The relationship between gadolinium enhancement and [18 F]fluorothymidine uptake in brain lesions with the use of hybrid PET/MRI.

BACKGROUND: To evaluate and compare the diagnostic power of [18F]FLT-PET with ceMRI in patients with brain tumours or other focal lesions. METHODS: 121 patients with suspected brain tumour or those after brain tumour surgery were enroled in this retrospective study (61 females, 60 males, mean age 37.3 years, range 1-80 years). All patients underwent [18F]FLT-PET/MRI with gadolinium contrast agent application. In 118 of these patients, a final diagnosis was made, verified by histopathology or by follow-up. Agreement between ceMRI and [18F]FLT-PET of the whole study group was established. Further, sensitivity and specificity of ceMRI and [18F]FLT-PET were calculated for differentiation of high-grade vs. low-grade tumours, high-grade vs. low-grade tumours together with non-tumour lesions and for differentiation of high-grade tumours from all other verified lesions. RESULTS: [18F]FLT-PET and ceMRI findings were concordant in 119 cases (98%). On closer analysis of a subset of 64 patients with verified gliomas, the sensitivity and specificity of both PET and ceMRI were identical (90% and 84%, respectively) for differentiating low-grade from high-grade tumours, if the contrast enhancement and [18F]FLT uptake were considered as hallmarks of high-grade tumour. For differentiation of high-grade tumours from low-grade tumours and lesions of nontumorous aetiology (e.g., inflammatory lesions or post-therapeutic changes) in a subgroup of 93 patients by visual evaluation, the sensitivity of both PET and ceMRI was 90%, whereas the specificity of PET was slightly higher (61%) compared to ceMRI (57%). By receiver operating characteristic analysis, the sensitivity and specificity were 82% and 74%, respectively, when the threshold of SUVmax in the tumour was set to 0.9 g/ml. CONCLUSION: We demonstrated a generally very high correlation of [18F]FLT accumulation with contrast enhancement visible on ceMRI and a comparable diagnostic yield in both modalities for differentiating high-grade tumours from low-grade tumours and lesions of other aetiology.

Human leukocyte antigen HLA-B*57:01 status in HIV-1 patients developing hypersensitivity reactions in Benin: a pilot study.

BACKGROUND: Antiretroviral drugs in people living with HIV-1 (PLHIV-1) often trigger side effects which may lead to discontinuation or failure of treatment. Human Leukocyte Antigen B*57:01 (HLA-B*57:01) allele is known to predict hypersensitivity reactions to Abacavir. Very few data are available on the prevalence of HLA-B*57:01 allele in PLHIV-1 in African countries. This study aimed to screen for HLA-B*57:01 allele in PLHIV-1 in Benin. METHODS: This pilot study was carried out on one hundred ten PLHIV-1 enrolled in two health facilities in Benin. Socio-demographic and clinical data were collected. Biological data were determined and HLA-B*57:01 allele was genotyped, using Single Specific Primer-Polymerase Chain Reaction in blood samples. RESULTS: 70% of participants were female. PLHIV-1 were under TDF + 3TC + DTG (47.2%) or TDF + 3TC + EFV (57.3%). Their median age was 41 [36-48.75] years and the average CD4 + T cell count was 249 [130-381.25] cells/µl. The average viral load in treatment failure PLHIV-1 was 4.7 [3.9-5.2] Log10. At the inclusion date, twenty-nine (26.4%) PLHIV-1 under TDF + 3TC + EFV have developed hypersensitivity reactions. None of 110 patients had shown HLA-B*5701 allele. CONCLUSION: Our study revealed that HLA-B*57:01 allele was very rare in PLHIV-1 in Benin, suggesting that its screening before starting the Abacavir regimen did not seem necessary.

Long-term effectiveness, safety, and tolerability of doravirine in antiretroviral-experienced people with HIV in real life.

