Rilpivirine plus cobicistat-boosted darunavir as a two-drug switch regimen in HIV-infected, virologically suppressed subjects on steady standard three-drug therapy: a randomized, controlled, non-inferiority trial (PROBE 2)

2020 ◽  
Vol 75 (5) ◽  
pp. 1332-1337 ◽  
Author(s):  
F Maggiolo ◽  
N Gianotti ◽  
L Comi ◽  
E Di Filippo ◽  
L Fumagalli ◽  
...  
Keyword(s):  
Tenofovir Disoproxil Fumarate ◽  
Drug Regimen ◽  
Serum Concentrations ◽  
Open Label ◽  
Once Daily ◽  
Hiv Rna ◽  
Randomized Controlled ◽  
Switch Regimen ◽  
Trial Participants ◽  
Virological Efficacy

Abstract Background We explored the combination of rilpivirine plus cobicistat-boosted darunavir [a two-drug regimen (2DR)] when switching from standard triple combined ART. Methods In this randomized, open-label, non-inferiority trial, participants had an HIV-RNA <50 copies/mL on a stable (>6 months) three-drug regimen. The primary endpoint was proportion with HIV-RNA <50 copies/mL at Week 24 (snapshot algorithm), with a –12% non-inferiority margin. ClinicalTrials.gov: NCT04064632. Results One hundred and sixty patients were allocated (1:1) to 2DR or to continue current ART (CAR). At Week 24, 72 (90.0%) of participants with 2DR and 75 (93.8%) with CAR maintained HIV-RNA <50 copies/mL [difference −3.75% (95% CI = −11.63 to 5.63)], confirming non-inferiority. Non-inferiority was confirmed considering an HIV-RNA >50 copies/mL (0% for 2DR; 3.7% for CAR; 95% CI = −0.4 to 7.9). Four patients reported adverse events not leading to treatment discontinuation (one patient in the 2DR group and three patients in the CAR group); eight subjects discontinued therapy in the 2DR group and three in the CAR group. With 2DR, lipid serum concentrations increased, but differences were statistically significant only for tenofovir disoproxil fumarate-containing CAR and in 2DR patients receiving a pre-switch regimen including tenofovir disoproxil fumarate. Median bone stiffness decreased in the CAR group from 86.1 g/cm2 (IQR = 74–98) to 83.2 g/cm2 (IQR = 74–97) and increased in the 2DR group from 84.9 g/cm2 (IQR = 74–103) to 85.5 g/cm2 (IQR = 74–101). The reduction within the CAR group was significant (P = 0.043). Conclusions Once-daily rilpivirine plus cobicistat-boosted darunavir is an effective 2DR that combines a high virological efficacy with a potential to avoid major NRTI toxicities.

scholarly journals Switching to Tenofovir Alafenamide in Elvitegravir-Based Regimens: Pharmacokinetics and Antiviral Activity in Cerebrospinal Fluid

2019 ◽  
Vol 71 (4) ◽  
pp. 982-988 ◽  
Author(s):  
Qing Ma ◽  
Andrew J Ocque ◽  
Gene D Morse ◽  
Chelsea Sanders ◽  
Alina Burgi ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Antiviral Activity ◽  
Virologic Failure ◽  
Plasma Concentrations ◽  
Open Label ◽  
Assay Sensitivity ◽  
Once Daily ◽  
Hiv Rna ◽  
The Central Nervous System ◽  
Tenofovir Alafenamide

Abstract Background Tenofovir alafenamide fumarate (TAF) co-formulated with elvitegravir (EVG; E), cobicistat (C), and emtricitabine (F), a recommended antiretroviral regimen, was evaluated for distribution and antiviral activity in cerebrospinal fluid (CSF) as well as neurocognitive (NC) performance change in participants switching from E/C/F/tenofovir disoproxil fumarate (TDF) to E/C/F/TAF. Methods This was a 24-week, single-arm, open-label study in treatment-experienced adults living with human immunodeficiency virus (HIV). Nine participants switched from E/C/F/TDF (150/150/200/300 mg once daily) to E/C/F/TAF (150/150/200/10 mg once daily) at week 12. CSF and total plasma concentrations of EVG, TDF, TAF, tenofovir (TFV), and HIV RNA levels were measured at baseline and week 24. NC performance was estimated by the Montreal Cognitive Assessment. Results EVG concentrations in CSF and the CSF:plasma ratio remained stable (P = .203) over time. Following the switch, TFV concentrations in CSF and plasma declined (P = .004), although the TFV CSF:plasma ratio increased (P = .004). At week 24, median TAF plasma concentration was 11.05 ng/mL (range, 2.84–147.1 ng/mL) 2 hours postdose but was below assay sensitivity 6 hours after dosing. TAF was below assay sensitivity in all CSF specimens. HIV RNA was ≤40 copies/mL in all CSF and plasma specimens. Three participants (33%) had NC impairment at baseline and 2 (22%) remained impaired at week 24. Conclusions Switch to E/C/F/TAF was associated with reductions in TFV concentrations in CSF but stable EVG concentrations that exceeded the 50% inhibitory concentration for wild-type HIV, suggesting that EVG achieves therapeutic concentrations in the central nervous system. No virologic failure or significant NC changes were detected following the switch. Clinical Trials Registration NCT02251236.

