Anthony Mills1, Jose R Arribas2, Jaime Andrade-Villanueva3, Giovanni DiPerri4, Jan Van Lunzen5, Ellen Koenig6, Richard Elion7, Matthias Cavassini8, Jose Valdez Madruga9, Jason Brunetta10, David Shamblaw11, Edwin DeJesus12, Chloe Orkin13, David A Wohl14, Indira Brar15, Jeffrey L Stephens16, Pierre-Marie Girard17, Gregory Huhn18, Andrew Plummer19, Ya-Pei Liu19, Andrew K Cheng19, Scott McCallister20. 1. Southern California Men's Medical Group, Los Angeles, CA, USA. 2. Hospital Universitario La Paz, IdiPAZ, Madrid, Spain. 3. Hospital Civil de Guadalajara CUCS, Universidad de Guadalajara, Guadalajara, Jal, Mexico. 4. University Hospital Amadeo De Savoia, Turin, Italy. 5. University Medical Center, Hamburg Eppendorf Infectious Diseases Unit, Hamburg, Germany. 6. Instituto Dominicano de Estudios Virologicos JDEZ, Santo Domingo, Dominican Republic. 7. George Washington University School of Medicine, Washington, DC, USA. 8. Infectious Disease Service, Lausanne University Hospital and Lausanne University, Lausanne, Switzerland. 9. Centro de Referenda e Treinamento Em DSTIAIDS, São Paulo, Brazil. 10. University of Toronto, Toronto, ON, Canada. 11. La Playa Medical Group, San Diego, CA, USA. 12. Orlando Immunology Center, Orlando, FL, USA. 13. Barts and the London NHS Trust, London, UK. 14. University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 15. Henry Ford Health System, Detroit, MI, USA. 16. Mercer University School of Medicine, Macon, GA, USA. 17. Infectious Diseases Department, Hopital Saint Antoine, Sorbonne Universites, Univ Paris and INSERM, Paris, France. 18. Ruth M Rothstein Core Center, Cook County Hospital, Chicago, IL, USA. 19. Gilead Sciences, Foster City, CA, USA. 20. Gilead Sciences, Foster City, CA, USA. Electronic address: scott.mccallister@gilead.com.
Abstract
BACKGROUND: Antiretroviral regimens containing tenofovir disoproxil fumarate have been associated with renal toxicity and reduced bone mineral density. Tenofovir alafenamide is a novel tenofovir prodrug that reduces tenofovir plasma concentrations by 90%, thereby decreasing off-target side-effects. We aimed to assess whether efficacy, safety, and tolerability were non-inferior in patients switched to a regimen containing tenofovir alafenamide versus in those remaining on one containing tenofovir disoproxil fumarate. METHODS: In this randomised, actively controlled, multicentre, open-label, non-inferiority trial, we recruited HIV-1-infected adults from Gilead clinical studies at 168 sites in 19 countries. Patients were virologically suppressed (HIV-1 RNA <50 copies per mL) with an estimated glomerular filtration rate of 50 mL per min or greater, and were taking one of four tenofovir disoproxil fumarate-containing regimens for at least 96 weeks before enrolment. With use of a third-party computer-generated sequence, patients were randomly assigned (2:1) to receive a once-a-day single-tablet containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg (tenofovir alafenamide group) or to carry on taking one of four previous tenofovir disoproxil fumarate-containing regimens (tenofovir disoproxil fumarate group) for 96 weeks. Randomisation was stratified by previous treatment regimen in blocks of six. Patients and treating physicians were not masked to the assigned study regimen; outcome assessors were masked until database lock. The primary endpoint was the proportion of patients who received at least one dose of study drug who had undetectable viral load (HIV-1 RNA <50 copies per mL) at week 48. The non-inferiority margin was 12%. This study was registered with ClinicalTrials.gov, number NCT01815736. FINDINGS: Between April 12, 2013 and April 3, 2014, we enrolled 1443 patients. 959 patients were randomly assigned to the tenofovir alafenamide group and 477 to the tenofovir disoproxil fumarate group. Viral suppression at week 48 was noted in 932 (97%) patients assigned to the tenofovir alafenamide group and in 444 (93%) assigned to the tenofovir disoproxil fumarate group (adjusted difference 4·1%, 95% CI 1·6-6·7), with virological failure noted in ten and six patients, respectively. The number of adverse events was similar between the two groups, but study drug-related adverse events were more common in the tenofovir alafenamide group (204 patients [21%] vs 76 [16%]). Hip and spine bone mineral density and glomerular filtration were each significantly improved in patients in the tenofovir alafenamide group compared with those in the tenofovir disoproxil fumarate group. INTERPRETATION: Switching to a tenofovir alafenamide-containing regimen from one containing tenofovir disoproxil fumarate was non-inferior for maintenance of viral suppression and led to improved bone mineral density and renal function. Longer term follow-up is needed to better understand the clinical impact of these changes. FUNDING: Gilead Sciences.
