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AIDS Research and Therapy May 2024Despite the decreased incidence of the human immunodeficiency virus (HIV) in Tanzania, the number of adolescents living with HIV is increasing. This study aimed to...
BACKGROUND
Despite the decreased incidence of the human immunodeficiency virus (HIV) in Tanzania, the number of adolescents living with HIV is increasing. This study aimed to describe factors independently associated with viral load non-suppression among adolescents living with HIV (ALHIV) on ART in the Tanga region.
METHODS
We conducted a retrospective study of routinely collected data from ALHIV on ART from October 2018 to April 2022. We extracted data from the Care and Treatment Clinics form number 2 (CTC2) database that included age, sex, BMI, World Health Organization HIV clinical disease stage, marital status, ART duration, viral load suppression, facility level, and Dolutegravir (DTG)-based regimen. We did descriptive analysis using frequencies to describe the study participants' socio-demographic and clinical characteristics. The Cox proportional hazard regression model was used to identify factors associated with viral load non-suppression (VLS). Viral load non-suppression was defined as viral load ≥ 1000 copies/ml. A total of 4735 ALHIV on ART were extracted from CTC2, then 2485 were excluded (2186 missed viral load results, 246 were lost to follow-up, and 53 deaths).
RESULTS
2250 ALHIV on ART were tested for viral load, of whom 2216 (98.62%) adolescents were on first-line ART, and 2024 (89.96%) participants were virally suppressed, while 226 (10.04%) were virally non-suppressed. In addition, 2131 (94.71%) of participants were using a DTG-based regimen; of them, 1969 (92.40%) were virally suppressed. Not using a DTG-based regimen (HR: 9.36, 95% CI 3.41-15.31) and dispensary facility level (HR: 3.61, 95% CI 1.44-7.03) were independently associated with increased hazard for viral load non-suppression. In addition, adolescents aged between 15 and 19 years are less likely to be virally suppressed (HR: 0.55, 95% CI 0.30-0.99).
CONCLUSIONS
The dispensary facility level and not using a DTG-based regimen were significantly associated with viral load non-suppression. HIV intervention strategies should ensure a DTG-based regimen utilization in all adolescents living with HIV, and techniques used by higher-level health facilities should be disseminated to lower-level facilities.
Topics: Humans; Adolescent; Tanzania; Female; Viral Load; Retrospective Studies; Male; HIV Infections; Anti-HIV Agents; Young Adult; Pyridones; Oxazines; Heterocyclic Compounds, 3-Ring; Proportional Hazards Models; Piperazines
PubMed: 38778318
DOI: 10.1186/s12981-024-00622-7 -
AIDS Research and Therapy May 2024Peritoneal dialysis (PD) is an effective renal replacement modality in people with HIV (PWH) with end-stage kidney disease (ESKD), particularly those with residual...
INTRODUCTION
Peritoneal dialysis (PD) is an effective renal replacement modality in people with HIV (PWH) with end-stage kidney disease (ESKD), particularly those with residual kidney function. Data on pharmacokinetics (PK) of antiretrovirals in patients on peritoneal dialysis are limited.
METHODS
A single-participant study was performed on a 49-year-old gentleman with ESKD on PD and controlled HIV on once daily dolutegravir (DTG) 50 mg + tenofovir alafenamide (TAF) 25 mg / emtricitabine (FTC) 200 mg. He underwent serial blood plasma, peripheral blood mononuclear cell, and urine PK measurements over 24 h after an observed DTG + FTC/TAF dose.
RESULTS
Plasma trough (Cmin) concentrations of TAF, tenofovir (TFV), FTC, and DTG were 0.05, 164, 1,006, and 718 ng/mL, respectively. Intracellular trough concentrations of TFV-DP and FTC-TP were 1142 and 11,201 fmol/million cells, respectively. Compared to published mean trough concentrations in PWH with normal kidney function, observed TFV and FTC trough concentrations were 15.5- and 20-fold higher, while intracellular trough concentrations of TFV-DP and FTC-TP were 2.2-fold and 5.4-fold higher, respectively. TFV and FTC urine levels were 20 times lower than in people with normal GFR.
