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Blood Jan 2021Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive T-cell malignancy that arises in a proportion of individuals who are long-term carriers of human...
Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive T-cell malignancy that arises in a proportion of individuals who are long-term carriers of human T-lymphotropic virus type 1. The median survival of aggressive subtypes is 8 to 10 months; with chemotherapy-based approaches, overall survival has remained largely unchanged in the ∼35 years since ATL was first described. Through the use of 4 representative case studies, we highlight advances in the biological understanding of ATL and the use of novel therapies such as mogamulizumab, as well as how they are best applied to different subtypes of ATL. We discuss the implementation of molecular methods that may guide diagnosis or treatment, although we accept that these are not universally available. In particular, we acknowledge discrepancies in treatment between different countries, reflecting current drug licensing and the difficulties in making treatment decisions in a rare disease, with limited high-quality clinical trial data.
Topics: Aged; Allografts; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Human T-lymphotropic virus 1; Humans; Interferon-alpha; Leukemia-Lymphoma, Adult T-Cell; Male; Methotrexate; Middle Aged; Practice Patterns, Physicians'; Prednisone; Raltegravir Potassium; Recurrence; Remission Induction; Therapies, Investigational; Vincristine; Virus Activation; Zidovudine
PubMed: 33075812
DOI: 10.1182/blood.2019004045 -
Acta Medica Portuguesa Jul 2022Although raltegravir has been available since 2007, data are lacking on the Portuguese population living with HIV who initiated this antiretroviral therapy. Hence, this...
INTRODUCTION
Although raltegravir has been available since 2007, data are lacking on the Portuguese population living with HIV who initiated this antiretroviral therapy. Hence, this study aimed to characterize the patients who initiated raltegravir-based regimens between January 2015 and December 2017, on sociodemographics, clinical features, and treatment satisfaction.
MATERIAL AND METHODS
Observational, retrospective, multicentre study conducted at 11 reference sites. Sociodemographic and clinical data were collected retrospectively from hospital medical records. For participants continuing raltegravir at study inclusion, the HIV Treatment Satisfaction Questionnaire was administered to assess satisfaction with raltegravir-based therapy. Descriptive statistics were performed. Treatment-naïve and treatment-experienced subgroups were compared for demographic and clinical variables.
RESULTS
A total of 302 patients were included; mostly men (69.5%) with a mean age of 49 years old. Approximately half of the patients had at least one non-AIDS-related comorbidity at baseline (53.3%), such as hypercholesterolemia, arterial hypertension, diabetes mellitus, and depression. Moreover, 52.3% were treatment-experienced patients with up to two treatments prior to raltegravir. Across the study time points, there was a reduction in the viral load and improvement in CD4 counts in both the treatment-naïve and treatment-experienced subgroups. Continuing users of raltegravir reported high treatment satisfaction (55.4 ± 7.2 points).
CONCLUSION
Raltegravir-based regimens seem like a valid therapeutic option in heterogeneous populations of HIV-infected patients, in patients with previous ART experience and as part of first-line therapeutic options alongside with the latest generation of drugs from its class.
Topics: Male; Humans; Middle Aged; Female; Raltegravir Potassium; Retrospective Studies; Portugal; Viral Load; HIV Infections
PubMed: 35333155
DOI: 10.20344/amp.16785 -
Journal of Global Antimicrobial... Jun 2022We aimed to investigate the incidence of low-level viremia (LLV) and its impact on virologic failure (VF) in people living with HIV (PLWH) on stable antiretroviral...
OBJECTIVES
We aimed to investigate the incidence of low-level viremia (LLV) and its impact on virologic failure (VF) in people living with HIV (PLWH) on stable antiretroviral therapy (ART) who switched to co-formulated elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide (EVG/c/FTC/TAF).
METHODS
PLWH aged 18 years or older who had received ART with plasma HIV RNA load (PVL) <50 copies/mL for 6 months or longer and switched to EVG/c/FTC/TAF between March and October 2018 were retrospectively included. The incidence of LLV (defined as PVL of 50-999 copies/mL) and VF (PVL ≥1000 copies/mL) was calculated and represented by Kaplan-Meier plots. The generalised estimating equation model was constructed to identify factors associated with LLV and VF. Resistance-associated mutations were determined using population sequencing.
RESULTS
A total of 1078 PLWH were included. The incidence rates of LLV and VF after the switch to EVG/c/FTC/TAF were 3.5 and 0.8 events per 100 person-years of follow-up, respectively, whereas the respective cumulative incidence of LLV and VF reached 11.7% and 2.9% within 3 years of follow-up. LLV was associated with any LLV episode before or after the switch and prior exposure to integrase strand transfer inhibitor-based ART. VF was associated with any LLV before or after the switch and prior exposure to raltegravir, but not the level or frequency of LLV.
