A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women.
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9 November 2020
HPTN 084 Study Demonstrates Superiority of Injectable Cabotegravir to Oral TDF/FTC for the Prevention of HIV in Cisgender Women in Sub-Saharan Africa
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What is HPTN 084?
HPTN 084 (The LIFE Study) is a study being done to evaluate the safety and efficacy of the injectable agent, cabotegravir (CAB LA) compared to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), for pre-exposure prophylaxis (PrEP) in HIV-uninfected women.
Who participated in the study?
HPTN 084 enrolled 3,224 women 18 to 45 years old in sub-Saharan Africa who were at risk for acquiring HIV.
Why is HPTN 084 important?
PrEP agents are needed that do not depend on daily or near-daily pill-taking. The development of alternative agents for PrEP, and/or more adherence-friendly schedules for currently available agents, could increase prevention choices and increase acceptability. Long-acting injectable agents have the potential to prevent HIV acquisition without relying on adherence to a daily oral regimen.
What happened during the study?
Once randomized to one of two arms, participants moved through the steps below and will be followed for up to 4 and a half years (active drugs are shown in bold text):
Step 1:
Arm A – Daily oral CAB (30 mg tablets) and oral TDF/FTC placebo for five weeks plus an HIV prevention package including behavioral risk reduction and adherence counseling, provision of condoms.
Arm B – Daily oral TDF/FTC (300 mg/200 mg fixed-dose combination tablets) and oral CAB placebo for five weeks plus an HIV prevention package including behavioral risk reduction and adherence counseling, provision of condoms.
A participant that becomes HIV-infected during Step 1 of the study will permanently discontinue study product and will be terminated from the study, and referred for HIV-related care.
Step 2:
Arm A – CAB LA (600 mg as a single intramuscular [IM] injection at two time points 4 weeks apart and every 8 weeks thereafter) and daily oral TDF/FTC placebo plus an HIV prevention package including behavioral risk reduction and adherence counseling, provision of condoms.
Arm B – Daily oral TDF/FTC (300/200 mg fixed-dose combination tablets) and IM placebo at two time points 4 weeks apart and every 8 weeks thereafter (matching vehicle, identical volume as active injectable product in Arm A) plus an HIV prevention package including behavioral risk reduction and adherence counseling, provision of condoms.
This step will continue until the required number of endpoints (111) is reached, estimated to be 81 weeks after enrolling the last participant.
A participant that becomes HIV-infected during Step 2 of the study will permanently discontinue study product, be placed on immediate suppressive ART, and be followed for 52 weeks after their last injection, after which their participation in the study will end and they will be transitioned to continued HIV-related care.
Step 3:
Arms A and B – Open-label daily TDF/FTC (in order to cover the pharmacokinetic [PK] tail for Arm A participants) will be provided no later than eight weeks after the last injection visit, for up to 48 weeks plus an HIV prevention package including behavioral risk reduction and adherence counseling, and provision of condoms. Participants will then transition to locally available HIV prevention services, including services for PrEP, if available.
A participant with confirmed HIV infection during Step 3 will be followed at least for the duration of Step 3.
What were the results of the study?
In November 2020, researchers from the HPTN announced the HPTN 084 clinical trial data indicating that a pre-exposure prophylaxis (PrEP) regimen of long-acting cabotegravir (CAB LA) injections once every eight weeks was safe and superior to daily oral tenofovir/emtricitabine (TDF/FTC) for HIV prevention among cisgender women in sub-Saharan Africa. During a planned review of study data, an independent Data and Safety Monitoring Board (DSMB) recommended the study sponsor―the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health―stop the blinded phase of the trial and share the results. The study was originally designed to continue through 2022. Read more.
