STUDY DESIGN: TREATMENT-NAIVE ADULTS

Clinical trials of the RPV* and FTC/TAF components of ODEFSEY®


ECHO/THRIVE pooled: Study design and baseline characteristics1-4

ECHO/THRIVE pooled: Phase 3, randomized, double-blind, multicenter,
international, active-controlled studies

Primary endpoint4
Proportion of adults with HIV-1 RNA <50 copies/mL at Week 48 as defined by the TLOVR algorithm, with a prespecified non-inferiority margin of 12%

Selected secondary endpoints4
Safety, tolerability, and resistance in virologic failures of an RPV-based regimen at Weeks 48 and 96

ECHO/THRIVE pooled: Selected baseline characteristics4
RPV + FTC/TDF
(n=550)
EFV + FTC/TDF
(n=546)
Median age, years (range) 36
(18-78)
36
(19-69)
Sex
Male (%) 78 79
Female (%) 22 21
Race/ethnicity
White (%) 63 61
Black/African American (%) 24 23
Hispanic/Latino ethnicity (%) 24 27
Asian (%) 10 13
Median HIV-1 RNA, log10 copies/mL 5 5
HIV-1 RNA ≤100,000 copies/mL (%) 52 47
Median CD4+ cell count, cells/µL 247 261
CD4+ cell count ≥200 cells/µL (%) 67 70

Warnings and precautions

  • Skin and hypersensitivity reactions: Severe skin and hypersensitivity reactions have been reported with the use of rilpivirine-containing regimens, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). In rilpivirine (RPV) clinical trials, most rashes were Grades 1-2 and occurred in the first 4-6 weeks of treatment; Grades 2-4 rash occurred in 1% of subjects. Discontinue ODEFSEY immediately if severe skin or hypersensitivity reactions occur, including severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis or eosinophilia. Monitor clinical status including laboratory parameters and initiate appropriate therapy.
  • Loss of virologic response due to drug interactions: See Contraindications and Drug Interactions sections. Consider the potential for drug interactions prior to and during ODEFSEY therapy and monitor for adverse reactions.
  • Prolongation of QTc interval: RPV doses 3 and 12 times higher than the recommended dose can prolong the QTc interval. Consider alternatives to ODEFSEY in patients at higher risk for Torsade de Pointes or when coadministered with a drug with known risk of Torsade de Pointes.

Studies 104/111 pooled: Study design and baseline characteristics5

Studies 104/111 pooled: Phase 3, randomized, double-blind, multicenter, international,
active-controlled studies

Primary endpoint5
Proportion of adults with HIV-1 RNA <50 copies/mL at Week 48 using the FDA snapshot algorithm, with a prespecified non-inferiority margin of 12%

Selected secondary endpoints5
Changes in serum creatinine, proteinuria, and lumbar spine and hip BMD at Week 48

Studies 104/111 pooled: Selected baseline characteristics5-7
FTC/TAF +
EVG/COBI#
(n=866)
FTC/TDF +
EVG/COBI#
(n=867)
Median age, years (range) 33
(18-74)
35
(18-76)
Sex
Male (%) 85 85
Female (%) 15 15
Race/ethnicity
White (%) 56 57
Black or African descent (%) 26 25
Hispanic/Latino ethnicity (%) 19 19
Asian (%) 11 10
Median HIV-1 RNA, log10 copies/mL 4.58 4.58
HIV-1 RNA ≤100,000 copies/mL (%) 77 78
Median CD4+ cell count, cells/µL 404 406
CD4+ cell count ≥200 cells/µL (%) 87 87
Median eGFR, mL/min 117 114
Dipstick proteinuria (any grade) (%) 10 10

Important Safety Information

BOXED WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

  • ODEFSEY® is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of ODEFSEY have not been established in patients coinfected with HIV-1 and HBV. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of ODEFSEY. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue ODEFSEY. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Contraindications

  • Coadministration: Do not use with drugs that induce CYP3A or increase gastric pH as this may lead to loss of efficacy and possible resistance to ODEFSEY or the NNRTI class. Do not use with carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, proton pump inhibitors (e.g., dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole), systemic dexamethasone (>1 dose) and St. John's wort.

