Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 887
Filter
1.
Biochem Pharmacol ; 227: 116440, 2024 Jul 17.
Article in English | MEDLINE | ID: mdl-39029631

ABSTRACT

Gastric ulcer is a highly prevalent digestive tract disease across the world, which is recurrent and hard to cure, sometimes transforming into gastric cancer if left untreated, posing great threat to human health. To develop new medicines for gastric ulcer, we ran a series of screens with ethanol stress model in GES-1 cells, and we uncovered that lamivudine rescued cells from ethanol toxicity. Then, we confirmed this discovery using the well-established ethanol-induced gastric ulcer model in mice and our findings suggest that lamivudine can directly activate phosphoglycerate kinase 1 (PGK1, EC 2.7.2.3), which binds and stimulates superoxide dismutase 1 (SOD1, EC 1.15.1.1) to inhibit ferroptosis and ultimately improve gastric ulcer. Moreover, AAV-PGK1 exhibited comparable gastroprotective effects to lamivudine. The findings are expected to offer novel therapeutic strategies for gastric ulcer, encompassing both lamivudine and AAV-PGK1.

2.
Eur J Med Res ; 29(1): 374, 2024 Jul 18.
Article in English | MEDLINE | ID: mdl-39026368

ABSTRACT

BACKGROUND: Renally adjusted lamivudine dosages are effective. However, some of the kidney failure patients managed with lamivudine-containing regimens are failing to suppress HIV in peritoneal dialysis (CAPD) effluent. The steady-state lamivudine pharmacokinetics among these patients was evaluated. METHODS: This overnight open-label pharmacokinetic study enrolled participants living with HIV and managed with CAPD. Lamivudine levels in blood serum and CAPD effluent samples were quantified using liquid chromatography coupled with a mass spectrometer. Pharmacokinetic measures were obtained through non-compartmental analysis. RESULTS: Twenty-eight participants were recruited with a median antiretroviral (ARV) drug duration of 8 (IQR,4.5-10.5) years and a CAPD duration of 13.3 (IQR,3.3-31.9) months. 14.3% (4/28) had detectable unsuppressed HIV-1 viral load in CAPD effluents. The majority (78,6%,22/28) of participants received a 50 mg dose, while 10.7% (3/28), and another 10.7% (3/28) received 75 mg and 300 mg dosages, respectively. Among those treated with 75 and 300 mg, 66.7% (2/3) and 33.3% (1/3) had detectable HIV-VL in CAPD, respectively. The peritoneal membrane characteristics and CAPD system strengths were variable across the entire study population. Lamivudine exposure was increased in blood serum (50 mg-AUC0-24 h, 651.3 ng/mL; 75 mg-AUC0-24 h, 677.84 ng/mL; 300 mg-AUC0-24 h, 3135.89 ng/mL) compared to CAPD effluents (50 mg-AUC0-24 h, 384.91 ng/mL; 75 mg-AUC0-24 h, 383.24 ng/mL; 300 mg-AUC0-24 h, 2001.60 ng/mL) among the entire study population. The Cmax (50 mg, 41.5 ng/mL; 75 mg, 53.2 ng/mL; 300 mg, 199.1 ng/mL) and Cmin (50 mg, 17.8 ng/mL; 75 mg, 16.4 ng/mL; 300 mg, 76.4 ng/mL) measured in serum were within the therapeutic levels. CONCLUSIONS: Steady-state lamivudine pharmacokinetic measures were variable among the entire study population. However, the total lamivudine exposure was within the therapeutic levels.


Subject(s)
HIV Infections , HIV-1 , Kidney Failure, Chronic , Lamivudine , Peritoneal Dialysis , Humans , Lamivudine/pharmacokinetics , Lamivudine/therapeutic use , Lamivudine/administration & dosage , Male , Middle Aged , Female , HIV-1/drug effects , Kidney Failure, Chronic/therapy , Adult , HIV Infections/drug therapy , RNA, Viral/blood , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/therapeutic use , Anti-HIV Agents/blood , Anti-HIV Agents/administration & dosage , Viral Load
3.
Infect Dis Ther ; 13(8): 1877-1891, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38961048

