title: Safety, efficacy, and pharmacokinetics of a single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in treatment-naive, HIV-infected adolescents: a single-arm, open-label trial.
abstract: The prodrug tenofovir alafenamide is associated with improved renal and bone safety compared with tenofovir disoproxil fumarate. We aimed to assess safety, pharmacokinetics, and efficacy of this single-tablet, fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-infected, treatment-naive adolescents.
  
  
  
  We did a 48 week, single-arm, open-label trial in treatment-naive adolescents with HIV from ten hospital clinics in South Africa, Thailand, Uganda, and the USA. Eligible participants were aged 12-18 years, with plasma HIV-1 RNA of at least 1000 copies per mL, a CD4 count of at least 100 cells per μL, and estimated glomerular filtration rate of at least 90 mL/min per 1·73 m2by the Schwartz formula, bodyweight of at least 35 kg, and an HIV-1 genotype with sensitivity to elvitegravir, emtricitabine, and tenofovir. Participants received a single-tablet regimen once per day with food (administered by their parent or carer) containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide. Study visits to the clinic occurred at weeks 1, 2, 4, 8, 12, 16, 24, 32, 40, and 48. The coprimary endpoints were the pharmacokinetic parameters of area under the curve (AUC) concentration at the end of the dosing interval (AUCtau) for elvitegravir and the AUC from time zero to the last quantifiable concentration (AUClast) for tenofovir alafenamide, incidence of treatment-emergent serious adverse events, and all adverse events that emerged after treatment started (including data for bone mineral density). All participants who received one dose of study drug were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT01854775.
  
  
  
  Between May 22, 2013, and July 22, 2014, we enrolled 50 participants, and all 50 received the assigned treatment; 24 participated in the intensive pharmacokinetic assessment. 48 patients completed the 48 weeks of treatment; two discontinued (one withdrew consent at week 8, one was lost to follow-up at week 12). The regimen was well tolerated and no discontinuations related to adverse events occurred. The mean AUCtaufor elvitegravir was 23 840 ng × h per mL (coefficient of variation [CV] 25·5%), and the mean AUClastfor tenofovir alafenamide was 189 ng × h per mL (CV 55·8%). Four participants (8%) had a serious adverse event, one of which (intermediate uveitis) was deemed related to the study regimen but resolved without treatment interruption. The most common study drug-related adverse events were nausea (in ten participants), abdominal pain (in six), and vomiting (in five). Exposures to the elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide regimen were similar to those previously noted in adults.
  
  
  
  The elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide regimen was well tolerated and achieved component plasma pharmacokinetic exposures similar to those in adults. Although non-comparative with a small sample size, these data support the use of this regimen in HIV-infected adolescents and its timely assessment in younger children.
  
  
  
  Gilead Sciences.
authors.affiliation: St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Aditya H
authors.initials: AH
authors.lastname: Gaur
authors.affiliation: Joint Clinical Research Centre, Kampala, Uganda.
authors.forename: Hilda
authors.initials: H
authors.lastname: Kizito
authors.affiliation: HIV-NAT Thai Red Cross AIDS Research Centre, Bangkok, Thailand.
authors.forename: Wasana
authors.initials: W
authors.lastname: Prasitsueubsai
authors.affiliation: Children's National Health System, Washington, DC, USA.
authors.forename: Natella
authors.initials: N
authors.lastname: Rakhmanina
authors.affiliation: Clinical HIV Research Unit, Department of Internal Medicine, University of Witwatersrand, Johannesburg, South Africa.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Rassool
authors.affiliation: Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Rana
authors.initials: R
authors.lastname: Chakraborty
authors.affiliation: Miller Children's Hospital, Long Beach, CA, USA.
authors.forename: Jagmohan
authors.initials: J
authors.lastname: Batra
authors.affiliation: Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Pope
authors.initials: P
authors.lastname: Kosalaraksa
authors.affiliation: Queen Savang Vadhana Memorial Hospital, Chon Buri, Thailand.
authors.forename: Wicharn
authors.initials: W
authors.lastname: Luesomboon
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Porter
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: Yongwu
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Myers
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: Lillian
authors.initials: L
authors.lastname: Ting
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: Devi
authors.initials: D
authors.lastname: SenGupta
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Quirk
authors.affiliation: Gilead Sciences Inc, Foster City, CA, USA. Electronic address: Martin.rhee@gilead.com.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Rhee
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000293:Adolescent; D000409:Alanine; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D018791:CD4 Lymphocyte Count; D002648:Child; D000069547:Cobicistat / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D000068679:Emtricitabine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000453:epidemiology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D059012:Lost to Follow-Up; D008297:Male; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood; D013019:South Africa / Q000453:epidemiology; D013607:Tablets; D000068698:Tenofovir / Q000031:analogs & derivatives; D013785:Thailand / Q000453:epidemiology; D014454:Uganda / Q000453:epidemiology; D014481:United States / Q000453:epidemiology; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D015363:Quinolones; D012367:RNA, Viral; D013607:Tablets; C509700:elvitegravir; D000068698:Tenofovir; C442442:tenofovir alafenamide; D000068679:Emtricitabine; D000225:Adenine; D000069547:Cobicistat; D000409:Alanine