the globe. The crystal packing is apparently driven by the CTDs. Since the three fold axes of the THCC and NTD are not collinear with a CTD’s three fold axis this naturally leads to a disorder in the THCC and the portion of the NTD not directly interacting with the CTD via crystal packing. The key avenue to resolve these oddities of the crystal structure analysis was a complete new analysis in space group P1 and determining the space group as P212121. This space group assignment was the one originally determined from the diffraction pattern but perhaps complicated by a translational non crystallographic symmetry. We found this crystal structure of a three domain multi macromolecular complex, with two misaligned three fold axes, a unique challenge, something not encountered before. A specific intermolecular interaction, possibly of functional significance in receptor binding in chlamydia, we suggest might allow design of a new chemotherapeutic agent against chlamydia.
Wang X, Boffito M, Dickinson L, et al., 2018, Plasma NRTI concentrations and renal function in people with HIV, Publisher: WILEY, Pages: S16-S17, ISSN: 1464-2662
Singh GKJ, Kaye S, Abbott JC, et al., 2018, Use of next-generation sequencing in the CHAT study (acute HCV in HIV): effect of baseline resistance-associated NS3 variants on treatment failure, HIV CLINICAL TRIALS, Vol: 19, Pages: 46-51, ISSN: 1528-4336
Ahmad SF, Brown JK, Campbell LL, et al., 2018, Pelvic Chlamydial Infection Predisposes to Ectopic Pregnancy by Upregulating Integrin beta 1 to Promote Embryo-tubal Attachment, EBIOMEDICINE, Vol: 29, Pages: 159-165, ISSN: 2352-3964
Wang X, Nwokolo N, Korologou-Linden R, et al., 2018, InterPrEP: internet-based pre-exposure prophylaxis with generic tenofovir disoproxil fumarate/emtrictabine in London - analysis of pharmacokinetics, safety and outcomes, HIV MEDICINE, Vol: 19, Pages: 1-6, ISSN: 1464-2662
Sweeney N, Meng J, Patterson H, et al., 2017, Delivery of large transgene cassettes by foamy virus vector, Scientific Reports, Vol: 7, ISSN: 2045-2322
Viral vectors are effective tools in gene therapy, but their limited packaging capacity can be restrictive. Larger clinically-relevant vectors are needed. Foamy viruses have the largest genomes among mammalian retroviruses and their vectors have shown potential for gene therapy in preclinical studies. However, the effect of vector genome size on titre has not been determined. We inserted increasing lengths of the dystrophin open reading frame in a foamy virus vector and quantified packaged vector RNA and integrated DNA. For both measures, a semi-logarithmic reduction in titre was observed as genome size increased. Concentrated titres were reduced 100-fold to approximately 106 transducing units per ml when vector genomes harboured a 12 kb insert, approximately twice that reported for lentivirus vectors in a comparable study. This potential was applied by optimising foamy virus vectors carrying the full-length dystrophin open-reading frame for transduction of human muscle derived cells. Full-length dystrophin protein was expressed and transduced cells remained able to form myotubes in vitro. Foamy virus vectors are well-suited for stable delivery of large transgene cassettes and warrant further investigation for development as a therapy for Duchenne or Becker muscular dystrophy.
Sweeney NP, Meng J, Patterson H, et al., A gene therapy vector for large transgenes-foamy virus vector delivers full-legth dystrophin to muscle derived cells, Nature Scientific Reports
Aloysius I, Zdravkov J, Whitlock G, et al., 2017, InterPrEP (II): internet-based pre-exposure prophylaxis (PrEP) with generic tenofovir DF/emtricitabine (TDF/FTC) in London: analysis of safety and outcomes, Publisher: WILEY, Pages: 25-25, ISSN: 1464-2662
Cooke GS, Gurrala R, Harrison E, et al., 2016, Novel pH sensing semiconductor for point-of-care detection of HIV-1 viremia, Scientific Reports, Vol: 6, ISSN: 2045-2322
The timely detection of viremia in HIV-infected patients receiving antiviral treatment is key to ensuring effective therapy and preventing the emergence of drug resistance. In high HIV burden settings, the cost and complexity of diagnostics limit their availability. We have developed a novel complementary metal-oxide semiconductor (CMOS) chip based, pH-mediated, point-of-care HIV-1 viral load monitoring assay that simultaneously amplifies and detects HIV-1 RNA. A novel low-buffer HIV-1 pH-LAMP (loop-mediated isothermal amplification) assay was optimised and incorporated into a pH sensitive CMOS chip. Screening of 991 clinical samples (164 on the chip) yielded a sensitivity of 95% (in vitro) and 88.8% (on-chip) at >1000 RNA copies/reaction across a broad spectrum of HIV-1 viral clades. Median time to detection was 20.8 minutes in samples with >1000 copies RNA. The sensitivity, specificity and reproducibility are close to that required to produce a point-of-care device which would be of benefit in resource poor regions, and could be performed on an USB stick or similar low power device.