ABSTRACT

INTRODUCTION: Once-daily fixed-dose combinations (FDC) containing abacavir (ABC), dolutegravir (DTG), and lamivudine (3TC) have been approved in the US for adults and children with HIV weighing ≥ 6 kg. This analysis assessed the ability of previously developed ABC, DTG, and 3TC pediatric population pharmacokinetic (PopPK) models using multiple formulations to describe and predict PK data in young children using dispersible tablet (DT) and tablet formulations of ABC/DTG/3TC FDC in the IMPAACT 2019 study. METHODS: IMPAACT 2019 was a Phase I/II study assessing the PK, safety, tolerability, and efficacy of ABC/DTG/3TC FDC in children with HIV-1. Intensive and sparse PK samples were collected over 48 weeks. Existing drug-specific pediatric PopPK models for ABC (2-compartment), DTG (1-compartment), and 3TC (1-compartment) were applied to the IMPAACT 2019 drug concentration data without re-estimation (external validation) of PopPK parameters. Drug exposures were then simulated across World Health Organization weight bands for children weighing ≥ 6 to < 40 kg for each drug and compared with pre-defined exposure target ranges. RESULTS: Goodness-of-fit and visual predictive check plots demonstrated that the previously developed pediatric PopPK models sufficiently described and predicted the data. Thus, new PopPK models describing the IMPAACT 2019 data were unnecessary. Across weight bands, the predicted geometric mean (GM) for ABC AUC0-24 ranged from 14.89 to 18.50 µg*h/ml, DTG C24 ranged from 0.74 to 0.95 µg/ml, and 3TC AUC0-24 ranged from 10.50 to 13.20 µg*h/ml. These exposures were well within the pre-defined target ranges set for each drug. CONCLUSION: This model-based approach leveraged existing pediatric data and models to confirm dosing of ABC/DTG/3TC FDC formulations in children with HIV-1. This analysis supports ABC/DTG/3TC FDC dosing in children weighing ≥ 6 kg.

4.
BMC Infect Dis ; 24(1): 720, 2024 Jul 22.
Article in English | MEDLINE | ID: mdl-39039487

ABSTRACT

BACKGROUND: Antiretroviral therapy (ART) has transformed HIV management, with various regimens available. Dolutegravir (DTG) plus lamivudine (3TC) dual therapy is now the one of the first line regimens. METHODS: A retrospective, observational study included treatment naïve people living with HIV (PLWH) with baseline HIV RNA viral load (VL) greater than 500,000 copies/mL from March 2020 to June 2022. PLWH on DTG + 3TC were included in the 2DR group, while others on INSTI-based three-drug regimens were divided in the 3DR group. Viral suppression, immunological recovery, and safety were assessed. RESULTS: The study included 52 PLWH, with no significant baseline differences. Virologic suppression rates at weeks 24 and 48 were similar in both groups, even with baseline HIV RNA VL greater than 1,000,000 copies/mL. CD4 + T cell counts improved rapidly. No serious adverse effects were reported. CONCLUSIONS: DTG + 3TC dual therapy demonstrates effectiveness in treatment naïve PLWH with high baseline HIV RNA VL, suggesting its potential as a first line regimen for all treatment naïve PLWH.


Subject(s)
Anti-HIV Agents , HIV Infections , Heterocyclic Compounds, 3-Ring , Lamivudine , Oxazines , Pyridones , Viral Load , Humans , Retrospective Studies , HIV Infections/drug therapy , HIV Infections/virology , Viral Load/drug effects , Female , Male , Pyridones/therapeutic use , Lamivudine/therapeutic use , Lamivudine/administration & dosage , Adult , Heterocyclic Compounds, 3-Ring/therapeutic use , Heterocyclic Compounds, 3-Ring/administration & dosage , Oxazines/therapeutic use , Middle Aged , CD4 Lymphocyte Count , Anti-HIV Agents/therapeutic use , Anti-HIV Agents/administration & dosage , Piperazines/therapeutic use , HIV-1/drug effects , Drug Therapy, Combination , RNA, Viral/blood , Treatment Outcome
5.
Adv Pharmacol ; 100: 1-38, 2024.
Article in English | MEDLINE | ID: mdl-39034049

ABSTRACT

A new drug can have its origin in either pharma, biotech or academia. In general, discovery scientists working in pharma and biotech are advantaged over their academic counterparts and the relative advantages and disadvantages associated are discussed in depth. Against all odds, an increasing number of important drugs have had their origins in academia. This article reports three case studies from the Liotta Research Group (LRG), which explores the special circumstances that allowed these drug development campaigns to be successful. The first involves the antiretroviral agent, emtricitabine. In this case efficient synthetic methodology, developed in the LRG, coupled with some key university and commercial sector partnerships, enabled a group of academic collaborators to discover and develop a highly effective HIV reverse transcriptase inhibitor. The second case study involves the discovery and development of the breakthrough hepatitis C drug, sofosbuvir. Based on key input from Professors Schinazi and Liotta at Emory University, scientists at the Emory startup, Pharmasset, identified the nucleoside core of the drug that would become sofosbuvir. Subsequent analysis of its phosphorylation profile by Pharmasset scientists suggested that converting it to its corresponding monophosphate prodrug would circumvent a kinase block and enable it to be an effective hepatitis C polymerase inhibitor. The third case study describes the formation of DRIVE (Drug Innovation Ventures at Emory)/EIDD (Emory Institute for Drug Development), which were created to circumvent unintended impediments for carrying out academic drug discovery and development. Although DRIVE/EIDD is a wholly-owned, not-for-profit subsidiary of Emory University, it contains many attributes that enables it to operate much more nimbly than a typical academic laboratory. With an experienced drug development team and no shareholders to distract them, DRIVE/EIDD was able to focus its attention of the development of drugs to address viral diseases of global concern. In particular, their strategy to identify and develop an antiviral agent active against multiple single-stranded RNA viruses led to molnupiravir, a broadly active, oral drug that received Emergency Use Authorization for the treatment of SARS-CoV-2 infections (i.e., COVID-19).