CONCLUSION
The risks of LLV and VF were low in PLWH who had achieved virologic suppression and switched to EVG/c/FTC/TAF, and the presence of LLV and prior exposure to raltegravir increased the risk of VF.
Topics: Anti-HIV Agents; Emtricitabine; HIV Infections; HIV-1; Humans; Incidence; Quinolones; Raltegravir Potassium; Retrospective Studies; Viremia
PubMed: 35172201
DOI: 10.1016/j.jgar.2022.02.007 -
Medicine Aug 2019The aim of this retrospective cohort study was to compare safety, efficacy and rates and reasons of discontinuation of the 3 currently approved integrase strand transfer... (Observational Study)
Observational Study
The aim of this retrospective cohort study was to compare safety, efficacy and rates and reasons of discontinuation of the 3 currently approved integrase strand transfer inhibitors (INSTIs) elvitegravir (EVG), dolutegravir (DTG), and raltegravir (RAL) in HIV-infected treatment-naïve and -experienced patients in a real-world cohort. One hundred four treatment-naïve patients were prescribed an INSTI-based combined antiretroviral therapy (cART)-regimen (first-line group) and 219 patients were switched to an INSTI-based cART-regimen from another treatment regimen (switch group) at our institution between May 2007 and December 2014. Twelve months after initiation of treatment, 92% of patients in the first-line group (EVG: 96%, n = 22/23; DTG: 92%, n = 34/37; RAL: 90%, n = 28/31) and 88% of patients in the switch group (EVG: 94%, n = 32/34; DTG: 90%, n = 69/77; RAL: 85%, n = 67/79) showed full virological suppression (viral load <50 copies/mL). Side effects of any kind occurred in 12% (n = 12/104) of patients in the first-line group, and 10% (n = 21/219) of patients in the switch group. In the switch group neuropsychiatric side effects (depression, vertigo, and sleep disturbances) occurred more frequently in patients treated with DTG (11%, n = 10) compared to the 2 other INSTI-based cART-regimen (EVG: 2%, n = 1; RAL: 1%, n = 1). Side effects only rarely led to discontinuation of treatment (first-line-group: 2%, n = 2/104; switch-group: 1%, n = 3/219). In this real-world setting, INSTI-based ART-regimens were highly efficacious with no significant differences between any of the 3 INSTIs. Overall, side effects were only rarely observed and generally mild in all subgroups. In light of a slightly higher incidence of vertigo and sleep disturbances in patients switched to DTG, awareness of the potential onset of psychiatric symptoms is warranted during follow-up in those patients.
Topics: Adult; Aged; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Female; HIV Infections; HIV Integrase Inhibitors; Heterocyclic Compounds, 3-Ring; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium; Retrospective Studies; Viral Load; Young Adult
PubMed: 31393378
DOI: 10.1097/MD.0000000000016721 -
International Journal of Molecular... Nov 2022Integrase inhibitors (INIs) are an important class of drugs for treating HIV-2 infection, given the limited number of drugs active against this virus. While the clinical...
Integrase inhibitors (INIs) are an important class of drugs for treating HIV-2 infection, given the limited number of drugs active against this virus. While the clinical efficacy of raltegravir and dolutegravir is well established, the clinical efficacy of bictegravir for treating HIV-2 infected patients has not been determined. Little information is available regarding the activity of bictegravir against HIV-2 isolates from patients failing raltegravir-based therapy. In this study, we examined the phenotypic and matched genotypic susceptibility of HIV-2 primary isolates from raltegravir-naïve and raltegravir-failing patients to raltegravir, dolutegravir, and bictegravir, and to the new spiro-β-lactam BSS-730A. The instantaneous inhibitory potential (IIP) was calculated to help predict the clinical activity of bictegravir and BSS-730A. Isolates from raltegravir-naïve patients were highly sensitive to all INIs and BSS-730A. Combined integrase mutations E92A and Q148K conferred high-level resistance to raltegravir, and E92Q and T97A conferred resistance to raltegravir and dolutegravir. The antiviral activity of bictegravir and BSS-730A was not affected by these mutations. BSS-730A displayed strong antiviral synergism with raltegravir. Mean IIP values at Cmax were similar for all INIs and were not significantly affected by resistance mutations. IIP values were significantly higher for BSS-730A than for INIs. The high IIP values of bictegravir and BSS-730A for raltegravir-naïve and raltegravir-resistant HIV-2 isolates highlight their potential value for treating HIV-2 infection. Overall, the results are consistent with the high clinical efficacy of raltegravir and dolutegravir for HIV-2 infection and suggest a promising clinical profile for bictegravir and BSS-730A.