Study Documents
HPTN 084 Open Label Extension (OLE)
HPTN 084 Dear Participant Letter
HPTN 084 Version 5.0
- HPTN 084 Protocol V5.0 - 6 October 2023
- HPTN 084 Summary of Changes from V4.0 to V5.0 - October 2023
- HPTN 084 Version 5.0 Training - 29 September 2023
HPTN 084 Version 4.0
- HPTN 084 Protocol V4.0 - 2 November 2022
- HPTN 084 Summary of Changes from V3.0 to V4.0 - 2 November 2022
- HPTN 084 Clarification Memo #1 to V4.0 Protocol
- HPTN 084 Version 4.0 Training - 24-25 January 2023
- HPTN 084 Training Agenda V4.0
- Day 1
- Day 2
- HPTN 084 Training Agenda V4.0
HPTN 084 Version 3.0
- HPTN 084 Protocol V3.0 - 12 August 2021
- HPTN 084 V3.0 LoA #1 - 24 September 2021
- HPTN 084 V3.0 LoA #2 - 3 February 2022
- HPTN 084 V3.0 LoA #3 - 14 March 2022
- HPTN 084 V3.0 CM#1 - 7 December 2021
- HPTN 084 Summary of Changes from V2.0 to V3.0 - 12 August 2021
- HPTN 084 Clarification Memo #2 to V3.0 Protocol - 21 July 2022
HPTN 084 Version 2.0
- HPTN 084 Protocol V2.0 - 6 November 2019
- HPTN 084 Summary of Changes from V1.0 to V2.0 - 6 November 2019
- HPTN 084 CM #1 - 22 January 2020
- HPTN 084 LoA #1 - 23 June 2020
- HPTN 084 LoA #2 - 10 Sept. 2020
- HPTN 084 LoA #3 - 22 October 2020
- HPTN 084 LoA #4 - 16 November 2020 (Includes Dear Participant Letter)
- HPTN 084 CM #2 - 16 October 2020
HPTN 084 Version 1.0
- HPTN 084 Protocol V1.0 - 2 March 2017
- HPTN 084 LoA #1 - 15 August 2017
- HPTN 084 LoA #2 - 24 January 2018
- HPTN 084 LoA #3 - 31 May 2018
- HPTN 084 CM #1 - 11 May 2017
- HPTN 084 CM #2 - 26 Sept. 2017
- HPTN 084 CM #3 - 2 August 2019
COVID-19 Resources
- DAIDS COVID-19 Guidance
- The COVID-19 Risk Communication Package For Healthcare Facilities
- WHO guidance for the rational use of personal protective equipment (PPE) for coronavirus disease (COVID-19): March 2020
- WHO guidance on getting your workplace ready for COVID-19
- WHO Q&A on COVID-19 and masks
- CDC Strategies to Optimize the Supply of PPE and Equipment
- Additional resources
Presentations
- HPTN 084 at IAS 2023
- HPTN 084 at CROI 2023
- Long acting cabotegravir: updated efficacy and safety results from HPTN 084 (AIDS 2022) (Slides)
- The relative cost-effectiveness of long-acting injectable cabotegravir versus oral pre-exposure prophylaxis: A modelled economic evaluation and threshold analysis in South Africa based on the HPTN 083 and 084 (AIDS 2022) (Slides)
- Acceptability of injectable versus daily oral pills for HIV prevention: Lesson from HPTN 084 (AIDS 2022) (Poster)
- Acceptability of injectable cabotegravir versus daily oral TDF/FTC for PrEP: Lesson from HPTN 084 (INTEREST 2022) (Poster) (Slides)
- Evaluation of CAB-LA Safety and PK in Pregnant Women in the Blinded Phase of HPTN 084 (CROI 2022) (Poster)
- Counterfactual Estimation of CAB-LA Efficacy Against Placebo Using External Trial Data (CROI 2022) (Slides)
- Estimated Long-acting PrEP Effectiveness in the HPTN 084 Cohort using a Model-Based Counterfactual (IAS 2021) (Slides)
- Long-Acting Injectable PrEP in Women: Laboratory Analysis of HIV Infections in HPTN 084 (IAS 2021) (Poster)
- Long-Acting Injectable Cabotegravir is Safe and Effective in Preventing HIV Infection in Cisgender Women: Results from HPTN 084 (HIV R4P 2021) (Video) (Abstract)
- Long-acting cabotegravir (CAB LA): Planning for Success Across Global at-risk Populations (AIDS 2020) (Poster) (Program)
- Community Presentations for HPTN 083 Results, including HPTN 084 implications (May 2020) (Slides) (Video)
- Cabotegravir for PrEP - Injection Training (Video)
Press
- HPTN 084 Study Demonstrates Superiority of CAB LA to Oral FTC/TDF for the Prevention of HIV
- HIV Prevention Trials Network (HPTN) Announces Initiation of HPTN 084: First Large-Scale Study in Women of a Long-Acting Injectable to Prevent HIV
Other Resources:
Publications:
- List of HPTN 084 Publications - Updated August 2023
- HPTN 084 V3 Publication Guidance - 26 April 2022
- Manuscript Concept Proposal Form
You can request access to private documents (i.e. SSPs) in Microsoft Team by emailing Jeff Webb jwebb@fhi360.org.
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➤ HPTN 084 SSP
(Click to Expand)
Full HPTN 084 SSP (Combined Sections)
HPTN 084 Study-Specific Procedures Manual Overview and Version Control
Section 1: Introduction
Section 2: Protocol
Section 3: Document Requirements
Section 4: Continuation in Protocol Version 4.0 (OLE)
Section 5: Study Procedures
Section 6: Visit Checklists
Section 7: Participant Retention
Section 8: Study Product Considerations
Section 9: Clinical Considerations
Section 10: Adverse Event Reporting and Safety Monitoring
Section 11: Laboratory and Specimen Management Procedures
Section 12: Counseling Considerations
Section 13: Data Management
Section 14: Computer Assisted Self-Interview (CASI)
Section 15: Reporting Plan
Section 16: Data Communiqués
Section 17: COVID-19 Measures
Appendix I: Guidance for the Management of “Discordant/discrepant” HIV Testing Results – HPTN 083 and 084
Study Details
To evaluate the safety and efficacy of the injectable agent, cabotegravir (CAB LA) compared to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), for pre-exposure prophylaxis (PrEP) in HIV-uninfected women.