Real-life data on doravirine (DOR) in different drug combinations are limited. We evaluated the effectiveness of DOR plus two nucleos(t)ide reverse transcriptase inhibitors (NRTI), mainly abacavir/lamivudine, and dual therapies in people with HIV (PWH), mostly virologically suppressed. Ambispective observational study that enrolled adults PWH who initiated a DOR-based regimen from September 2020 to February 2022 at a referral center in Spain. Participants were grouped as follows: A, received DOR plus two NRTI; B, dual therapy (DT) with DOR plus dolutegravir (DTG) or darunavir/cobicistat (DRVc); C, DOR plus ≥two antiretroviral drugs. The primary endpoints were treatment effectiveness at week 48 by intention-to-treat (ITT) and per-protocol analysis (OT). A cohort of 187 participants, 91% virologically suppressed, were analyzed after a median follow-up of 112 weeks (80-136). Group A received DOR plus abacavir/lamivudine (ABV/3TC) (n = 109) or tenofovir/emtricitabine (TFV/3TC) (n = 45). At week 48, the effectiveness of DOR plus ABV/3TC by ITT was 90.8% (CI95, 88.0-93.6), better than with TFV/FTC [73.3% (66.7-79.9); P = 0.003]. Only one virologic failure was observed. Mild adverse effects were the cause of treatment discontinuation in 7.8%, followed by switching to a single-tablet regimen. In group B, the effectiveness by ITT was 92.9% (CI95, 88.0-97.8) at week 48. No adverse effects or virologic failure were registered in this group. DOR plus two NRTI or DT have long-term effectiveness and safety as a switching option for PWH, mostly virologically suppressed. The DOR plus ABV/3TC combination has shown even better effectiveness than TFV/FTC.IMPORTANCEDOR-based regimens have shown long-term effectiveness and safety in PWH, mostly virologically suppressed. The combination of DOR plus ABV/3TC has shown even better safety and effectiveness than TFV/FTC. DOR plus two NRTI offers cost benefits compared to other regimens.

Baseline and on Treatment Biodistribution Variability of 18 F-FLT Uptake in Patients With Advanced Melanoma: Brief Communication.

PURPOSE: This prospective study evaluates the biodistribution of 18 F-FLT PET in patients with advanced melanoma before and after treatment with BRAF/MEK inhibitors. PATIENTS AND METHODS: Eighteen BRAF-positive unresectable stage IIIc or IV melanoma patients referred for 18 F-FLT PET/CT before (BL) and during (D14) BRAF/MEK inhibition were included. 18 F-FLT accumulation in the liver, bone marrow, blood, and muscle was quantified. RESULTS: Baseline interpatient 18 F-FLT uptake had a coefficient-of-variation between 17.5% and 21.5%. During treatment, liver uptake increased (SUV meanBL = 4.86 ± 0.98, SUV meanD14 = 6.31 ± 1.36, P < 0.001) and bone marrow uptake decreased (SUV meanBL = 7.67 ± 1.65, SUV meanD14 = 6.78 ± 1.19, P < 0.025). Both changes were unrelated to baseline metabolic tumor volume or tumor response. CONCLUSIONS: To assess 18 F-FLT PET, both liver and bone marrow uptake may be used as normal tissue references at baseline, but 18 F-FLT biodistribution significantly changes in longitudinal response studies when treated with BRAF/MEK inhibitors.

Noninvasive Stratification of Colon Cancer by Multiplex PET Imaging.

PURPOSE: The current approach for molecular subtyping of colon cancer relies on gene expression profiling, which is invasive and has limited ability to reveal dynamics and spatial heterogeneity. Molecular imaging techniques, such as PET, present a noninvasive alternative for visualizing biological information from tumors. However, the factors influencing PET imaging phenotype, the suitable PET radiotracers for differentiating tumor subtypes, and the relationship between PET phenotypes and tumor genotype or gene expression-based subtyping remain unknown. EXPERIMENTAL DESIGN: In this study, we conducted 126 PET scans using four different metabolic PET tracers, [18F]fluorodeoxy-D-glucose ([18F]FDG), O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET), 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT), and [11C]acetate ([11C]ACE), using a spectrum of five preclinical colon cancer models with varying genetics (BMT, AKPN, AK, AKPT, KPN), at three sites (subcutaneous, orthograft, autochthonous) and at two tumor stages (primary vs. metastatic). RESULTS: The results demonstrate that imaging signatures are influenced by genotype, tumor environment, and stage. PET imaging signatures exhibited significant heterogeneity, with each cancer model displaying distinct radiotracer profiles. Oncogenic Kras and Apc loss showed the most distinctive imaging features, with [18F]FLT and [18F]FET being particularly effective, respectively. The tissue environment notably impacted [18F]FDG uptake, and in a metastatic model, [18F]FET demonstrated higher uptake. CONCLUSIONS: By examining factors contributing to PET-imaging phenotype, this study establishes the feasibility of noninvasive molecular stratification using multiplex radiotracer PET. It lays the foundation for further exploration of PET-based subtyping in human cancer, thereby facilitating noninvasive molecular diagnosis.