Warnings and precautions

  • Skin and hypersensitivity reactions: Severe skin and hypersensitivity reactions have been reported with the use of rilpivirine-containing regimens, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). In rilpivirine (RPV) clinical trials, most rashes were Grades 1-2 and occurred in the first 4-6 weeks of treatment; Grades 2-4 rash occurred in 1% of subjects. Discontinue ODEFSEY immediately if severe skin or hypersensitivity reactions occur, including severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis or eosinophilia. Monitor clinical status including laboratory parameters and initiate appropriate therapy.
  • Loss of virologic response due to drug interactions: See Contraindications and Drug Interactions sections. Consider the potential for drug interactions prior to and during ODEFSEY therapy and monitor for adverse reactions.
  • Prolongation of QTc interval: RPV doses 3 and 12 times higher than the recommended dose can prolong the QTc interval. Consider alternatives to ODEFSEY in patients at higher risk for Torsade de Pointes or when coadministered with a drug with known risk of Torsade de Pointes.
  • Depressive disorders: Evaluate patients with severe depressive symptoms to assess if symptoms are due to ODEFSEY and if the risks of continued treatment outweigh the benefits. In RPV adult clinical trials (N=686), the incidence of depressive disorders was 9%, Grades 3-4 depressive disorders was 1%, discontinuation due to depressive disorders was 1%, and suicidal ideation and suicide attempt was reported in 4 and 2 subjects, respectively. In an RPV adolescent clinical trial (N=36), the incidence of depressive disorders was 19%, Grades 3-4 depressive disorders was 6%, and suicidal ideation and suicide attempt were reported in 1 subject.
  • Hepatotoxicity: Hepatic adverse events have been reported, including cases of hepatic toxicity, in patients without pre-existing hepatic disease or other identifiable risk factors. In patients with hepatic abnormalities (e.g., hepatitis, elevated liver-associated tests), order laboratory tests before starting treatment and monitor for hepatotoxicity during treatment; consider testing and monitoring in all patients.
  • Immune reconstitution syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported.
  • New onset or worsening renal impairment: Cases of acute renal failure and Fanconi syndrome have been reported with the use of tenofovir prodrugs. In clinical trials of FTC and tenofovir alafenamide (TAF) with elvitegravir and cobicistat, there have been no cases of Fanconi syndrome or proximal renal tubulopathy (PRT). Do not initiate ODEFSEY in patients with estimated creatinine clearance (CrCl) <30 mL/min. Patients with impaired renal function and/or taking nephrotoxic agents (including NSAIDs) are at increased risk of renal-related adverse reactions. Discontinue ODEFSEY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.
    Renal monitoring: In all patients, monitor CrCl, urine glucose, and urine protein prior to initiating and during therapy. In patients with chronic kidney disease, additionally monitor serum phosphorus.
  • Lactic acidosis and severe hepatomegaly with steatosis: Fatal cases have been reported with the use of nucleoside analogs, including FTC and TDF. Discontinue ODEFSEY if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity develop, including hepatomegaly and steatosis in the absence of marked transaminase elevations.
  • Bone loss and mineralization defects: Decreases in bone mineral density (BMD) have been reported with the use of tenofovir prodrugs. Consider monitoring BMD in patients with a history of pathologic fracture or risk factors for bone loss. Mineralization defects, including osteomalacia associated with PRT, have been reported with the use of TDF-containing products.

Adverse reactions

  • Most common adverse reactions with RPV (incidence ≥2%, Grades 2-4) are depressive disorders (2%), insomnia (2%) and headache (2%); and with FTC and TAF (incidence ≥10%, all grades) is nausea (10%).