Subject(s)
Drug Discovery , Humans , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19 Drug Treatment , Drug Development/methods , Emtricitabine/therapeutic use , Sofosbuvir
6.
BMC Chem ; 18(1): 129, 2024 Jul 08.
Article in English | MEDLINE | ID: mdl-38978116

ABSTRACT

HIV treatment has greatly improved over the years, with the introduction of antiretroviral drugs that target the virus and suppress its replication. Dolutegravir and lamivudine are two such antiretroviral drugs that are commonly used in HIV treatment regimens. Herein, three spectrophotometric methods manipulating ratio spectra were developed for the simultaneous analysis of dolutegravir and lamivudine in their binary mixtures. These methods include mathematical processing stages like ratio difference method or signal processing approaches such as the first derivative of the ratio spectra, and continuous wavelet transform. The developed spectrophotometric methods exploit the characteristic spectral differences between dolutegravir and lamivudine in order to quantify them simultaneously. These methods have shown promising results in terms of sensitivity and selectivity as validated per the ICH guidelines. Moreover, these methods offer a straightforward and economical alternative to more intricate analytical methodologies like high-performance liquid chromatography. By incorporating the analytical eco-scale and AGREE for greenness evaluation of the proposed methods, we can further ensure that these techniques are effective and environmentally friendly, aligning with the principles of green chemistry. This evaluation will provide a comprehensive understanding of the environmental friendliness of these spectrophotometric methods in pharmaceutical analysis.

7.
J Infect Dis ; 2024 Jul 24.
Article in English | MEDLINE | ID: mdl-39047063

ABSTRACT

BACKGROUND: We previously reported the effect of contraception on cervical tenofovir concentrations in Ugandan women living with HIV. Here we explored the role of cervicovaginal cytokines and drug metabolizing enzymes and transporters (DMETs) to elucidate FGT drug disposition in a Ugandan cohort. METHODS: Cervicovaginal fluid and cervical biopsies were collected from Ugandan women living with HIV receiving tenofovir/lamivudine-based therapy and intramuscular depot medroxyprogesterone acetate (DMPA-IM; n=25), copper IUD (cuIUD; n=12), or condoms (n=13) as contraception. Cytokines were measured in cervicovaginal fluid (CVF). Ectocervical tenofovir diphosphate (TFVdp) and lamivudine triphosphate (3TCtp), dATP/dCTP concentrations, and immune marker/DMETs gene expression were measured in cervical biopsies. RESULTS: Cervical 3TCtp was not correlated with any CVF cytokines. Cervical TFVdp was correlated with IL-10, IL-7, and IL-17 in CVF. CCR5 mRNA expression in cervical biopsies was higher in cuIUD-users versus condoms-users. Using multivariable linear regression, CVF IL-17, tissue dATP, plasma estradiol, and plasma tenofovir were all significant predictors of cervical TFVdp. Tissue dCTP and plasma lamivudine were significant predictors of cervical 3TCtp. CONCLUSIONS: TFVdp concentrations in cervix appear to be influenced by local inflammation. In contrast, 3TCtp FGT exposure was not affected by genital inflammation or DMETS. CuIUD users have more immune cells present, which may in turn influence local TFVdp disposition.

8.
Eur J Pharm Sci ; 200: 106835, 2024 Jun 20.
Article in English | MEDLINE | ID: mdl-38908413

ABSTRACT

Lamivudine (LMD), an enantiomer of 2'-deoxy-3'-thiacytidine, plays a crucial role in combatting HIV-1 and managing hepatitis B virus infections. Despite its effectiveness, challenges arise from its difficult flowability and tendency to agglomerate during storage, necessitating a granulation step before tablet compression, as direct compression has proven ineffective. This study aimed to optimize Lamivudine spherical agglomerates using response surface methodology, delving into the intricate relationship between design factors (concentration of tween, span, and acetone) and experimental outcomes (yield and particle size) through central composite design. Analysis of variance (ANOVA) was employed for optimization, with the Quasi-emulsion solvent-diffusion (QESD) crystallization technique utilized for the checkpoint batch. This technique, involving a single solvent and antisolvent with surfactants, showcased remarkable enhancements in flowability and reduced storage agglomeration. The impact of various surfactants [Hydroxy Propyl Methyl Cellulose (HPMC), polysorbate 80, and sorbitane monooleate] on particle morphology, flowability, and storage agglomeration during crystallization was thoroughly assessed. While achieving direct compression into tablets, the porous structure of LMD agglomerates presented challenges in tablet press production speeds, prompting adjustments such as reducing punch speed or implementing a precompression step. Positive outcomes were realized for disintegration and in vitro drug release in comparison to direct compression and wet granulation methods. In conclusion, the QESD crystallization technique successfully yielded hollow, spherical LMD agglomerates with enhanced properties, representing a significant milestone in pharmaceutical formulation.