Wang X, Nwokolo N, Korologou-Linden R, et al., 2016, InterPrEP: internet-based pre-exposure prophylaxis (PrEP) with generic tenofovir DF/emtricitabine (TDF/FTC) in London -analysis of pharmacokinetics, safety and outcomes, Publisher: JOHN WILEY & SONS LTD
Sweeney NP, Regan C, Liu J, et al., 2016, Rapid and efficient stable gene transfer to mesenchymal stromal cells using a modified foamy virus vector, Molecular Therapy, Vol: 24, Pages: 1227-1236, ISSN: 1525-0024
Mesenchymal stromal cells (MSCs) hold great promise for regenerative medicine. Stable ex vivo gene transfer to MSCs could improve the outcome and scope of MSC therapy, but current vectors require multiple rounds of transduction, involve genotoxic viral promoters and/or the addition of cytotoxic cationic polymers in order to achieve efficient transduction. We describe a self-inactivating foamy virus vector (FVV), incorporating the simian macaque foamy virus envelope and using physiological promoters, which efficiently transduces murine MSCs (mMSCs) in a single-round. High and sustained expression of the transgene, whether GFP or the lysosomal enzyme, arylsulphatase A (ARSA), was achieved. Defining MSC characteristics (surface marker expression and differentiation potential), as well as long-term engraftment and distribution in the murine brain following intracerebroventricular delivery, are unaffected by FVV transduction. Similarly, greater than 95% of human MSCs (hMSCs) were stably transduced using the same vector, facilitating human application. This work describes the best stable gene transfer vector available for mMSCs and hMSCs.
Wang X, Penchala SD, Amara A, et al., 2016, A Validated Method for Quantification of Dolutegravir Using Ultra Performance Liquid Chromatography Coupled With UV Detection, Therapeutic Drug Monitoring, Vol: 38, Pages: 327-331, ISSN: 1536-3694
Nwokolo N, Wang X, Boffito M, et al., 2016, ESTABLISHMENT OF A MONITORING SERVICE FOR MEN WHO HAVE SEX WITH MEN (MSM) TAKING GENERIC CO-FORMULATED TENOFOVIR DISOPROXIL FUMARATE (TDF)/EMTRICITABINE (FTC) AS PRE-EXPOSURE PROPHYLAXIS (PREP) AGAINST HIV INFECTION, Publisher: BMJ PUBLISHING GROUP, Pages: A6-A6, ISSN: 1368-4973
Bissett SL, 2016, HPV vaccine-induced cross-neutralising antibodies target complex epitopes on the major capsid protein
The current human papillomavirus (HPV) vaccines consist of major capsid protein (L1) virus-like particles (VLP) and target the two most prevalent oncogenic genotypes, HPV16 and HPV18. Prophylactic HPV vaccination is highly effective at preventing HPV16 and HPV18 infection and associated cervical disease, with type-specific neutralising antibodies thought to be the immune mediators of vaccine type protection. A degree of vaccine-induced cross-protection has also been demonstrated against genetically-related genotypes in the Alpha-7 (HPV18-like) and Alpha-9 (HPV16-like) species groups and although the underlying immune mechanism is uncertain, cross-protection is coincident with the detection of cross-neutralising antibodies. The aim of this thesis was to delineate the HPV L1 domains that are recognised by inter-genotype cross-neutralising antibodies. The formal analysis of the vaccine-induced A9 L1 antibody response demonstrated that cross-neutralising antibodies were a minor component of the total HPV16 antibody response and comprised antibody specificities which recognised single and multiple non-vaccine genotypes. The bioinformatic examination of A9 capsid amino acid sequences demonstrated that the L1L2 pseudovirions (PsV) used to measure cross-neutralising responses were generally representative of available contemporary sequences. The potential impact of amino acid variation within the L1 capsid protein was investigated for HPV31 and found differences in cross-neutralising antibody recognition of the L1 variants; however, this was of a low magnitude. L1 crystallographic homology models predicted structural changes in the loops between HPV16 and the non-vaccine A9 genotypes, informing the design and generation of chimeric PsV with inter-genotype loop swaps. These chimeric PsV demonstrated that cross-neutralising antibodies recognise DE and FG loop amino acid residues within close proximity to each other on the capsid surface. These data contribute to our understan
Quinn K, Winston A, Kaye S, et al., 2016, Slow emergence of resistance to C34-PEG4-Chol; a novel HIV fusion inhibitor, 22nd Annual Conference of the British HIV Association (BHIVA), Publisher: Wiley, Pages: 29-29, ISSN: 1464-2662
Singh G, Nelson M, Hicks G, et al., 2016, Baseline telaprevir (TVR) resistance mutations do not predict failure in the response guided treatment of genotype 1 acute hepatitis C (HCV) in individuals with HIV co-infection, HIV Medicine, Vol: 17, Pages: 26-26, ISSN: 1464-2662
Horner PJ, Wills GS, Righarts A, et al., 2016, Chlamydia trachomatis Pgp3 antibody persists and correlates with self-reported infection and behavioural risks in a blinded cohort study, PLOS One, Vol: 11, ISSN: 1932-6203
Erlwein O, Sweeney NP, de Leon R, et al., 2015, Determination of sequences required for HERV-K transduction and its recognition by foreign retroviral virions, Journal of Virology, Vol: 90, Pages: 3243-3246, ISSN: 1098-5514
Sequences necessary for transduction of HERV-Kcon, a consensus of the HERV-K(HML-2) family were analysed and found to reside in the leader/gag region. They act in an orientation-dependent way and consist of at least two sites working together. Having defined these sequences, we exploited this information to produce a simple system to investigate to what extent virions of HERV-Kcon, MLV and HIV-1 have the ability to transduce each other's genomes, leading to potential contamination of gene therapy vectors.
Hoehn KB, Gall A, Bashford-Rogers R, et al., 2015, Dynamics of immunoglobulin sequence diversity in HIV-1 infected individuals, PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 370, ISSN: 0962-8436
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