CONCLUSIONS
In a single ESKD PWH on PD, daily TAF was associated with plasma TFV and intracellular TFV-DP trough concentrations 15-fold and 2-fold higher than those of people with uncompromised kidney function, potentially contributing to nephrotoxicity. This suggests that TFV accumulates on PD; thus, daily TAF in PD patients may require dose adjustment or regimen change to optimize treatment, minimize toxicity, and preserve residual kidney function.
Topics: Humans; Male; Heterocyclic Compounds, 3-Ring; Oxazines; Pyridones; Middle Aged; Tenofovir; Emtricitabine; Peritoneal Dialysis; Piperazines; HIV Infections; Anti-HIV Agents; Alanine; Adenine; Kidney Failure, Chronic
PubMed: 38773606
DOI: 10.1186/s12981-024-00616-5 -
Cancer Medicine May 2024Cyclin-dependent kinase (CDK) 4/6 inhibitor plus endocrine therapy (ET) become standard-of-care for patients with hormone receptor-positive, human epidermal growth... (Comparative Study)
Comparative Study
Abemaciclib plus endocrine therapy versus chemotherapy after progression on prior palbociclib in HR+/HER2- metastatic breast cancer: A single center real-world study in China.
BACKGROUND
Cyclin-dependent kinase (CDK) 4/6 inhibitor plus endocrine therapy (ET) become standard-of-care for patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (MBC). However, the optimal therapeutic paradigm after progression on CDK4/6 inhibitor remains unclear. This study aimed to evaluate the efficacy and safety of abemaciclib with switching ET versus chemotherapy after progression on prior palbociclib-based ET in Chinese patients with HR+/HER2- MBC.
METHODS
From 414 consecutive patients with HR+/HER2- MBC who had been treated with palbociclib plus ET from September 2018 to May 2022 in Peking University Cancer Hospital, we identified 80 patients who received abemaciclib plus switching ET or chemotherapy after progression on palbociclib, matched for age, original stage at diagnosis, disease-free interval, and tumor burden at 1:1 ratio. The primary endpoint was progression-free survival (PFS) compared using the Kaplan-Meier method. A Cox proportional hazard model was performed to identify clinical factors associated with PFS in the abemaciclib group.
RESULTS
The median PFS was 6.0 months (95% confidence interval [CI]: 3.94-8.06) in abemaciclib group and 4.0 months (95% CI, 2.52-5.49) in chemotherapy group (p = 0.667). And, there was no difference in median PFS between the sequential and nonsequential arm (6.0 vs. 6.0 months) in the abemaciclib group though fewer lines of prior systemic therapy and longer PFS from prior palbociclib in the sequential arm. However, patients with prior palbociclib as the first-line therapy had a significantly longer median PFS versus prior palbociclib as ≥2nd-line therapy (11.0 vs. 5.0 months, p = 0.043). Based on multivariable analysis, ER+/PR+ was an independent factor associated with longer PFS. There was no significant difference in overall survival between the abemaciclib and chemotherapy groups (p = 0.069).
CONCLUSION
Our findings indicate that abemaciclib plus switching ET might be one of feasible treatment options for Chinese patients with HR+/HER2- MBC after progression on prior palbociclib-based therapy in addition to chemotherapy.
Topics: Humans; Female; Breast Neoplasms; Middle Aged; Piperazines; Pyridines; Antineoplastic Combined Chemotherapy Protocols; Aminopyridines; Receptor, ErbB-2; Benzimidazoles; China; Receptors, Estrogen; Progression-Free Survival; Receptors, Progesterone; Aged; Adult; Retrospective Studies; Disease Progression; Antineoplastic Agents, Hormonal
PubMed: 38770648
DOI: 10.1002/cam4.7249 -
Nature Communications May 2024Deficiencies in the BRCA1 tumor suppressor gene are the main cause of hereditary breast and ovarian cancer. BRCA1 is involved in the Homologous Recombination DNA repair...