Low-dose ritonavir-boosted darunavir once daily versus ritonavir-boosted lopinavir for participants with less than 50 HIV RNA copies per mL (WRHI 052): a randomised, open-label, phase 3, non-inferiority trial

2019 ◽  
Vol 6 (7) ◽  
pp. e428-e437 ◽  
Author(s):  
Willem D F Venter ◽  
Michelle Moorhouse ◽  
Simiso Sokhela ◽  
Celicia Serenata ◽  
Godspower Akpomiemie ◽  
...  
Keyword(s):  
Low Dose ◽  
Open Label ◽  
Phase 3 ◽  
Once Daily ◽  
Hiv Rna ◽  
Open Label Phase

scholarly journals Switching from entecavir to tenofovir disoproxil fumarate for HBeAg-positive chronic hepatitis B patients: a phase 4, prospective study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fumitaka Suzuki ◽  
Yoshiyuki Suzuki ◽  
Yoshiyasu Karino ◽  
Yasuhito Tanaka ◽  
Masayuki Kurosaki ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis B ◽  
Chronic Hepatitis B ◽  
Tenofovir Disoproxil Fumarate ◽  
Hepatitis B Surface Antigen ◽  
Primary Objective ◽  
Open Label ◽  
Once Daily ◽  
Hbsag Seroclearance ◽  
Positive Chronic Hepatitis

Abstract Background Tenofovir disoproxil fumarate (TDF) is widely used and recommended as first-line treatment for patients infected with the hepatitis B virus (HBV). However, current data are limited regarding the efficacy and safety of switching to TDF for the treatment of chronic hepatitis B in hepatitis B e-antigen (HBeAg)-positive patients who are virologically suppressed with another nucleos(t)ide analogue. The primary objective of this study was to evaluate the hepatitis B surface antigen (HBsAg) reduction potential of switching from entecavir (ETV) to TDF at week 48 in HBeAg-positive chronic hepatitis B patients with undetectable serum HBV-DNA. Methods In this multicenter, single-arm, open-label, phase 4 clinical study, 75 participants currently treated with ETV 0.5 mg once daily were switched to TDF 300 mg once daily for 96 weeks. Results At week 48, 3/74 participants (4%) achieved 0.25 log10 reduction of HBsAg levels from baseline (the primary endpoint). Mean HBsAg reduction was −0.14 log10 IU/mL and 12% (9/74) achieved 0.25 log10 reduction by 96 weeks. No participants achieved HBsAg seroclearance. HBsAg reduction at weeks 48 and 96 was numerically greater in participants with higher alanine aminotransferase levels (≥ 60 U/L). Seventeen participants (25%) achieved HBeAg seroclearance up to week 96. No participants experienced viral breakthrough. All drug-related adverse events (18 participants [24%]) were mild in intensity, including an increase in urine beta-2-microglobulin (15 participants [20%]). Conclusions In conclusion, HBsAg reduction was limited after switching from ETV to TDF in this study population. Further investigation is warranted to better understand the clinical impact of switching from ETV to TDF. ClinicalTrials.gov: NCT03258710 registered August 21, 2017. https://clinicaltrials.gov/ct2/show/NCT03258710?term=NCT03258710&draw=2&rank=1

scholarly journals Injectable Amoxicillin Versus Injectable Ampicillin Plus Gentamicin in the Treatment of Severe Pneumonia in Children Aged 2 to 59 Months: Protocol for an Open-Label Randomized Controlled Trial