9.
Open Forum Infect Dis ; 11(5): ofae227, 2024 May.
Article in English | MEDLINE | ID: mdl-38737429

ABSTRACT

TANGO results have established the durable efficacy of dolutegravir/lamivudine in virologically suppressed individuals who switched from 3- or 4-drug tenofovir alafenamide (TAF)-based regimens. In this post hoc subgroup analysis, 144-week efficacy and tolerability of dolutegravir/lamivudine in participants who switched from elvitegravir/cobicistat/emtricitabine/TAF were consistent with the overall switch population. Clinical Trials Registration: NCT03446573.

10.
Cancers (Basel) ; 16(9)2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38730705

ABSTRACT

Outcomes for glioblastoma (GBM) remain poor despite standard-of-care treatments including surgical resection, radiation, and chemotherapy. Intratumoral heterogeneity contributes to treatment resistance and poor prognosis, thus demanding novel therapeutic approaches. Drug repositioning studies on antiretroviral therapy (ART) have shown promising potent antineoplastic effects in multiple cancers; however, its efficacy in GBM remains unclear. To better understand the pleiotropic anticancer effects of ART on GBM, we conducted a comprehensive drug repurposing analysis of ART in GBM to highlight its utility in translational neuro-oncology. To uncover the anticancer role of ART in GBM, we conducted a comprehensive bioinformatic and in vitro screen of antiretrovirals against glioblastoma. Using the DepMap repository and reversal of gene expression score, we conducted an unbiased screen of 16 antiretrovirals in 40 glioma cell lines to identify promising candidates for GBM drug repositioning. We utilized patient-derived neurospheres and glioma cell lines to assess neurosphere viability, proliferation, and stemness. Our in silico screen revealed that several ART drugs including reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs) demonstrated marked anti-glioma activity with the capability of reversing the GBM disease signature. RTIs effectively decreased cell viability, GBM stem cell markers, and proliferation. Our study provides mechanistic and functional insight into the utility of ART repurposing for malignant gliomas, which supports the current literature. Given their safety profile, preclinical efficacy, and neuropenetrance, ARTs may be a promising adjuvant treatment for GBM.

11.
Spectrochim Acta A Mol Biomol Spectrosc ; 317: 124398, 2024 Sep 05.
Article in English | MEDLINE | ID: mdl-38710140

ABSTRACT

In this study, graphene quantum dots (GQDs) were employed for quantitatively analyzing lamivudine using a fluorescence quenching technique. This approach allows for sensitive determination of the concentration of lamivudine in different matrices without requiring derivatization. The mechanism behind the fluorescence intensity quenching between GQDs and lamivudine molecules was explored using the Stern Volmer equation, revealing dynamic quenching behavior. Additionally, various factors affecting fluorescence quenching efficiency such as pH, GQDs concentration, and incubation time were carefully tuned. Moreover, our developed method successfully met ICH guidelines for validation parameters including linearity, accuracy, precision, and selectivity demonstrating excellent performance. The results showed good accuracy and precision, with a mean recovery value of 101.91% for method accuracy and a relative standard deviation of 0.682 and 1.489 for intraday and interday precision, respectively. Finally, the greenness and blueness of the developed method were also investigated to assess its environmental friendliness and analytical practicality. Greenness evaluation using the AGREE tool demonstrated that the developed method has a low environmental impact with an AGREE score of 0.75, Besides, the blueness evaluating using the BAGI tool indicated that the developed method is practical, reliable, and well-suited for routine analysis of lamivudine in various samples.


Subject(s)
Graphite , Lamivudine , Quantum Dots , Spectrometry, Fluorescence , Graphite/chemistry , Quantum Dots/chemistry , Lamivudine/analysis , Spectrometry, Fluorescence/methods , Green Chemistry Technology/methods , Reproducibility of Results , Limit of Detection , Hydrogen-Ion Concentration , Fluorescent Dyes/chemistry
12.
New Microbiol ; 47(1): 111-115, 2024 May.
Article in English | MEDLINE | ID: mdl-38700892

ABSTRACT

Lamivudine (3TC)/dolutegravir (DTG) single tablet regimen (STR) has shown long-term efficacy and tolerability in people living with HIV (PLWH). Dolutegravir has been approved for use in children, while data on the efficacy of 3TC plus DTG in maintaining virological suppression in this population are still under evaluation. In this case series, we describe three children with perinatally acquired HIV who maintained virological suppression after switching antiretroviral therapy to DTG/3TC. We present three case reports of three children enrolled in the Italian Register for HIV Infection in Children: a 9-year-old boy, a 10-year-old girl, and a 2-year-old girl with perinatally acquired HIV who immediately started antiretroviral therapy with a three-drug regimen upon diagnosis, which occurred at delivery, after 6 months of life, and after 2 years of life, respectively. They achieved and maintain virological suppression after 1, 6, and 7 months of therapy, respectively; then a switch strategy was performed with a two-drug regimen with DTG/3TC STR at the age of 7 years for the first child and at the age of 9 years for the second, while the third was switched to a DTG plus 3TC not STR, owing to weight requirements, at the age of 2 years and 10 months. All children maintained virological suppression at last follow-up visit (January 2024), showing an excellent growth curve and maintaining good adherence and tolerability to DTG plus 3TC. A two-drug regimen with DTG/3TC demonstrated efficacy in maintaining virological suppression in a switch strategy in these children, with important advantages such as better tolerability and comfort of taking a single tablet once daily.