Deficiencies in the BRCA1 tumor suppressor gene are the main cause of hereditary breast and ovarian cancer. BRCA1 is involved in the Homologous Recombination DNA repair pathway and, together with BARD1, forms a heterodimer with ubiquitin E3 activity. The relevance of the BRCA1/BARD1 ubiquitin E3 activity for tumor suppression and DNA repair remains controversial. Here, we observe that the BRCA1/BARD1 ubiquitin E3 activity is not required for Homologous Recombination or resistance to Olaparib. Using TULIP2 methodology, which enables the direct identification of E3-specific ubiquitination substrates, we identify substrates for BRCA1/BARD1. We find that PCNA is ubiquitinated by BRCA1/BARD1 in unperturbed conditions independently of RAD18. PCNA ubiquitination by BRCA1/BARD1 avoids the formation of ssDNA gaps during DNA replication and promotes continuous DNA synthesis. These results provide additional insight about the importance of BRCA1/BARD1 E3 activity in Homologous Recombination.
Topics: Humans; BRCA1 Protein; Ubiquitin-Protein Ligases; Proliferating Cell Nuclear Antigen; DNA Replication; Ubiquitination; Tumor Suppressor Proteins; Phthalazines; Piperazines; Homologous Recombination; Female; HEK293 Cells; Cell Line, Tumor; DNA
PubMed: 38769345
DOI: 10.1038/s41467-024-48427-6 -
Natural Products and Bioprospecting May 2024Four extracts of the marine-derived fungus Penicillium velutinum J.F.H. Beyma were obtained via metal ions stress conditions based on the OSMAC (One Strain Many...
Four extracts of the marine-derived fungus Penicillium velutinum J.F.H. Beyma were obtained via metal ions stress conditions based on the OSMAC (One Strain Many Compounds) strategy. Using a combination of modern approaches such as LC/UV, LC/MS and bioactivity data analysis, as well as in silico calculations, influence metal stress factors to change metabolite profiles Penicillium velutinum were analyzed. From the ethyl acetate extract of the P. velutinum were isolated two new piperazine derivatives helvamides B (1) and C (2) together with known saroclazin A (3) (4S,5R,7S)-4,11-dihydroxy-guaia-1(2),9(10)-dien (4). Their structures were established based on spectroscopic methods. The absolute configuration of helvamide B (1) as 2R,5R was determined by a combination of the X-ray analysis and by time-dependent density functional theory (TD-DFT) calculations of electronic circular dichroism (ECD) spectra. The cytotoxic activity of the isolated compounds against human prostate cancer PC-3 and human embryonic kidney HEK-293 cells and growth inhibition activity against yeast-like fungi Candida albicans were assayed.
PubMed: 38769256
DOI: 10.1007/s13659-024-00449-9 -
The Pan African Medical Journal 2024Adolescent girls and young women in Africa are at high risk of HIV and should be considered a key population for HIV prevention initiatives. Oral Tenofovir/Emtricitabine...
Adolescent girls and young women in Africa are at high risk of HIV and should be considered a key population for HIV prevention initiatives. Oral Tenofovir/Emtricitabine as pre-exposure prophylaxis (PrEP) has been shown to be effective on an individual and population level among key populations in Europe, Australia, and the US. However, studies in sub-Saharan Africa in a generalised epidemic have been less promising with adherence to daily tablets identified as a major problem. Long-acting PrEP drugs are being developed as a response to this problem. The first of these long-acting agents, injectable Cabotegravir given every two months has shown superiority to oral PreP and has been approved by the US Food and Drug Administration (FDA). Another long-acting PrEP drug in development is Lenacapavir which is an investigational, first-in-class long-acting HIV-1 capsid inhibitor that can be given as a six-monthly injection. These long-acting drugs could be a highly effective public health HIV prevention intervention. If made readily available to a vulnerable population of adolescent young women who are at high risk of HIV they could play an important role in protecting this key population against HIV and potentially reduce the population level risk of HIV.