Drug interactions

  • Prescribing information: Consult the full prescribing information for ODEFSEY for more information on Contraindications, Warnings, and potentially significant drug interactions, including clinical comments.
  • Metabolism: Drugs that induce CYP3A or P-gp and drugs that increase gastric pH can decrease the concentrations of components of ODEFSEY. Drugs that inhibit CYP3A or P-gp can increase the concentrations of components of ODEFSEY.
  • QT prolonging drugs: Consider alternatives to ODEFSEY in patients taking a drug with known risk of Torsade de Pointes.
  • Drugs affecting renal function: Coadministration of ODEFSEY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of FTC and tenofovir and the risk of adverse reactions.

Dosage and administration

  • Dosage: Patients 12 years and older who weigh ≥35 kg: 1 tablet taken orally once daily with a meal.
  • Renal impairment: Not recommended in patients with CrCl <30 mL/min.
  • Testing prior to initiation: Test patients for HBV infection and assess CrCl, urine glucose and urine protein.
  • Testing after initiation: In virologically-suppressed patients, additional monitoring of HIV-1 RNA and regimen tolerability is recommended.

Pregnancy and lactation

  • Pregnancy: There is insufficient human data on the use of ODEFSEY during pregnancy. An Antiretroviral Pregnancy Registry (APR) has been established; available data from the APR for FTC shows no difference in the rates of birth defects compared with a US reference population.
  • Lactation: Women infected with HIV-1 should be instructed not to breastfeed, due to the potential for HIV-1 transmission.

Indication

ODEFSEY is indicated as a complete regimen for the treatment of HIV-1 infection in patients 12 years and older who have no antiretroviral (ARV) treatment history with HIV-1 RNA ≤100,000 copies/mL; or to replace a stable ARV regimen in patients who are virologically-suppressed (HIV-1 RNA <50 copies/mL) for ≥6 months with no history of treatment failure and no known resistance to any component of ODEFSEY.

View full Prescribing Information for ODEFSEY and DESCOVY®, including BOXED WARNINGS.

*Administered in combination with FTC/TDF.
Administered in combination with EVG and COBI as an STR.
Studies were combined for a prespecified pooled efficacy and safety analysis.
§Of the pooled population, 550 of 686 adults received RPV + FTC/TDF, and 288 of those 550 had a baseline viral load ≤100,000 copies/mL; 546 of 682 adults received EFV + FTC/TDF, and 255 of those 546 adults had a baseline viral load ≤100,000 copies/mL.
||The dual NRTI backbone in ECHO was FTC/TDF and in THRIVE (per investigator's choice) was FTC/TDF (60%), ZDV/3TC (30%), or ABC/3TC (10%).
Studies were combined for a prespecified pooled efficacy and safety analysis.
#Administered as an STR.

References:

  1. COMPLERA® [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2017.
  2. Cohen CJ, Molina JM, Cassetti I, et al; ECHO, THRIVE Study Groups. Week 96 efficacy and safety of rilpivirine in treatment-naive, HIV-1 patients in two Phase III randomized trials. AIDS. 2013;27(6):939-950.
  3. Molina JM, Cahn P, Grinsztejn B, et al; ECHO Study Group. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet. 2011;378(9787):238-246.
  4. Nelson MR, Elion RA, Cohen CJ, et al. Rilpivirine versus efavirenz in HIV-1-infected subjects receiving emtricitabine/tenofovir DF: pooled 96-week data from ECHO and THRIVE studies. HIV Clin Trials. 2013;14(3):81-91.
  5. Sax PE, Wohl D, Yin MT, et al; GS-US-292-0104/0111 Study Team. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015;385(9987):2606-2615.
  6. DeJesus E, Sax P, Yin M, et al. Renal and bone safety of tenofovir alafenamide vs tenofovir disoproxil fumarate. Poster presented at: HIV Drug Therapy in the Americas; April 16-18, 2015; Mexico City, Mexico. Poster P030.
  7. Arribas J, Thompson M, Sax P, et al. Significant efficacy and long-term safety difference with TAF-based STR in naive adults. Poster presented at: CROI 2017; February 13-16, 2017; Seattle, WA. Poster 453.