10.2196/17735 ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. e17735
Author(s):  
Lubaba Shahrin ◽  
Mohammod Jobayer Chisti ◽  
Abu Sadat Mohammad Sayeem Bin Shahid ◽  
Abu Sayem Mirza Mohammad Hasibur Rahman ◽  
Md. Zahidul Islam ◽  
...  
Keyword(s):  
Hospital Stay ◽  
Diarrheal Disease ◽  
Controlled Trial ◽  
Severe Pneumonia ◽  
World Health ◽  
Open Label ◽  
Once Daily ◽  
Danger Signs ◽  
Randomized Controlled ◽  
Daily Dose

Background Pneumonia causes about 0.9 million deaths worldwide each year. The World Health Organization (WHO) guidelines for the standard management of severe pneumonia requires parenteral ampicillin every 6 hours and once-daily parenteral gentamicin for 5 to 7 days. Although this treatment has contributed to the reduction of mortality, it requires nursing interventions every 6 hours for 7 days. Further intervention trials should be conducted to search for alternate antibiotics with better adherence, reduced cost, and reduced hospital stay. Parenteral amoxicillin is an effective alternative to ampicillin, as it has a longer half-life and broader coverage. Objective The aim of this clinical trial is to compare the efficacy of a dose of injectable amoxicillin every 12 hours plus a once-daily dose of injectable gentamicin with a dose of injectable ampicillin every 6 hours plus a once-daily dose of injectable gentamicin in children hospitalized for severe pneumonia. Methods This randomized, controlled, open-label, noninferiority trial is being conducted in Dhaka Hospital of the International Centre for Diarrheal Disease Research, Bangladesh. A sample size of 308 children with severe pneumonia will give adequate power to this study. Children aged 2 to 59 months are randomized to either intravenous ampicillin or intravenous amoxicillin, plus intravenous gentamicin in both study arms. The monitoring of the patients is carried out according to the WHO protocol for the treatment of severe pneumonia. The primary objective is the rate of treatment failure, defined by the persistence of danger signs of severe pneumonia beyond 48 hours or deterioration within 24 hours of initiation of the therapy. The secondary objectives are (1) improvement in or the resolution of danger signs since enrollment, (2) length of hospital stay, (3) death during hospitalization, and (4) rate of nosocomial infections. Results Enrollment in the study started on January 1, 2018, and ended on October 31, 2019. Data entry and analysis are in progress. Findings from the study are expected to be disseminated in October 2020. Conclusions Our study's findings will improve compliance with the use of antibiotics that require less frequent doses for the treatment of severe pneumonia. Trial Registration ClinicalTrials.gov NCT03369093; https://clinicaltrials.gov/ct2/show/NCT03369093 International Registered Report Identifier (IRRID) DERR1-10.2196/17735

scholarly journals Pharmacokinetics of Tenofovir Disoproxil Fumarate and Ritonavir-Boosted Saquinavir Mesylate Administered Alone or in Combination at Steady State

2006 ◽  
Vol 50 (4) ◽  
pp. 1304-1310 ◽  
Author(s):  
Gregory E. Chittick ◽  
Jian Zong ◽  
M. Robert Blum ◽  
Jeffrey J. Sorbel ◽  
John A. Begley ◽  
...  
Keyword(s):  
Steady State ◽  
Tenofovir Disoproxil Fumarate ◽  
Venous Access ◽  
Open Label ◽  
Fixed Sequence ◽  
Once Daily ◽  
Chromatography Tandem Mass Spectrometry ◽  
Drug Concentrations ◽  
Liquid Chromatography Tandem Mass ◽  
Dosing Intervals