Topics: Humans; Pre-Exposure Prophylaxis; Female; HIV Infections; Adolescent; Anti-HIV Agents; Pyridones; Medication Adherence; Africa South of the Sahara; Delayed-Action Preparations; Diketopiperazines
PubMed: 38766564
DOI: 10.11604/pamj.2024.47.102.36052 -
The Journal of Clinical Investigation May 2024The diversity of structural variants (SVs) in melanoma and how they impact oncogenesis are incompletely known. We performed harmonized analysis of SVs across melanoma...
The diversity of structural variants (SVs) in melanoma and how they impact oncogenesis are incompletely known. We performed harmonized analysis of SVs across melanoma histologic and genomic subtypes, and we identified distinct global properties between subtypes. These included the frequency and size of SVs and SV classes, their relation to chromothripsis events, and the impact on cancer-related genes of SVs that alter topologically associated domain (TAD) boundaries. Following our prior identification of double-stranded break repair deficiency in a subset of triple-wild-type cutaneous melanoma, we identified MRE11 and NBN loss-of-function SVs in melanomas with this mutational signature. Experimental knockouts of MRE11 and NBN, followed by olaparib cell viability assays in melanoma cells, indicated that dysregulation of each of these genes may cause sensitivity to PARP inhibitors in cutaneous melanomas. Broadly, harmonized analysis of melanoma SVs revealed distinct global genomic properties and molecular drivers, which may have biological and therapeutic impact.
Topics: Melanoma; Humans; Cell Line, Tumor; Skin Neoplasms; Carcinogenesis; MRE11 Homologue Protein; Cell Cycle Proteins; Neoplasm Proteins; Phthalazines; Nuclear Proteins; Genomic Structural Variation; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 38758740
DOI: 10.1172/JCI177270 -
Journal of Medicinal Chemistry Jun 2024The trafficking chaperone PDE6D (or PDEδ) was proposed as a surrogate target for K-Ras, leading to the development of a series of inhibitors that block its prenyl...
The trafficking chaperone PDE6D (or PDEδ) was proposed as a surrogate target for K-Ras, leading to the development of a series of inhibitors that block its prenyl binding pocket. These inhibitors suffered from low solubility and suspected off-target effects, preventing their clinical development. Here, we developed a highly soluble, low nanomolar PDE6D inhibitor (PDE6Di), Deltaflexin3, which has the lowest off-target activity as compared to three prominent reference compounds. Deltaflexin3 reduces Ras signaling and selectively decreases the growth of mutant and -dependent cancer cells. We further show that PKG2-mediated phosphorylation of Ser181 lowers K-Ras binding to PDE6D. Thus, Deltaflexin3 combines with the approved PKG2 activator Sildenafil to more potently inhibit PDE6D/K-Ras binding, cancer cell proliferation, and microtumor growth. As observed previously, inhibition of Ras trafficking, signaling, and cancer cell proliferation remained overall modest. Our results suggest reevaluating PDE6D as a K-Ras surrogate target in cancer.
Topics: Humans; Cyclic Nucleotide Phosphodiesterases, Type 6; Sildenafil Citrate; Proto-Oncogene Proteins p21(ras); Cell Proliferation; Cell Line, Tumor; Antineoplastic Agents; Mutation; Animals; Structure-Activity Relationship; Phosphodiesterase Inhibitors
PubMed: 38758695
DOI: 10.1021/acs.jmedchem.3c02129 -
The Journal of Antimicrobial... Jul 2024Poor adherence to ART and pre-exposure prophylaxis (PrEP) can impact patient and public health. Point-of-care testing (POCT) may aid monitoring and adherence... (Randomized Controlled Trial)
Randomized Controlled Trial
Tenofovir, emtricitabine, lamivudine and dolutegravir concentrations in plasma and urine following drug intake cessation in a randomized controlled directly observed pharmacokinetic trial to aid point-of-care testing.