Dominant roles of BRCA1 in cellular tolerance to a chain-terminating nucleoside analog, alovudine.

Alovudine is a chain-terminating nucleoside analog (CTNA) that is frequently used as an antiviral and anticancer agent. Generally, CTNAs inhibit DNA replication after their incorporation into nascent DNA during DNA synthesis by suppressing subsequent polymerization, which restricts the proliferation of viruses and cancer cells. Alovudine is a thymidine analog used as an antiviral drug. However, the mechanisms underlying the removal of alovudine and DNA damage tolerance pathways involved in cellular resistance to alovudine remain unclear. Here, we explored the DNA damage tolerance pathways responsible for cellular tolerance to alovudine and found that BRCA1-deficient cells exhibited the highest sensitivity to alovudine. Moreover, alovudine interfered with DNA replication in two distinct mechanisms: first: alovudine incorporated at the end of nascent DNA interfered with subsequent DNA synthesis; second: DNA replication stalled on the alovudine-incorporated template strand. Additionally, BRCA1 facilitated the removal of the incorporated alovudine from nascent DNA, and BRCA1-mediated homologous recombination (HR) contributed to the progressive replication on the alovudine-incorporated template. Thus, we have elucidated the previously unappreciated mechanism of alovudine-mediated inhibition of DNA replication and the role of BRCA1 in cellular tolerance to alovudine.

Paediatric abacavir-lamivudine fixed-dose dispersible tablets and ritonavir-boosted lopinavir granules in neonates exposed to HIV (PETITE study): an open-label, two-stage, single-arm, phase 1/2, pharmacokinetic and safety trial.

BACKGROUND: Existing solid antiretroviral fixed-dose combination formulations are preferred over liquid formulations in children, but their suitability for neonates is unknown. We evaluated the pharmacokinetics and safety of paediatric abacavir-lamivudine fixed-dose dispersible tablets and ritonavir-boosted lopinavir granules in neonates. METHODS: In this open-label, two-stage, single-arm, phase 1/2, pharmacokinetic and safety trial, generic abacavir- lamivudine (120:60 mg) double-scored dispersible tablets and lopinavir boosted with ritonavir (40:10 mg) granules were studied. Neonates exposed to HIV (≥37 weeks gestational age) of no more than 3 days of age with birthweights of 2000-4000 g were identified through routine care in a tertiary hospital in Cape Town, South Africa. In stage 1, the pharmacokinetics and safety of two single doses were assessed to select the multidose strategy for stage 2. Neonates received a single dose of abacavir-lamivudine (30:15 mg, a quarter of a tablet) and lopinavir boosted with ritonavir (40:10 mg - one sachet) orally between 3 days and 14 days of age, and a second dose of a quarter tablet of abacavir-lamivudine and lopinavir boosted with ritonavir (80:20 mg, two sachets) 10-14 days later in stage 1. The multidose strategy selected in stage 2 was a quarter of the abacavir-lamivudine (30:15 mg) fixed-dose dispersible tablet once per day and two sachets of the lopinavir boosted with ritonavir (80:20 mg) granules twice per day from birth to age 28 days. In both stages two intensive pharmacokinetic visits were done, one at less than 14 days of life (pharmacokinetics 1) and another 10-14 days later (pharmacokinetics 2). Safety visits were done 1-2 weeks after each pharmacokinetic visit. Primary objectives were to assess pharmacokinetics and safety of abacavir, lamivudine, and lopinavir. Pharmacokinetic endpoints were area under the concentration time curve (AUC), maximum concentration, and concentration at end of dosing interval in all participants with at least one evaluable pharmacokinetic visit. Safety endpoints included grade 3 or worse adverse events, and grade 3 or worse treatment-related adverse events, occurring between study drug initiation and end of study. This completed trial is registered with the Pan African Clinical Trials Registry (PACTR202007806554538). FINDINGS: Between Aug 18, 2021, and Aug 18, 2022, 24 neonates were enrolled into the trial and received study drugs. Eight neonates completed stage 1, meeting interim pharmacokinetic and safety criteria. In stage 2, 16 neonates received study drugs. Geometric mean abacavir and lamivudine exposures (AUC0-24) were higher at 6-14 days (51·7 mg × h/L for abacavir and 17·2 mg × h/L for lamivudine) than at 19-24 days of age (25·0 mg × h/L and 11·3 mg × h/L), whereas they were similar for lopinavir over this period (AUC 0-12 58·5 mg × h/L vs 46·4 mg × h/L). Abacavir geometric mean AUC0-24 crossed the upper reference range at pharmacokinetics 1, but rapidly decreased. Lamivudine and lopinavir AUC0-tau were within range. No grade 2 or worse adverse events were related to study drugs. One neonate had a grade 1 prolonged corrected QT interval using the Fridericia method that spontaneously resolved. INTERPRETATION: Abacavir-lamivudine dispersible tablets and ritonavir-boosted lopinavir granules in neonates were safe and provided drug exposures similar to those in young infants. Although further safety data are needed, this regimen presents a new option for HIV prevention and treatment from birth. Accelerating neonatal pharmacokinetic studies of novel antiretroviral therapies is essential for neonates to also benefit from state-of-the-art treatments. FUNDING: Unitaid.