Subject(s)
Anti-HIV Agents , HIV Infections , Heterocyclic Compounds, 3-Ring , Lamivudine , Oxazines , Piperazines , Pyridones , Humans , Lamivudine/therapeutic use , Lamivudine/administration & dosage , Heterocyclic Compounds, 3-Ring/therapeutic use , Heterocyclic Compounds, 3-Ring/administration & dosage , Male , Child , Female , HIV Infections/drug therapy , HIV Infections/virology , Child, Preschool , Anti-HIV Agents/therapeutic use , Anti-HIV Agents/administration & dosage , HIV-1/drug effects
13.
Integr Pharm Res Pract ; 13: 31-42, 2024.
Article in English | MEDLINE | ID: mdl-38650710

ABSTRACT

Background: A key strategy for quality improvement is drug use evaluation, which looks at the safe, appropriate use of medication principles. Tenofovir/Lamivudine/Dolutegravir (TLD-FDC) usage has not yet been sufficiently examined in published literature. The purpose of this study was to assess how TLD were used by HIV-positive patients Using WHO drug use evaluation standards in Lumame Primary Hospital, North West Ethiopia. Methods: Using WHO drug use evaluation standards, a retrospective study design was used to evaluate the appropriateness of TLD use. Systematic random sampling was utilized to gather patient medical records containing TLD. Accordingly, 100 records that met the inclusion criteria were selected and reviewed between April 1 and 15, 2021. Five criteria, namely, indication, dose, contraindication, drug interaction, and TLD safety monitoring were used to evaluate the appropriateness of TLD utilization. Results: 80% of patients were transited to TLD from other regimens. The median time on TLD was found to be 13 months with 9 months to 18 months IQR. The latest CD4 count as well as CD4 count at the initiation or transition of TLD was not done for 75% and 89% of the patients, respectively. 3/4 (75%) of the patients were found to have a scheduled medication refill history. TLD dosing, indications, and contraindications were found to be 100% appropriate. No, TLD safety monitoring tests were done for 21% of the patients in this study. However, viral load, liver/kidney function, and serum creatinine tests were done for 77% (95% CI: 74%-79%), 5% (95% CI: 2%-8%), and 14% (95% CI: 11%-17%) of the patients, respectively. More over, In 93% (95% CI: 91%-95%) of the patients, the TLD interaction was appropriate; in 7%, it was not. All recording, documenting, and reporting technologies were available and used efficiently, except for the Electronic Dispensing Tool. Conclusion: Generally, good adherence to national and WHO guidelines was obtained regarding dose, indication, and contraindications. However, improvement in safety monitoring tests and CPT utilization is recommended. Drug interactions satisfied the majority of the criteria's threshold, while certain standards were not followed.

14.
Open Forum Infect Dis ; 11(5): ofae198, 2024 May.
Article in English | MEDLINE | ID: mdl-38680613

ABSTRACT

Background: Lamivudine + dolutegravir maintenance dual therapy (DT) could be less effective than 3-drug therapy (TT) in the context of resistance-associated mutations to nucleoside reverse transcriptase inhibitors (NRTIs). The ARCA database was queried to test this hypothesis with a trial emulation strategy. Methods: People with HIV taking 2 NRTIs plus a protease inhibitor or a non-NRTI who switched to DT or dolutegravir-based TT were followed up from the first HIV RNA <50 copies/mL (baseline) to virologic failure (VF; ie, 2 consecutive HIV RNA ≥50 copies/mL or 1 HIV RNA ≥200 copies/mL). Those switching to DT within 6 months were assigned to the treatment arm and all other patients to the control arm. Each participant was also cloned, assigned to the opposite strategy, and censored at the time of deviation from that strategy. Using inverse probability of censoring weight Cox regression models, we calculated hazard ratios of VF for DT vs TT stratified for the presence of resistance-associated mutations. Results: Overall 626 people were analyzed: 204 with DT and 422 with TT (73% men; mean age, 44 years). Ten and 31 VFs occurred with DT and TT, respectively, over a median 5.8 years. When compared with a fully active TT, the DT had similar efficacy (adjusted hazard ratio, 0.88; 95% CI, .29-2.61; P = .812) when full susceptibility was confirmed at historical genotype. When previous M184V/I was present in both groups, the risk of VF was higher for DT vs TT but was not statistically significant (adjusted hazard ratio, 3.06; 95% CI, .45-20.84; P = .252). Conclusions: DT was not associated with a significantly higher risk of VF than dolutegravir-based TT.