Topics: Humans; HIV-2; Raltegravir Potassium; HIV Integrase Inhibitors; Drug Resistance, Viral; beta-Lactams; HIV-1; Anti-HIV Agents; HIV Infections; Heterocyclic Compounds, 4 or More Rings
PubMed: 36430777
DOI: 10.3390/ijms232214300 -
Journal of Acquired Immune Deficiency... Nov 2023Few data are available about the efficacy, durability, and tolerability of doravirine (DOR) + integrase strand inhibitors (INI) as a switching strategy among...
BACKGROUND
Few data are available about the efficacy, durability, and tolerability of doravirine (DOR) + integrase strand inhibitors (INI) as a switching strategy among antiretroviral therapy (ART)-experienced people living with HIV (PLWH).
SETTING
Retrospective, multicenter cohort study investigating the durability, efficacy, and tolerability of 2 off-label drug associations of DOR + INI among ART-experienced PLWH.
METHODS
The study included PLWH who switched to DOR combined with either raltegravir (RAL) or dolutegravir (DTG) between June 1, 2020, and December 31, 2021, with at least 1 follow-up (FU) visit. Virologic, biometric, and metabolic parameters were evaluated at baseline (T0) and at 1-3 (T1), 6 (T2), and 12 (T3) months. Univariate and multivariate survival analyses assessed the 28-week probability of persistence on the regimens. Patient satisfaction was measured using the HIV Treatment Satisfaction Questionnaire.
RESULTS
Ninety-five PLWH were included, 52 in DOR + RAL and 43 in DOR + DTG. Six treatment discontinuations were reported during a mean of 37 (±17) weeks of FU (incidence of 2.7 × 1000 person-weeks FU). Only 2 were the result of virological failure without resistance mutations. DOR + DTG demonstrated significantly higher 28-week persistence than DOR + RAL (HR 1.90, 95% CI: 1.24-2.90, log-rank: P = 0.003). Weight, waist circumference, and fasting lipids reduced considerably at T3 vs T0. Overall, high satisfaction with the new treatment was reported, particularly in the DOR + RAL (68 (64-72)/72), compared with the DOR + DTG group (58 (50-65)/72, P < 0.001).
CONCLUSIONS
Our experience revealed few treatment discontinuations, improved metabolic parameters, and high patient satisfaction among ART-experienced PLWH switching to DOR combined with INI, irrespective of the specific INI used.
Topics: Humans; Cohort Studies; HIV Infections; HIV Integrase Inhibitors; Retrospective Studies; Off-Label Use; Raltegravir Potassium; Anti-HIV Agents; Pyridones; Heterocyclic Compounds, 3-Ring; Integrases
PubMed: 37757865
DOI: 10.1097/QAI.0000000000003248 -
The Journal of Antimicrobial... Mar 2020NEAT001/ANRS143 demonstrated non-inferiority of once-daily darunavir/ritonavir (800/100 mg) + twice-daily raltegravir (400 mg) versus... (Randomized Controlled Trial)
Randomized Controlled Trial
Population pharmacokinetics and pharmacogenetics of ritonavir-boosted darunavir in the presence of raltegravir or tenofovir disoproxil fumarate/emtricitabine in HIV-infected adults and the relationship with virological response: a sub-study of the NEAT001/ANRS143 randomized trial.
OBJECTIVES
NEAT001/ANRS143 demonstrated non-inferiority of once-daily darunavir/ritonavir (800/100 mg) + twice-daily raltegravir (400 mg) versus darunavir/ritonavir + tenofovir disoproxil fumarate/emtricitabine (245/200 mg once daily) in treatment-naive patients. We investigated the population pharmacokinetics of darunavir, ritonavir, tenofovir and emtricitabine and relationships with demographics, genetic polymorphisms and virological failure.
METHODS
Non-linear mixed-effects models (NONMEM v. 7.3) were applied to determine pharmacokinetic parameters and assess demographic covariates and relationships with SNPs (SLCO3A1, SLCO1B1, NR1I2, NR1I3, CYP3A5*3, CYP3A4*22, ABCC2, ABCC10, ABCG2 and SCL47A1). The relationship between model-predicted darunavir AUC0-24 and C24 with time to virological failure was evaluated by Cox regression.
RESULTS
Of 805 enrolled, 716, 720, 347 and 361 were included in the darunavir, ritonavir, tenofovir and emtricitabine models, respectively (11% female, 83% Caucasian). No significant effect of patient demographics or SNPs was observed for darunavir or tenofovir apparent oral clearance (CL/F); coadministration of raltegravir did not influence darunavir or ritonavir CL/F. Ritonavir CL/F decreased by 23% in NR1I2 63396C>T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P<0.001). No significant relationship was demonstrated between darunavir AUC0-24 or C24 and time to virological failure [HR (95% CI): 2.28 (0.53-9.80), P=0.269; and 1.82 (0.61-5.41), P=0.279, respectively].