ABSTRACT A phase I study was conducted to formally evaluate the steady-state pharmacokinetics (PK) of tenofovir disoproxil fumarate (TDF) and ritonavir (RTV)-boosted saquinavir mesylate (SQV) when coadministered in healthy volunteers. Forty subjects received multiple doses of TDF (300 mg, once daily) and SQV/RTV (1,000 mg/100 mg, twice daily) alone and together under steady-state conditions in an open-label, fixed sequence design. Blood samples for tenofovir (TFV) and SQV/RTV PK were drawn over respective 24- and 12-h dosing intervals, and drug concentrations were measured by liquid chromatography-tandem mass spectrometry. Safety was assessed periodically by clinical and laboratory monitoring. Thirty-two subjects completed the study and were fully evaluable; three subjects discontinued participation in the study due to adverse events, three subjects withdrew for personal reasons, and two subjects withdrew because of inadequate venous access for blood sampling. Steady-state TFV PK were not significantly altered upon coadministration with SQV/RTV. Steady-state SQV (administered as SQV/RTV) AUCtau, C max, and C tau increased 29, 22, and 47%, respectively, upon coadministration with TDF, and all subjects achieved a C tau of >100 ng/ml. These modestly increased SQV exposures are not clinically meaningful given its clinical use with RTV already results in >10-fold-higher SQV levels. Steady-state RTV AUCtau and C max levels were not significantly altered, whereas C tau was 23% higher upon coadministration of SQV/RTV and TDF. Thus, no clinically relevant interactions between TDF and RTV-boosted SQV were observed under conditions simulating clinical practice.

scholarly journals Injectable Amoxicillin Versus Injectable Ampicillin Plus Gentamicin in the Treatment of Severe Pneumonia in Children Aged 2 to 59 Months: Protocol for an Open-Label Randomized Controlled Trial (Preprint)

2020 ◽  
Author(s):  
Lubaba Shahrin ◽  
Mohammod Jobayer Chisti ◽  
Abu Sadat Mohammad Sayeem Bin Shahid ◽  
Abu Sayem Mirza Mohammad Hasibur Rahman ◽  
Md. Zahidul Islam ◽  
...  
Keyword(s):  
Hospital Stay ◽  
Diarrheal Disease ◽  
Controlled Trial ◽  
Severe Pneumonia ◽  
World Health ◽  
Open Label ◽  
Once Daily ◽  
Danger Signs ◽  
Randomized Controlled ◽  
Daily Dose

BACKGROUND Pneumonia causes about 0.9 million deaths worldwide each year. The World Health Organization (WHO) guidelines for the standard management of severe pneumonia requires parenteral ampicillin every 6 hours and once-daily parenteral gentamicin for 5 to 7 days. Although this treatment has contributed to the reduction of mortality, it requires nursing interventions every 6 hours for 7 days. Further intervention trials should be conducted to search for alternate antibiotics with better adherence, reduced cost, and reduced hospital stay. Parenteral amoxicillin is an effective alternative to ampicillin, as it has a longer half-life and broader coverage. OBJECTIVE The aim of this clinical trial is to compare the efficacy of a dose of injectable amoxicillin every 12 hours plus a once-daily dose of injectable gentamicin with a dose of injectable ampicillin every 6 hours plus a once-daily dose of injectable gentamicin in children hospitalized for severe pneumonia. METHODS This randomized, controlled, open-label, noninferiority trial is being conducted in Dhaka Hospital of the International Centre for Diarrheal Disease Research, Bangladesh. A sample size of 308 children with severe pneumonia will give adequate power to this study. Children aged 2 to 59 months are randomized to either intravenous ampicillin or intravenous amoxicillin, plus intravenous gentamicin in both study arms. The monitoring of the patients is carried out according to the WHO protocol for the treatment of severe pneumonia. The primary objective is the rate of treatment failure, defined by the persistence of danger signs of severe pneumonia beyond 48 hours or deterioration within 24 hours of initiation of the therapy. The secondary objectives are (1) improvement in or the resolution of danger signs since enrollment, (2) length of hospital stay, (3) death during hospitalization, and (4) rate of nosocomial infections. RESULTS Enrollment in the study started on January 1, 2018, and ended on October 31, 2019. Data entry and analysis are in progress. Findings from the study are expected to be disseminated in October 2020. CONCLUSIONS Our study's findings will improve compliance with the use of antibiotics that require less frequent doses for the treatment of severe pneumonia. CLINICALTRIAL ClinicalTrials.gov NCT03369093; https://clinicaltrials.gov/ct2/show/NCT03369093 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/17735

DURATION-8 Randomized Controlled Trial 104-Week Results—Once-Weekly Exenatide (ExQW) plus Once-Daily Dapagliflozin (DAPA) vs. ExQW or DAPA Alone

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 104-LB ◽  
Author(s):  
SERGE JABBOUR ◽  
CRISTIAN GUJA ◽  
ELISE HARDY ◽  
SUDIPTA BHATTACHARYA ◽  
PETER K. OHMAN ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Controlled Trial ◽  
Once Daily ◽  
Randomized Controlled
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