15.
Infect Dis Ther ; 13(4): 891-906, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38570443

ABSTRACT

INTRODUCTION: Dolutegravir/lamivudine (DTG/3TC) and dolutegravir/rilpivirine (DTG/RPV) are fixed-dose, complete, single-tablet, two-drug regimens (2DRs) indicated for HIV-1. DTG/3TC is approved for antiretroviral therapy (ART)-naive people with HIV-1 and virologically suppressed individuals to replace current ART; DTG/RPV is indicated for virologically suppressed individuals as a switch option. Virologic efficacy and effectiveness of these DTG-based 2DRs have been demonstrated in phase 3 clinical trials and real-world cohorts, primarily from Europe. This study characterized real-world use of DTG-based 2DRs for HIV-1 treatment in the USA. METHODS: TANDEM was a retrospective medical chart review across 24 US sites. Individuals aged ≥ 18 years who initiated DTG/3TC or DTG/RPV before September 30, 2020, with ≥ 6 months of follow-up were included. One cohort included ART-naive people who initiated DTG/3TC (n = 126), and two other cohorts included virologically suppressed (HIV-1 RNA < 50 copies/mL) people on stable ART regimens for ≥ 3 months before switch to either DTG/3TC (n = 192) or DTG/RPV (n = 151). Clinical characteristics, treatment history, and outcomes are described. RESULTS: Virologically suppressed individuals were older than those who were ART-naive, and the ART-naive cohort had higher proportions of individuals assigned male at birth and of Hispanic ethnicity. The most common healthcare provider-reported reason for choosing a DTG-based 2DR was avoidance of long-term toxicities (25-33% across cohorts), followed by simplification/streamlining of treatment. Among ART-naive people on DTG/3TC, 94% achieved virologic suppression after initiation, and 83% maintained suppression at last follow-up; discontinuation rate was < 1%. Among cohorts who switched to DTG-based 2DRs, 96% maintained virologic suppression on DTG/3TC and 93% on DTG/RPV; 2% on DTG/3TC and 3% on DTG/RPV discontinued. CONCLUSION: Motivation for selecting DTG-based 2DRs was primarily driven by a desire to avoid or manage toxicities and simplify treatment. Results demonstrate that DTG/3TC and DTG/RPV are effective in real-world settings, with few discontinuations, reflecting data from clinical trials.

16.
Infect Dis Ther ; 13(4): 875-889, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38570444

ABSTRACT

INTRODUCTION: Dolutegravir/lamivudine (DTG/3TC) was first approved by the US Food and Drug Administration in 2019 for the treatment of antiretroviral therapy (ART)-naive people with HIV-1 based on results from the pivotal GEMINI-1/GEMINI-2 trials. Around that time, immediate initiation of treatment upon diagnosis was recommended in the US Department of Health and Human Services guidelines. Here we report results from 126 treatment-naive people with HIV-1 who initiated DTG/3TC as part of a test-and-treat strategy (n = 61) or with high baseline viral loads (HIV-1 RNA ≥ 100,000 copies/ml; n = 16) from the TANDEM study. METHODS: TANDEM was a US-based, retrospective chart review study that included a cohort of 126 individuals aged ≥ 18 years with no prior history of ART who initiated DTG/3TC before September 30, 2020, and had ≥ 6 months of follow-up. Test-and-treat was defined as ART initiation shortly after diagnosis without available viral load, CD4 + cell count, or HIV-1 resistance data. Outcomes included virologic suppression (HIV-1 RNA < 50 copies/ml; overall and by baseline viral load) and discontinuations. Analyses were descriptive. RESULTS: Among 61 individuals who initiated DTG/3TC in a test-and-treat setting (median [interquartile range (IQR)] treatment duration, 1.3 [0.9-1.7] years), 57 (93%) achieved virologic suppression, and 51 (84%) remained suppressed; 1 (< 1%) individual discontinued DTG/3TC due to persistent low-level viremia. The most common healthcare provider (HCP)-reported reason for initiating DTG/3TC was avoidance of long-term toxicities among individuals in the test-and-treat subgroup. Of 16 treatment-naive individuals with high baseline viral loads (median [IQR] treatment duration, 100,000-250,000 copies/ml: 1.2 [0.8-1.8] years; > 250,000 copies/ml: 1.0 [0.7-1.1] years), 14 (88%) achieved virologic suppression, 13 (81%) remained suppressed, and none discontinued DTG/3TC. Patient preference was the most common HCP-reported reason for initiating DTG/3TC in this subgroup. CONCLUSIONS: Results demonstrate real-world effectiveness of DTG/3TC, with few discontinuations, in people with HIV-1 in test-and-treat settings or with high baseline viral loads.