CONCLUSIONS
Darunavir concentrations were unaltered in the presence of raltegravir and not associated with virological failure. Polymorphisms investigated had little impact on study-drug pharmacokinetics. Darunavir/ritonavir + raltegravir may be an appropriate option for patients experiencing NRTI-associated toxicity.
Topics: Adult; Anti-HIV Agents; Constitutive Androstane Receptor; Darunavir; Emtricitabine; Female; HIV Infections; Humans; Liver-Specific Organic Anion Transporter 1; Male; Multidrug Resistance-Associated Protein 2; Pharmacogenetics; Raltegravir Potassium; Ritonavir; Tenofovir; Viral Load
PubMed: 31754703
DOI: 10.1093/jac/dkz479 -
Clinical Infectious Diseases : An... Aug 2021Moderate-to-severe hepatic steatosis in people living with human immunodeficiency virus (HIV) without viral hepatitis or excessive alcohol intake was associated with... (Observational Study)
Observational Study
Moderate-to-severe hepatic steatosis in people living with human immunodeficiency virus (HIV) without viral hepatitis or excessive alcohol intake was associated with cumulative exposure to stavudine, elvitegravir, and raltegravir. Prospective trials are required to establish a causal association. Clinical Trials Registration. NCT02382822.
Topics: HIV Infections; Humans; Prospective Studies; Quinolones; Raltegravir Potassium
PubMed: 33493297
DOI: 10.1093/cid/ciab057 -
AIDS (London, England) Feb 2021Following an alert on neural tube defects and dolutegravir, we sought to evaluate if the exposure integrase strand transfer inhibitors (INSTIs) at conception was...
OBJECTIVES
Following an alert on neural tube defects and dolutegravir, we sought to evaluate if the exposure integrase strand transfer inhibitors (INSTIs) at conception was associated with birth defects or other adverse pregnancy outcomes.
METHODS
In the prospective national French Perinatal Cohort (EPF), we studied birth defects and other perinatal outcomes by matching each pregnant woman exposed to INSTIs with a pregnant woman exposed to darunavir/ritonavir receiving the same backbone of nucleoside reverse transcriptase inhibitors and matched for other characteristics such as age, geographic origin, centre and year of delivery.
RESULTS
Among 808 women exposed to INSTIs during pregnancy (raltegravir = 703, dolutegravir = 57 and elvitegravir = 48), we reported a slightly higher rate of birth defects in infants exposed at conception to raltegravir (6.7%) vs. infants exposed to raltegravir later in pregnancy: 2.9% if initiated during pregnancy as first-line, and 2.5% as second-line treatment, P =0.04. When compared with matched controls, raltegravir exposure at conception was not significantly associated with birth defects: 6.4 vs. 2.3%, P = 0.08. There was no cluster of birth defect type and no neural tube defects were observed. Other perinatal outcomes, such as preterm birth and stillbirths, did not differ significantly between raltegravir-exposed women and matched counterparts. No difference in any outcome was observed for elvitegravir/cobicistat or dolutegravir.
CONCLUSION
We found a nonsignificant trend for an association between exposure to raltegravir at conception and birth defects, which needs to be evaluated by larger prospective surveillance data, as these drugs are increasingly prescribed in women living with HIV.
Topics: Abnormalities, Drug-Induced; Congenital Abnormalities; Female; HIV Infections; HIV Integrase Inhibitors; Heterocyclic Compounds, 3-Ring; Humans; Infant, Newborn; Integrases; Oxazines; Piperazines; Pregnancy; Premature Birth; Prospective Studies; Pyridones; Raltegravir Potassium
PubMed: 33048878
DOI: 10.1097/QAD.0000000000002719 -
Clinical Pharmacokinetics Nov 2020Predicting drug pharmacokinetics in pregnant women including placental drug transfer remains challenging. This study aimed to develop and evaluate maternal-fetal...
Predicting drug pharmacokinetics in pregnant women including placental drug transfer remains challenging. This study aimed to develop and evaluate maternal-fetal physiologically based pharmacokinetic models for two antiretroviral drugs, dolutegravir and raltegravir.
Topics: Female; Fetus; HIV Infections; HIV Integrase Inhibitors; Heterocyclic Compounds, 3-Ring; Humans; Maternal Exposure; Oxazines; Piperazines; Placenta; Pregnancy; Pyridones; Raltegravir Potassium
PubMed: 32451908
DOI: 10.1007/s40262-020-00897-9