High efficacy of particle beam therapies against tumors under hypoxia and prediction of the early stage treatment effect using 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography.

OBJECTIVE: Compared with radiation therapy using photon beams, particle therapies, especially those using carbons, show a high relative biological effectiveness and low oxygen enhancement ratio. Using cells cultured under normoxic conditions, our group reported a greater suppressive effect on cell growth by carbon beams than X-rays, and the subsequent therapeutic effect can be predicted by the cell uptake amount of 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) the day after treatment. On the other hand, a hypoxic environment forms locally around solid tumors, influencing the therapeutic effect of radiotherapy. In this study, the influence of tumor hypoxia on particle therapies and the ability to predict the therapeutic effect using 18F-FLT were evaluated. METHODS: Using a murine colon carcinoma cell line (colon 26) cultured under hypoxic conditions (1.0% O2 and 5.0% CO2), the suppressive effect on cell growth by X-ray, proton, and carbon irradiation was evaluated. In addition, the correlation between decreased 18F-FLT uptake after irradiation and subsequent suppression of cell proliferation was investigated. RESULTS: Tumor cell growth was suppressed most efficiently by carbon-beam irradiation. 18F-FLT uptake temporarily increased the day after irradiation, especially in the low-dose irradiation groups, but then decreased from 50 h after irradiation, which is well correlated with the subsequent suppression on tumor cell growth. CONCLUSIONS: Carbon beam treatment shows a strong therapeutic effect against cells under hypoxia. Unlike normoxic tumors, it is desirable to perform 18F-FLT positron emission tomography 2-3 days after irradiation for early prediction of the treatment effect.

Proliferation and apoptosis after whole-body irradiation: longitudinal PET study in a mouse model.

PURPOSE: A reliable method for regional in vivo imaging of radiation-induced cellular damage would be of great importance for the detection of therapy-induced injury to healthy tissue and the choice of adequate treatment of radiation emergency patients in both civilian and military events. This study aimed to investigate in a mouse model if positron emission tomography (PET) imaging with proliferation and apoptosis markers is potentially suitable for this purpose. METHODS: Four groups, including twenty mice (wild-type C57BL/6) each, were whole-body irradiated with 0 Gy, 0.5 Gy, 1 Gy, and 3 Gy and examined by PET over a six-month period at defined time points. 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) and 2-(5-[18F]fluoropentyl)-2-methyl malonic acid ([18F]ML-10) were used to visualise proliferation and apoptosis. Regional standard uptake values were compared with respect to irradiation dose over time. Histologic data and peripheral blood cell values were correlated with the PET results. RESULTS: The hematopoietic bone marrow showed a significantly increased [18F]FLT signal at early time points after radiation exposure (day 3 and day 7). This correlated with blood parameters, especially leukocytes, and histological data. A significantly increased [18F]FLT signal also occurred in the gastrointestinal tract and thymus at early time points. An increased [18F]ML-10 signal related to irradiation doses was observed in the bone marrow on day 8, but there was a high variability of standard uptake values and no correlation with histological data. CONCLUSION: [18F]FLT showed potential to visualise the extent, regional distribution and recovery from radiation-induced cellular damage in the bone marrow, gastrointestinal tract and thymus. The potential of [18F]FLT imaging to assess the extent of bone marrow affected by irradiation might be especially useful to predict the subsequent severity of hematopoietic impairment and to adapt the therapy of the bone marrow reserve. [18F]ML-10 PET proved to be not sensitive enough for the reliable detection of radiation induced apoptosis.