BACKGROUND
Poor adherence to ART and pre-exposure prophylaxis (PrEP) can impact patient and public health. Point-of-care testing (POCT) may aid monitoring and adherence interventions.
OBJECTIVES
We report the pharmacokinetics of tenofovir [dosed as tenofovir disoproxil (TDF) and tenofovir alafenamide (TAF)], emtricitabine (FTC), lamivudine (3TC) and dolutegravir (DTG) in plasma and urine following drug cessation to evaluate adherence targets in urine for POCT.
METHODS
Subjects were randomized (1:1) to receive DTG/FTC/TAF or DTG/3TC/TDF for 15 days. Plasma and spot urine were collected on Day 15 (0-336 h post final dose). Drug concentrations were quantified using LC-MS, and non-linear mixed-effects models applied to determine drug disposition between matrices and relationship with relevant plasma [dolutegravir protein-adjusted 90% inhibitory concentration (PA-IC90 = 64 ng/mL) and minimum effective concentration (MEC = 324 ng/mL)] and urinary thresholds [tenofovir disoproxil fumarate 1500 ng/mL].
RESULTS
Of 30 individuals enrolled, 29 were included (72% female at birth, 90% Caucasian). Median (range) predicted time to plasma dolutegravir PA-IC90 and MEC were 83.5 (41.0-152) and 49.0 h (23.7-78.9), corresponding to geometric mean (90%) urine concentrations of 5.42 (4.37-6.46) and 27.4 ng/mL (22.1-32.7). Tenofovir in urine reached 1500 ng/mL by 101 h (58.6-205) with an equivalent plasma concentration of 6.20 ng/mL (4.21-8.18).
CONCLUSIONS
These data support use of a urinary tenofovir threshold of <1500 ng/mL (tenofovir disoproxil fumarate-based regimens) as a marker of three or more missed doses for a POCT platform. However, due to low dolutegravir concentrations in urine, POCT would be limited to a readout of recent dolutegravir intake (one missed dose).
Topics: Humans; Pyridones; Oxazines; Heterocyclic Compounds, 3-Ring; Male; Emtricitabine; Adult; Piperazines; Lamivudine; Point-of-Care Testing; Female; HIV Infections; Tenofovir; Anti-HIV Agents; Middle Aged; Pre-Exposure Prophylaxis; Young Adult; Plasma; Medication Adherence
PubMed: 38758205
DOI: 10.1093/jac/dkae147 -
Journal of Investigative Medicine High... 2024Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract and arise from the interstitial cells of Cajal in the mesenteric...
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract and arise from the interstitial cells of Cajal in the mesenteric plexus. These tumors can originate in any part of the GI tract; however, a higher burden has been observed in the stomach and small intestines. Mesenteric GISTs are exceedingly rare, with unique clinicopathological features and a poorer prognosis. Herein, we describe a unique case of a 66-year-old female with a remote history of appendectomy who presented to the emergency room complaining of severe abdominal pain and vomiting. On imaging, the patient was found to have a large inflammatory mass associated with small bowel loops, and the pathology confirmed a mesenteric GIST. The tumor was resected, and the genomic test results confirmed the KIT (exon 11) mutation. Although the tumor had a low mitotic rate, the tumor was large enough to warrant the initiation of adjuvant imatinib mesylate for 36 months with regular bloodwork and imaging.
Topics: Humans; Gastrointestinal Stromal Tumors; Female; Aged; Abdomen, Acute; Imatinib Mesylate; Mesentery; Proto-Oncogene Proteins c-kit; Tomography, X-Ray Computed; Mutation; Antineoplastic Agents
PubMed: 38757744
DOI: 10.1177/23247096241253348