17.
Antimicrob Agents Chemother ; 68(5): e0150423, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38587380

ABSTRACT

A fixed-dose combination (FDC) of 50 mg dolutegravir and 300 mg lamivudine is indicated for the treatment of HIV-1 infection. This analysis aimed to characterize the population pharmacokinetics (PK) of dolutegravir and lamivudine based on data from a phase 3 study (TANGO) in virologically suppressed adults living with HIV-1 switching to dolutegravir/lamivudine FDC. These analyses included 362 participants who contributed 2,629 dolutegravir and 2,611 lamivudine samples collected over 48 weeks. A one-compartment model with first-order absorption and elimination parameterized by apparent oral clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (Ka) described dolutegravir PK. Covariate search yielded body weight, bilirubin, and ethnicity as predictors of CL/F, and weight was predictive for V/F. The estimates of CL/F, V/F, and Ka were 0.858 L/h, 16.7 L, and 2.15 h-1, respectively. A two-compartment model with first-order absorption and elimination parameterized by CL/F, apparent intercompartmental clearance (Q/F), apparent central volume of distribution (V2/F), apparent peripheral volume of distribution (V3/F), and Ka described lamivudine PK. Covariate search yielded eGFR and race as predictors of CL/F, and weight was predictive for V2/F. The estimated parameter values were CL/F = 19.6 L/h, Q/F = 2.97 L/h, V2/F = V3/F = 105 L, and Ka = 2.30 h-1. The steady-state prediction suggested that the effect of covariates dolutegravir and lamivudine exposures was small (<20%) and not clinically relevant. Therefore, no dose adjustments are recommended based on these analyses. The results support the use of dolutegravir/lamivudine FDC in the treatment of HIV-1 infection in adults.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT03446573.


Subject(s)
Anti-HIV Agents , HIV Infections , HIV-1 , Heterocyclic Compounds, 3-Ring , Lamivudine , Oxazines , Piperazines , Pyridones , Humans , Lamivudine/pharmacokinetics , Lamivudine/therapeutic use , Lamivudine/administration & dosage , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/therapeutic use , Oxazines/pharmacokinetics , HIV Infections/drug therapy , HIV Infections/virology , Piperazines/pharmacokinetics , Pyridones/pharmacokinetics , Adult , Male , Female , HIV-1/drug effects , Middle Aged , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/therapeutic use , Anti-HIV Agents/administration & dosage , Drug Combinations
18.
Contemp Clin Trials ; 142: 107540, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38636725

ABSTRACT

BACKGROUND: There is increasing interest in utilising two-drug regimens for HIV treatment with the goal of reducing toxicity and improve acceptability. The D3 trial evaluates the efficacy and safety of DTG/3TC in children and adolescents and includes a nested pharmacokinetics(PK) substudy for paediatric drug licensing. METHODS: D3 is an ongoing open-label, phase III, 96-week non-inferiority randomised controlled trial(RCT) conducted in South Africa, Spain, Thailand, Uganda and the United Kingdom. D3 has enrolled 386 children aged 2- < 15 years, virologically suppressed for ≥6 months, with no prior treatment failure. Participants were randomised 1:1 to receive DTG/3TC or DTG plus two nucleoside reverse transcriptase inhibitors(NRTIs), stratified by region, age (2- < 6, 6- < 12, 12- < 15 years) and DTG use at enrolment (participants permitted to start DTG at enrolment). The primary outcome is confirmed HIV-1 RNA viral rebound ≥50 copies/mL by 96-weeks. The trial employs the Smooth Away From Expected(SAFE) non-inferiority frontier, which specifies the non-inferiority margin and significance level based on the observed event risk in the control arm. The nested PK substudy evaluates WHO weight-band-aligned dosing in the DTG/3TC arm. DISCUSSION: D3 is the first comparative trial evaluating DTG/3TC in children and adolescents. Implications of integrating a PK substudy and supplying data for prompt regulatory submission, were carefully considered to ensure the integrity of the ongoing trial. The trial uses an innovative non-inferiority frontier for the primary analysis to allow for a lower-than-expected confirmed viral rebound risk in the control arm, while ensuring interpretability of results and maintaining the planned sample size in an already funded trial. TRIAL REGISTRATION: International Standard Randomised Clinical Trial Number Register: ISRCTN17157458. European Clinical Trials Database: 2020-001426-57. CLINICALTRIALS: gov: NCT04337450.


Subject(s)
HIV Infections , HIV-1 , Heterocyclic Compounds, 3-Ring , Lamivudine , Oxazines , Piperazines , Pyridones , Humans , Adolescent , HIV Infections/drug therapy , Pyridones/administration & dosage , Pyridones/therapeutic use , Pyridones/pharmacokinetics , Child , Oxazines/administration & dosage , Oxazines/therapeutic use , Child, Preschool , Lamivudine/administration & dosage , Lamivudine/therapeutic use , Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Heterocyclic Compounds, 3-Ring/therapeutic use , Piperazines/administration & dosage , Male , Female , HIV-1/drug effects , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/therapeutic use , Anti-HIV Agents/pharmacokinetics , Viral Load , Equivalence Trials as Topic , RNA, Viral , Drug Therapy, Combination , Drug Combinations , Reverse Transcriptase Inhibitors/administration & dosage , Reverse Transcriptase Inhibitors/therapeutic use , Reverse Transcriptase Inhibitors/pharmacokinetics
19.
Open Forum Infect Dis ; 11(4): ofae160, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38567196