Initial antiretroviral therapy regimen and risk of heart failure.

OBJECTIVES: Heart failure risk is elevated in people with HIV (PWH). We investigated whether initial antiretroviral therapy (ART) regimens influenced heart failure risk. DESIGN: Cohort study. METHODS: PWH who initiated an ART regimen between 2000 and 2016 were identified from three integrated healthcare systems. We evaluated heart failure risk by protease inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTI), and integrase strand transfer inhibitor (INSTI)-based ART, and comparing two common nucleotide reverse transcriptase inhibitors: tenofovir disoproxil fumarate (tenofovir) and abacavir. Follow-up for each pairwise comparison varied (i.e. 7 years for protease inhibitor vs. NNRTI; 5 years for tenofovir vs. abacavir; 2 years for INSTIs vs. PIs or NNRTIs). Hazard ratios were from working logistic marginal structural models, fitted with inverse probability weighting to adjust for demographics, and traditional cardiovascular risk factors. RESULTS: Thirteen thousand six hundred and thirty-four PWH were included (88% men, median 40 years of age; 34% non-Hispanic white, 24% non-Hispanic black, and 24% Hispanic). The hazard ratio (95% CI) were: 2.5 (1.5-4.3) for protease inhibitor vs. NNRTI-based ART (reference); 0.5 (0.2-1.8) for protease inhibitor vs. INSTI-based ART (reference); 0.1 (0.1-0.8) for NNRTI vs. INSTI-based ART (reference); and 1.7 (0.5-5.7) for tenofovir vs. abacavir (reference). In more complex models of cumulative incidence that accounted for possible nonproportional hazards over time, the only remaining finding was evidence of a higher risk of heart failure for protease inhibitor compared with NNRTI-based regimens (1.8 vs. 0.8%; P  = 0.002). CONCLUSION: PWH initiating protease inhibitors may be at higher risk of heart failure compared with those initiating NNRTIs. Future studies with longer follow-up with INSTI-based and other specific ART are warranted.

In vivo detection of poststroke cerebral cell proliferation in rodents and humans.

OBJECTIVE: F-18-fluorothymidine (FLT) is a positron emission tomography (PET) tracer for imaging cell proliferation in vivo. We aimed to assess FLT uptake as a marker for cerebral cell proliferation in a rat model of ischemic stroke and patients with cerebral infarct, correlating with disease severity and outcomes. METHODS: Cerebral FLT PET was performed in rats subjected to transient middle cerebral artery occlusion (MCAO) and patients with cerebral infarct. PET data were analyzed and expressed as average standardized uptake value ratios (SUVRs) using cerebellar cortex as reference. Infarct volume was analyzed by 2,3,5-triphenyltetrazolium chloride staining in rats and by magnetic resonance imaging in patients. Neurological function was assessed using modified Neurological Severity Score (mNSS) for rats and National Institutes of Health Stroke Scale (NIHSS) for patients. RESULTS: Seven days post-MCAO, rats' FLT PET displayed higher SUVRs in the infarcted brain, declining gradually until Day 28. FLT-binding ratio (SUVR in the infarcted brain divided by that in contralateral side) correlated positively with stroke severity (p < 0.001), and to early mNSS decline in rats with mild to moderate stroke severity (p = 0.031). In 13 patients with cerebral infarct, FLT PET showed high SUVR in the infarcted regions. FLT-binding ratio correlated positively with infarct volume (p = 0.006). Age-adjusted initial NIHSS (p = 0.035) and early NIHSS decline (p = 0.076) showed significance or a trend toward positive correlation with the FLT-binding ratio. INTERPRETATION: In vivo FLT PET detects poststroke cerebral cell proliferation, which is associated with stroke severity and/or outcomes in MCAO rats and patients with cerebral infarct.