BACKGROUND: Antiretroviral regimens containing tenofovir disoproxil fumarate have been associated with renal toxicity and reduced bone mineral density. Tenofovir alafenamide is a novel tenofovir prodrug that reduces tenofovir plasma concentrations by 90%, thereby decreasing off-target side-effects. We aimed to assess whether efficacy, safety, and tolerability were non-inferior in patients switched to a regimen containing tenofovir alafenamide versus in those remaining on one containing tenofovir disoproxil fumarate. METHODS: In this randomised, actively controlled, multicentre, open-label, non-inferiority trial, we recruited HIV-1-infected adults from Gilead clinical studies at 168 sites in 19 countries. Patients were virologically suppressed (HIV-1 RNA <50 copies per mL) with an estimated glomerular filtration rate of 50 mL per min or greater, and were taking one of four tenofovir disoproxil fumarate-containing regimens for at least 96 weeks before enrolment. With use of a third-party computer-generated sequence, patients were randomly assigned (2:1) to receive a once-a-day single-tablet containing elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg (tenofovir alafenamide group) or to carry on taking one of four previous tenofovir disoproxil fumarate-containing regimens (tenofovir disoproxil fumarate group) for 96 weeks. Randomisation was stratified by previous treatment regimen in blocks of six. Patients and treating physicians were not masked to the assigned study regimen; outcome assessors were masked until database lock. The primary endpoint was the proportion of patients who received at least one dose of study drug who had undetectable viral load (HIV-1 RNA <50 copies per mL) at week 48. The non-inferiority margin was 12%. This study was registered with ClinicalTrials.gov, number NCT01815736. FINDINGS: Between April 12, 2013 and April 3, 2014, we enrolled 1443 patients. 959 patients were randomly assigned to the tenofovir alafenamide group and 477 to the tenofovir disoproxil fumarate group. Viral suppression at week 48 was noted in 932 (97%) patients assigned to the tenofovir alafenamide group and in 444 (93%) assigned to the tenofovir disoproxil fumarate group (adjusted difference 4·1%, 95% CI 1·6-6·7), with virological failure noted in ten and six patients, respectively. The number of adverse events was similar between the two groups, but study drug-related adverse events were more common in the tenofovir alafenamide group (204 patients [21%] vs 76 [16%]). Hip and spine bone mineral density and glomerular filtration were each significantly improved in patients in the tenofovir alafenamide group compared with those in the tenofovir disoproxil fumarate group. INTERPRETATION: Switching to a tenofovir alafenamide-containing regimen from one containing tenofovir disoproxil fumarate was non-inferior for maintenance of viral suppression and led to improved bone mineral density and renal function. Longer term follow-up is needed to better understand the clinical impact of these changes. FUNDING: Gilead Sciences.
Authors: Samuel F Freedman; Carrie Johnston; John J Faragon; Eugenia L Siegler; Tessa Del Carmen Journal: Eur Geriatr Med Date: 2018-12-06 Impact factor: 1.710
Authors: James M Mikula; Maura M Manion; Frank Maldarelli; Lucila M Suarez; Jaha F Norman-Wheeler; Alex G Ober; Robin L Dewar; Jeffrey B Kopp; H Clifford Lane; Alice K Pau Journal: Antivir Ther Date: 2016-03-08