Multi-site, double blind, two-arm, randomized (1:1), controlled superiority trial of the safety and efficacy of CAB LA compared to daily oral TDF/FTC for HIV prevention.
HIV-uninfected women at risk for acquiring HIV, 18 to 45 years old.
Approximately 3,200 women will be enrolled.
Approximately 4.6 years total, with individual participants being followed on randomized study product between 1.6 years (for the last enrolling participants) to approximately 3.6 years (for the earliest enrolling participants), and on oral TDF/ FTC for an additional 48 weeks. Accrual will require approximately 2 years.
Once randomized to one of two arms, participants will move through the following steps:
Step 1, Oral Run-in Phase:
Arm A – Daily oral cabotegravir (CAB) and oral TDF/FTC placebo for five weeks plus an HIV prevention package including behavioral risk reduction and adherence counseling, provision of condoms.
Arm B – Daily TDF/FTC and oral CAB placebo for five weeks plus an HIV prevention package
including behavioral risk reduction and adherence counseling, provision of condoms.
Step 2, Injection Phase:
Arm A – CAB LA as a single intramuscular [IM] injection at two time points four
weeks apart and every eight weeks thereafter and daily oral TDF/FTC placebo plus an HIV
prevention package including behavioral risk reduction and adherence counseling, provision of
condoms.
Arm B – Daily TDF/FTC and IM placebo (matching vehicle, identical volume as active injectable product in Arm A) at two time points four weeks apart and every eight weeks thereafter plus an HIV prevention package including behavioral risk reduction and adherence counseling, provision of condoms.
Step 2 will continue until the required number of endpoints (111) is reached, estimated to be 81 weeks after enrolling the last participant.
Step 3, Follow-up Phase:
Arms A and B – Open-label daily TDF/FTC (in order to cover the pharmacokinetic [PK] tail for Arm A participants) will be provided no later than eight weeks after the last injection visit, for up to 48 weeks plus an HIV prevention package including behavioral risk reduction and adherence counseling, and provision of condoms. Participants will then transition to locally available HIV prevention services, including services for PrEP, if available.
• Efficacy: To evaluate the relative efficacy of oral CAB/CAB LA (oral run-in and injections, Steps 1 and 2) vs. daily oral TDF/FTC for HIV prevention (Steps 1 and 2).
• Safety: To evaluate the relative safety of oral CAB/CAB LA (oral run-in and injections, Steps 1 and 2) vs. daily oral TDF/FTC for HIV prevention (Steps 1 and 2).
• To compare HIV incidence among participants receiving oral CAB/CAB LA vs. daily oral TDF/FTC (Steps 1, 2 and 3).
• To evaluate relative efficacy of oral CAB/CAB LA vs. oral TDF/FTC in subgroups defined by the baseline factors of: age, herpes simplex virus-2 (HSV-2) serostatus, contraceptive method, and body mass index (BMI).
• To describe and model the relationship between HIV incidence and drug concentration, within each arm.
• To describe the distribution and correlates of drug concentration, within each arm.
• To compare the acceptability of and preferences for CAB LA vs. oral TDF/FTC.
Tertiary
• To estimate and compare sexual risk behaviors, as measured by self-report and rates of incident sexually transmitted infections (STIs), between study arms.
• To compare Grade >2 adverse event (AE) rates in women with baseline BMI </≥ 25 kg/m2, within each study arm.
• To compare pregnancy incidence and outcomes between arms.
• To evaluate rates of HIV drug resistance among participants who acquire HIV infection during the study among participants receiving oral CAB/CAB LA vs. oral TDF/FTC.
• To determine plasma concentrations of medroxyprogesterone (DMPA) or norethisterone (NET-EN) when co-administered with CAB LA.
• To determine lutenizing hormone (LH), follicular stimulating hormone (FSH), and progesterone in subjects receiving either DMPA or NET-EN when co-administered with CAB LA.
Exploratory
• To compare the estimated programmatic cost, cost-effectiveness and disease impact indicators of CAB LA vs. daily oral TDF/FTC vs. no PrEP for HIV-uninfected women in the study sites locations.
• To perform secondary laboratory assessments that may include evaluation of factors related to HIV infection, hepatitis infection, and other infections; antiretroviral (ARV) drug use; pharmacogenomics; characterization of HIV in infected participants; and evaluation of laboratory assays related to the study objectives.