Cost-effectiveness analysis of antiretroviral drugs for treatment-naive HIV infection in China.

INTRODUCTION: Dolutegravir (DTG)-based regimen was included in the expanded formulary of China's National Free Antiretroviral Treatment Program at the end of 2021. Yet high price of DTG and lack of health economic evaluation in China present barriers for implementation of the regimen. The study aims to investigate the lifetime cost-effectiveness of DTG-based regimen for treatment-naive HIV infection in China. METHODS: A decision-analytic Markov model was used to obtain the costs and effectiveness of four regimens: Arm A, efavirenz (EFV)-based regimen; Arm B, DTG-based regimen; Arm C, elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (EVG/c/FTC/TAF) regimen; Arm D, abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) regimen. The potential impact of national centralized drug procurement policy was assessed in scenario analysis. The results were further validated through sensitivity analysis. RESULTS: Compared with other three regimens, DTG-based regimen led to the fewest cumulative adverse reactions, opportunistic infections and deaths. Compared with EFV-based regimen, the base-case ICERs for DTG-based regimen were 13,357 (USD/QALY) and 13,424 (USD/QALY) from the healthcare system and societal perspective respectively. In the policy scenario analysis with the procurement price of DTG equal to that of LPV/r, DTG-based regimen would be dominant. The model results remained robust in sensitivity analyses. CONCLUSIONS: DTG-based regimen for treatment-naive patients is likely to be cost-effective and deserve wider implementation in China. This study strongly suggests the centralized procurement of DTG to minimize cost and maximize cost-effectiveness.

Abacavir Drug Exposures in African Children Under 14 kg Using Pediatric Solid Fixed Dose Combinations According to World Health Organization Weight Bands.

BACKGROUND: The pharmacokinetics of abacavir (ABC) in African children living with HIV (CLHIV) weighing <14 kg and receiving pediatric fixed dose combinations (FDC) according to WHO weight bands dosing are limited. An ABC population pharmacokinetic model was developed to evaluate ABC exposure across different World Health Organization (WHO) weight bands. METHODS: Children enrolled in the LIVING study in Kenya and Uganda receiving ABC/lamivudine (3TC) dispersible tablets (60/30 mg) according to WHO weight bands. A population approach was used to determine the pharmacokinetic parameters. Monte Carlo simulations were conducted using an in silico population with demographic characteristics associated with African CLHIV. ABC exposures (AUC0-24) of 6.4-50.4 mg h/L were used as targets. RESULTS: Plasma samples were obtained from 387 children. A 1-compartment model with allometric scaling of clearance (CL/F) and volume of distribution (V/F) according to body weight best characterized the pharmacokinetic data of ABC. The maturation of ABC CL/F was characterized using a sigmoidal Emax model dependent on postnatal age (50% of adult CL/F reached by 0.48 years of age). Exposures to ABC were within the target range for children weighing 6.0-24.9 kg, but children weighing 3-5.9 kg were predicted to be overexposed. CONCLUSIONS: Lowering the ABC dosage to 30 mg twice daily or 60 mg once daily for children weighing 3-5.9 kg increased the proportion of children within the target and provided comparable exposures. Further clinical study is required to investigate clinical implications and safety of the proposed alternative ABC doses.

Pharmacokinetics, safety, and tolerability of dispersible and immediate-release abacavir, dolutegravir, and lamivudine tablets in children with HIV (IMPAACT 2019): week 24 results of an open-label, multicentre, phase 1-2 dose-confirmation study.