ABSTRACT

Background: Confirming the efficacy of dolutegravir/lamivudine in clinical practice solidifies recommendations on its use. Methods: Prospective cohort study (DUALING) in 24 human immunodeficiency virus (HIV) treatment centers in the Netherlands. HIV RNA-suppressed cases were on triple-drug antiretroviral regimens without prior virological failure or resistance and started dolutegravir/lamivudine. Cases were 1:2 matched to controls on triple-drug antiretroviral regimens by the use of dolutegravir-based regimens, age, sex, transmission route, CD4+ T-cell nadir, and HIV RNA zenith. The primary endpoint was the treatment failure rate in cases versus controls at 1 year by intention-to-treat and on-treatment analyses with 5% noninferiority margin. Results: The 2040 participants were 680 cases and 1380 controls. Treatment failure in the 390 dolutegravir-based cases versus controls occurred in 8.72% and 12.50% (difference: -3.78% [95% confidence interval {CI}, -7.49% to .08%]) by intention-to-treat and 1.39% and 0.80% (difference: 0.59% [95% CI, -.80% to 1.98%]) by on-treatment analyses. The treatment failure risk in 290 non-dolutegravir-based cases was also noninferior to controls. Antiretroviral regimen modifications unrelated to virological failure explained the higher treatment failure rate by intention-to-treat. A shorter time on triple-drug antiretroviral therapy and being of non-Western origin was associated with treatment failure. Treatment failure, defined as 2 consecutive HIV RNA >50 copies/mL, occurred in 4 cases and 5 controls but without genotypic resistance detected. Viral blips occured comparable in cases and controls but cases gained more weight, especially when tenofovir-based regimens were discontinued. Conclusions: In routine care, dolutegravir/lamivudine was noninferior to continuing triple-drug antiretroviral regimens after 1 year, supporting the use of dolutegravir/lamivudine in clinical practice. Clinical Trials Registration: NCT04707326.

20.
HIV Med ; 25(6): 754-758, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38494173

ABSTRACT

OBJECTIVES: Dolutegravir + lamivudine (DTG + 3TC) is a first-line regimen for people with HIV. However, there are still concerns about its efficacy in people with tuberculosis (TB)/HIV due to the lack of available evidence and drug-drug interaction with rifampicin. METHODS: A single-centre retrospective observational case series was conducted in Guangxi Zhuang Autonomous Region, China. We included all people with TB/HIV on combined use of once-daily (q.d.) dosing DTG + 3TC and rifampicin (RIF)-containing anti-TB regimens between 2020 and 2022. HIV-RNA, CD4 cell counts were collected and analysed. RESULTS: In all, 21 people with HIV (PWH) were included in this study. All the PWH were treatment-naïve and told to take DTG + 3TC q.d. with food. The median age was 53 years, and 71.43% were male. A total of 71.43% PWH had baseline viral load (VL) > 100 000 copies/mL, and 33.33% had baseline VL greater than 500 000 copies/mL. Only one PWH had CD4 cell count greater than 200 cells/µL, and the median CD4 count was 20 cells/µL. A total of 16 PWH started DTG + 3TC after initiation of the RIF-based anti-TB regimen, and the other five PWH initiated DTG + 3TC before the treatment of TB. All the PWH had at least 24 weeks of follow-up visits and all of the TB treatments were successful. A total of 20 PWH (95.24%) achieved viral suppression (VL <50 copies/mL). All detected viral loads between weeks 24 and 48 were less than 200 copies/mL. Among the PWH who started DTG + 3TC after the initiation of RIF-based anti-TB regimen, all achieved viral suppression by week 24 except the non-suppressed PWH. CD4 counts were greatly improved after antiretroviral treatment: the median CD4 counts were raised from 20 to 171 cells/µL at week 48. No serious adverse events were reported. CONCLUSIONS: This case series preliminarily validates the efficacy of DTG + 3TC q.d. with food when combined with RIF-based anti-TB regimens in people with TB/HIV.


Subject(s)
HIV Infections , Heterocyclic Compounds, 3-Ring , Lamivudine , Oxazines , Pyridones , Rifampin , Tuberculosis , Viral Load , Humans , Male , Retrospective Studies , Lamivudine/therapeutic use , Lamivudine/administration & dosage , Female , Oxazines/therapeutic use , Middle Aged , Heterocyclic Compounds, 3-Ring/therapeutic use , Heterocyclic Compounds, 3-Ring/administration & dosage , Pyridones/therapeutic use , Pyridones/administration & dosage , Rifampin/therapeutic use , Rifampin/administration & dosage , HIV Infections/drug therapy , HIV Infections/complications , Tuberculosis/drug therapy , Adult , CD4 Lymphocyte Count , Viral Load/drug effects , China , Piperazines , Anti-HIV Agents/therapeutic use , Anti-HIV Agents/administration & dosage , Treatment Outcome , Drug Therapy, Combination , Antitubercular Agents/therapeutic use , Antitubercular Agents/administration & dosage
SELECTION OF CITATIONS
SEARCH DETAIL
...