BACKGROUND: Child-friendly fixed-dose combination (FDC) antiretroviral therapy (ART) options are limited. We evaluated the pharmacokinetics, safety, and tolerability of dispersible and immediate-release FDC abacavir, dolutegravir, and lamivudine taken once per day in children younger than 12 years with HIV. METHODS: IMPAACT 2019 was an international, phase 1-2, multisite, open-label, non-comparative dose-confirmation study of abacavir, dolutegravir, and lamivudine in children younger than 12 years. Participants were enrolled across five weight bands: those weighing 6 kg to less than 25 kg received abacavir (60 mg), dolutegravir (5 mg), and lamivudine (30 mg) dispersible tablets (three to six tablets depending on body weight), and those weighing 25 kg to less than 40 kg received abacavir (600 mg), dolutegravir (50 mg), and lamivudine (300 mg) in an immediate-release tablet. At entry, participants were ART naive or ART experienced and virologically suppressed on stable ART for 6 months or more. Dose confirmation was based on pharmacokinetic and safety criteria in the first five to seven participants in each weight band to week 4; all participants were followed up to week 48. We present the results for the primary objectives to assess pharmacokinetics, confirm dosing, and evaluate safety through 24 weeks across all weight bands. The trial is registered with ClinicalTrials.gov (NCT03760458). FINDINGS: 57 children were enrolled and initiated study drug (26 [46%] female and 31 [54%] male; 37 [65%] Black, 18 [32%] Asian, and 1 [2%] had race reported as unknown). Within each weight band, 6 kg to less than 10 kg, 10 kg to less than 14 kg, 14 kg to less than 20 kg, 20 kg to less than 25 kg, and 25 kg or higher: the geometric mean dolutegravir area under the concentration time curve over the 24 h dosing interval (AUC0-24 h) was 75·9 h·µg/mL (33·7%), 91·0 h·µg/mL (36·5%), 71·4 h·µg/mL (23·5%), 84·4 h·µg/mL (26·3%), and 71·8 h·µg/mL (13·9%); dolutegravir concentrations 24 h after dosage (C24 h) were 0·91 µg/mL (67·6%), 1·22 µg/mL (77·5%), 0·79 µg/mL (44·2%), 1·35 µg/mL (95·5%), and 0·98 µg/mL (27·9%); abacavir AUC0-24 h was 17·7 h·µg/mL (38·8%), 19·8 h·µg/mL (50·6%), 15·1 h·µg/mL (40·3%), 17·4 h·µg/mL (19·4%), and 25·7 h·µg/mL (14·6%); lamivudine AUC0-24 h was 10·7 h·µg/mL (46·0%), 14·2 h·µg/mL (23·9%), 13·0 h·µg/mL (15·6%), 14·5 h·µg/mL (16·6%), and 21·7 h·µg/mL (26·2%), respectively. Pharmacokinetic targets and safety criteria were met within each weight band, and thus dosing of abacavir, dolutegravir, and lamivudine was confirmed at the originally selected doses. 54 (95%) of participants were treatment experienced and all who continued taking the study drug remained virologically suppressed (<200 copies per mL) through week 24. Virological suppression was achieved in two of three participants who were ART naive by week 24. There were no grade 3 or higher adverse events related to abacavir, dolutegravir, and lamivudine and no discontinuations because of toxicity to week 24. Both formulations were well tolerated. INTERPRETATION: Dosing of abacavir, dolutegravir, and lamivudine was confirmed in children weighing 6 kg to less than 40 kg, and both FDC formulations were safe, well tolerated, and efficacious through 24 weeks of treatment. These findings support global efforts to expand the availability of FDC abacavir, dolutegravir, and lamivudine to children with HIV. FUNDING: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, ViiV Healthcare, and GlaxoSmithKline.

The Prevalence of HLA-B*57 Serotype Associated with Hypersensitivity Reactions in the Treatment of HIV Infection in the Turkish Population.

OBJECTIVES: The aim of our study is to reveal the prevalence of HLA-B*57 in the Turkish population and to provide new perspectives to physicians starting abacavir therapy in HIV patients. BACKGROUND: Abacavir, one of the drugs used to treat HIV infection, can cause hypersensitivity reactions in some patients. These hypersensitivity reactions have been shown to be associated with the HLA-B*57:01 allele. High-resolution HLA-B*57:01 scanning has a time and cost disadvantage compared with low-resolution HLA-B*57 scanning. Before starting abacavir treatment, we will discuss whether high-resolution scanning is more beneficial in individuals who are positive on HLAB* 57 screening. This is the study with the largest cohort to investigate the prevalence of HLA-B*57 in Turkey. METHODS: The results of 25 thousand 318 people who applied to Bursa Uludag University Faculty of Medicine, Department of Immunology for HLA-B* typing were scanned. RESULTS: In our study, the HLA-B*57 serotype was detected in 827 (3.3%) individuals. CONCLUSION: Considering these results, it can be assumed that the prevalence of HLA-B*57:01 in Turkey is lower than 3.3%. Instead of a high-resolution HLA-B*57:01 scan in all patients starting abacavir therapy, a high-resolution HLA-B*57:01 scan might be of greater benefit in patients who are positive on a low-resolution HLA-B*57 scan.

Visualization research on ENT1/NIS dual-function gene therapy to reverse drug resistance mediated by MUC1 in GEM-resistant pancreatic cancer.

PURPOSE: To use bifunctional target genes to increase the intracellular transport of gemcitabine (GEM) to reverse chemotherapy resistance and to simultaneously use reporter gene imaging to localize therapeutic genes. The therapeutic effect was evaluated by [18F]FLT PET/CT to visualize the effect of gene therapy. METHODS: A viral gene vector containing the pancreatic cancer-targeting promoter MUC1 for specific transcription of equilibrative nucleoside transporter 1 (ENT1) and NIS (nuclide transport channel) was employed. [125I]NaI uptake tests and [131I]NaI SPECT imaging were performed to verify the function of NIS and the target function of MUC1. The correlation between [18F]FLT uptake and GEM resistance were assessed, and the influence ENT1 and thymidine kinase 1 (TK1) expression on [18F]FLT micro-PET/CT was measured, which provides a theoretical basis for the use of [18F]FLT micro-PET/CT to evaluate the efficacy of gene therapy. RESULTS: First, functions of gene therapy were confirmed: ENT1 reversed the drug resistance of GEM-resistant pancreatic cancer cells by increasing GEM intracellular transport; MUC1 drove NIS target gene expression in pancreatic cancer; and therapeutic genes could be localized using [131I]NaI SPECT reporter gene imaging. Second, the [18F]FLT uptake ratio was affected by drug resistance and GEM treatment. The mechanism underlying this effect was related to ENT1 and TK1. Increased expression of ENT1 inhibited the expression of TK1 after GEM chemotherapy to reduce the uptake of [18F]FLT. Finally, micro-PET/CT indicated that the SUVmax of [18F]FLT could predict survival time. SUVmax exhibited an increasing trend in resistant pancreatic cancer but a trend of inhibition after upregulation of ENT1, which was more significant after GEM treatment. CONCLUSIONS: Bifunctional targeted genes can localize therapeutic genes through reporter gene imaging, reverse the drug resistance of GEM-resistant pancreatic cancer and be visually evaluated through [18F]FLT micro-PET/CT.

Abacavir safety and effectiveness in young infants with HIV in South African observational cohorts.

BACKGROUND: WHO guidelines recommend abacavir in first-line antiretroviral treatment for children and neonates. However, there is no approved dose <3 months of age, and data in neonates are limited. METHODS: We included infants who initiated ART aged <3 months, between 2006 and 2019, in nine South African cohorts. In those who received abacavir or zidovudine, we described antiretroviral discontinuation rates; and 6- and 12-month viral suppression (<400 copies/mL). We compared infants aged <28 and ≥28 days, those weighing <3 and ≥3 kg. RESULTS: Overall 837/1643 infants (51%) received abacavir and 443 (27%) received zidovudine. Median (interquartile range, IQR) age was 52 days (23-71), CD4 percentage was 27.9 (19.2-38.0), and weight was 4.0 kg (3.0-4.7) at ART initiation. In those with ≥1 month's follow-up, 100/718 (14%) infants discontinued abacavir, at a median of 17.5 months (IQR 6.5-39.5). Abacavir discontinuations did not differ by age or weight category (p = 0.4 and 0.2, respectively); and were less frequent than zidovudine discontinuations (adjusted hazard ratio 0.14, 95% confidence interval 0.10-0.20). Viral suppression at 12 months occurred in 43/79 (54%) and 130/250 (52%) of those who started abacavir aged <28 and ≥28 days, respectively (p = 0.8); 11/19 (58%) and 31/60 (52%) in those who weighed <3 and ≥3 kg, respectively (p = 0.6); and 174/329 (53%) in those on abacavir versus 77/138 (56%) in those on zidovudine (adjusted odds ratio 1.8, 95% confidence interval 1.0-3.2). CONCLUSION: Our data suggest that abacavir may be used safely in infants <28 days old or who weigh <3 kg.