Early ART to Limit Infection and Establishment of Reservoir (EARLIER)

Effect of Antiretroviral Treatment Initiated During Acute HIV-1 Infection on Measures of HIV-1 Persistence and on HIV-1-Specific Immune Responses

The study was done to:

• Start antiretroviral therapy (ART) early in those recently or acutely infected with HIV-1
• See how starting ART as soon as the infection is found affects the amount of HIV-1 in blood and how well the body fights the HIV-1 infection
• Look at the amount of HIV-1 DNA (genetic material for HIV-1) seen in CD4+ T-cells (infection-fighting cells in blood) after 48 weeks of ART
• See how early treatment for HIV affects the numbers of HIV-1 infection fighting cells (CD4+ and CD8+ T-cells) in blood

Study Overview

• Status: Active, not recruiting
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide or bictegravir/emtricitabine/tenofovir alafenamide or other medically-appropriate FDA-approved antiretroviral therapy

Detailed Description

This was a Phase II, prospective, open-label two-step study to measure the effects of early ART on the establishment of HIV-1 reservoir and HIV-1-specific immunity. Participants were enrolled if they fulfilled the inclusion criteria for acute HIV-1 infection (AHI) diagnosis within 7 days prior to entry and had an enrollment visit with the immediate initiation of ART. Plasma and serum samples for Fiebig staging were collected at the time of ART initiation.

Participants were followed for up to 216 weeks (72 weeks on Step 1 and 144 weeks on Step 2). Evaluations at weeks 2 and 8 on Step 1 were performed via telephone.

The Fiebig stage-classification system was used to characterize the progression from HIV-1 exposure to HIV-1 seroconversion at the time of ART initiation. In this study, the five Fiebig stages of interest were simplified into three study groups as described below (based on HIV-1 antibody diagnostic profile at time of ART initiation).

The primary analysis was based on Step 1. Step 2 was added to the study for long term follow-up. The rationale for the extended follow-up period was to expand the number of available participants for future therapeutic and cure studies without the burden of frequent visits and the cost of study-provided laboratory testing.

Group 1: Fiebig I/II (non-reactive HIV-1 antibody)

Group 2: Fiebig III/IV (reactive HIV-1 antibody and negative or indeterminate results on the Western Blot (WB) or Geenius HIV-1/HIV-2)

Group 3: Fiebig V (reactive HIV-1 antibody and positive WB or Geenius HIV-1/HIV-2 without p31 band)

Although participants in Fiebig VI (positive WB or Geenius HIV-1/HIV-2 with p31 band) were not specifically targeted for enrollment in this study, it was possible that a small number of participants would be determined to be in Fiebig VI (positive Western blot or Geenius HIV-1/HIV-2 with p31 band) based on analysis of the entry samples. Participants who were determined to be in Fiebig VI were followed on the study for no more than 24 weeks on Step 1, allowing ample time for them to pursue alternative sources for ART. Enrolled participants without HIV or in Fiebig VI were replaced.

The study-provided regimen was single tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/COBI/FTC/TAF) or bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). Other non-study-provided antiretroviral (ARV) regimens were also allowed for participants who were pregnant, breastfeeding, or unable/unwilling to take EVG/COBI/FTC/TAF or BIC/FTC/TAF, or for participants whose local health care/primary care provider preferred starting a different initial ARV regimen.

• Study Type: Interventional
• Enrollment (Actual): 195
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • Rio de Janeiro, Brazil, 21045
    • Instituto de Pesquisa Clinica Evandro Chagas (12101)
  • RS
    • Porto Alegre, RS, Brazil, 9043010
      • Hospital Nossa Senhora da Conceicao CRS (12201)
• Malawi
  • Lilongwe, Malawi
    • Malawi CRS (12001)
• Peru
  • Lima, Peru, 18
    • Barranco CRS
  • Lima
    • San Isidro, Lima, Peru
      • San Miguel CRS (11302)
• Thailand
  • Patumwan
    • Bangkok, Patumwan, Thailand, 10330
      • 31802 Thai Red Cross AIDS Research Center Treatment (TRC-ARC Treatment) CRS
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • 31788 Alabama CRS
  • California
    • San Diego, California, United States, 92103
      • Ucsd, Avrc Crs (701)
    • Torrance, California, United States, 90502
      • Harbor-UCLA Med. Ctr. CRS (603)
  • District of Columbia
    • Washington, District of Columbia, United States, 20009
      • Whitman Walker Health CRS (31791)
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • The Ponce de Leon Center CRS (5802)
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University CRS (2701)
    • Chicago, Illinois, United States, 60612
      • Rush Univ. Med. Ctr. ACTG CRS (2702)
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital ACTG CRS (101)
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hosp. ACTG CRS (107)
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University CRS (2101)
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • 31786 New Jersey Medical School Clinical Research Center CRS
  • New York
    • New York, New York, United States, 10032
      • Columbia Physicians and Surgeons CRS (30329)
    • New York, New York, United States, 10010
      • 7804 Weill Cornell Chelsea CRS
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27516
      • 3201 Chapel Hill CRS
    • Greensboro, North Carolina, United States, 27401
      • Greensboro CRS (3203)
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Univ. of Cincinnati CRS (2401)
    • Columbus, Ohio, United States, 43210
      • The Ohio State Univ. AIDS CRS (2301)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • 6201 Penn Therapeutics CRS
    • Pittsburgh, Pennsylvania, United States, 15213
      • Pittsburgh CRS (1001)
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • The Miriam Hosp. ACTG CRS (2951)
  • Texas
    • Dallas, Texas, United States, 75208
      • 31443 Trinity Health and Wellness Center CRS
    • Houston, Texas, United States, 77030
      • 31473 Houston AIDS Research Team (HART) CRS
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington AIDS CRS (1401)
• Zimbabwe
  • Harare, Zimbabwe
    • Milton Park CRS (30313)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Appropriate documentation from medical records of diagnosis of acute HIV-1 infection (AHI) within 7 days prior to enrollment, that includes one of the following:

1. A detectable HIV-1 RNA within 28 days prior to study entry AND a non-reactive HIV-1 antibody within 7 days prior to entry OR
2. A detectable HIV-1 RNA or a reactive HIV-1 antibody within 28 days prior to study entry AND a negative/indeterminate WB or negative/indeterminate Geenius HIV-1/HIV-2 Supplemental Assay within 7 days prior to entry OR
3. A documented non-reactive HIV-1 antibody or negative HIV-1 RNA within 90 days prior to study entry AND a documented reactive HIV-1 antibody or positive WB that is negative for p31 band or a positive Geenius HIV-1/HIV-2 Supplemental Assay that is negative for p31 band within 7 days prior to entry OR
4. ARCHITECT or GSCOMBO S/CO ≥10 within 7 days prior to entry AND a non-reactive HIV-1 antibody within 7 days prior to entry OR
5. ARCHITECT or GSCOMBO S/CO ≥1 within 7 days prior to entry AND a non-reactive HIV-1 antibody within 7 days prior to entry AND a known prior S/CO <0.5 within 90 days prior to entry OR
6. ARCHITECT or GSCOMBO S/CO >0.5 but <10 within 7 days prior to entry AND a non-reactive HIV-1 antibody within 7 days prior to entry AND detectable HIV-1 RNA within 7 days prior to entry

Note A: HIV-1 RNA result must be reported from an FDA-approved or CE-marked assay.

Note B: Since characterization of Fiebig stage using samples at the time of ART initiation was performed with results known within 12 weeks based on standardized, centralized testing, an estimated Fiebig group at enrollment based on inclusion criteria as shown in the table above will provide additional real-time monitoring for accruals into each study group.

• Ability and willingness of candidate to provide written informed consent.
• Ability and willingness to initiate ART at enrollment.
• Ability and willingness to participate in scheduled study visits for up to 72 weeks.
• Female candidates of reproductive potential who are not pregnant at the time of enrollment and who will receive the study-provided EVG/COBI/FTC/TAF and must agree not to participate in the conception process (ie, active attempt to become pregnant, in vitro fertilization), and if participating in sexual activity that could lead to pregnancy, the female candidate must agree to use at least one reliable form of contraceptive while receiving study-provided treatment.

Female candidates are considered to be of reproductive potential if any of the following conditions apply:

• Candidate has experienced menarche.
• Candidate has not undergone bilateral tubal ligation, bilateral oophorectomy, or hysterectomy.
• Candidate has not experienced menopause, defined as lack of menstruation within the preceding 12 months.

Acceptable contraceptive methods include:

• Condoms (male or female) with or without a spermicidal agent
• Diaphragm or cervical cap with spermicide
• Intrauterine device
• Hormonal contraceptive

Female candidates who are not of reproductive potential or whose male partner(s) has documented azoospermia are not required to use contraceptives. Any statement of self-reported sterility or that of her partner must be entered in the source documents.

NOTE: Acceptable documentation of lack of reproductive potential is oral or written documentation from the individual.

Female candidates who are prescribed a non-study-provided ARV regimen should discuss the safety of that regimen during conception and pregnancy with the prescribing physician. Such individuals should follow medical guidance regarding any potential need for contraception while using the non-study-provided ARV regimen.

Note: Pregnant and breastfeeding women may enroll in the study provided that they meet the eligibility requirements and have access to non-study-provided ARV regimens.

Exclusion Criteria:

• Positive HIV-1 antibody test ≥90 days prior to study entry.
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Any acute, chronic, or recent and clinically significant medical condition that, in the opinion of the site investigator, would interfere with adherence to study requirements or jeopardize the safety or rights of the participant.
• Receipt of an investigational study agent within 28 days prior to enrollment
• Chronic or recurrent use of medications that modify host immune response, eg, oral or parenteral steroids, cancer chemotherapy.
• AHI diagnosis within 60 days after receiving any investigational ARV or HIV-1 vaccine or immune prophylaxis for HIV-1 infection.
• Use of ARVs for pre- or post-exposure prophylaxis within 60 days prior to the diagnosis of AHI.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm 1: Fiebig I/II; Participants enrolled during Fiebig stages I or II (non-reactive HIV-1 antibody).	Drug: elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide or bictegravir/emtricitabine/tenofovir alafenamide or other medically-appropriate FDA-approved antiretroviral therapy; Participants received one tablet of elvitegravir 150mg/cobicistat 150mg/emtricitabine 200mg/tenofovir alafenamide 10mg by mouth daily with food or one tablet of bictegravir 50mg/emtricitabine 200mg/tenofovir alafenamide 25mg by mouth daily with or without food. Other non-study-provided ARV regimens were allowed for participants who were pregnant, breastfeeding, or unable/unwilling to take EVG/COBI/FTC/TAF or BIC/FTC/TAF, or for participants whose local health care/primary care provider preferred starting a different initial ARV regimen.; Other Names: Single-tablet regimen EVG/COBI/FTC/TAF or Genvoya; Single-tablet regimen BIC/FTC/TAF or Biktarvy
EXPERIMENTAL: Arm 2: Fiebig III/IV; Participants enrolled during Fiebig stages III or IV (reactive HIV-1 antibody and negative or indeterminate results on the Western blot or Geenius HIV-1/HIV-2).	Drug: elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide or bictegravir/emtricitabine/tenofovir alafenamide or other medically-appropriate FDA-approved antiretroviral therapy; Participants received one tablet of elvitegravir 150mg/cobicistat 150mg/emtricitabine 200mg/tenofovir alafenamide 10mg by mouth daily with food or one tablet of bictegravir 50mg/emtricitabine 200mg/tenofovir alafenamide 25mg by mouth daily with or without food. Other non-study-provided ARV regimens were allowed for participants who were pregnant, breastfeeding, or unable/unwilling to take EVG/COBI/FTC/TAF or BIC/FTC/TAF, or for participants whose local health care/primary care provider preferred starting a different initial ARV regimen.; Other Names: Single-tablet regimen EVG/COBI/FTC/TAF or Genvoya; Single-tablet regimen BIC/FTC/TAF or Biktarvy
EXPERIMENTAL: Arm 3: Fiebig V; Participants enrolled during Fiebig stage V (reactive HIV-1 antibody and positive Western blot or Geenius HIV-1/HIV-2 without p31 band).	Drug: elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide or bictegravir/emtricitabine/tenofovir alafenamide or other medically-appropriate FDA-approved antiretroviral therapy; Participants received one tablet of elvitegravir 150mg/cobicistat 150mg/emtricitabine 200mg/tenofovir alafenamide 10mg by mouth daily with food or one tablet of bictegravir 50mg/emtricitabine 200mg/tenofovir alafenamide 25mg by mouth daily with or without food. Other non-study-provided ARV regimens were allowed for participants who were pregnant, breastfeeding, or unable/unwilling to take EVG/COBI/FTC/TAF or BIC/FTC/TAF, or for participants whose local health care/primary care provider preferred starting a different initial ARV regimen.; Other Names: Single-tablet regimen EVG/COBI/FTC/TAF or Genvoya; Single-tablet regimen BIC/FTC/TAF or Biktarvy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants With Undetectable Cell-associated HIV-1 DNA (CAHD)	Proportion of participants with 0 copies of CAHD per 5 million CD4+ blood-derived CD4+ T-cells (assayed by quantitative polymerase chain reaction [qPCR]), assessed separately and jointly by integrase and gag assays. In order for a participant to be considered as having 0 copies of CAHD for joint assays, the participant must be found to have an undetectable CAHD result from both integrase and gag assays. If all participants in both arms had undetectable CAHD then the statistical test was not performed.	At week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HIV-1-specific CD4+ and T-cell Responses to Nef, Gag, Pol and Env by Flow Cytometry	Percent of HIV-1-specific CD4+ T-cells expressing any cytokine/marker (CD40L, CD107a, IFNg, MIP1B, TNFa) to each of the 4 protein stimulants (nef, gag, pol and env) by flow cytometry while HIV-1 RNA is suppressed on ART. The results for a specific participant are calculated by subtracting the corresponding background control value (media control). If the result would be less than zero after background subtraction, the result was set to zero. Cytokine/Marker Names: CD40 ligand (CD40L); Cluster of Differentiation 107a (CD107a); Interferon gamma (IFNg); Macrophage Inflammatory Protein beta (MIP1B); Tumor Necrosis Factor alpha (TNFa)	At week 48
HIV-1-specific CD8+ and T-cell Responses to Nef, Gag, Pol and Env by Flow Cytometry	Percent of HIV-1-specific CD8+ T-cells expressing any cytokine/marker (CD40L, CD107a, IFNg, MIP1B, TNFa) to each of the 4 protein stimulants (nef, gag, pol and env) by flow cytometry while HIV-1 RNA is suppressed on ART. The results for a specific participant are calculated by subtracting the corresponding background control value (media control). If the result would be less than zero after background subtraction, the result was set to zero. Cytokine/Marker Names: CD40 ligand (CD40L); Cluster of Differentiation 107a (CD107a); Interferon gamma (IFNg); Macrophage Inflammatory Protein beta (MIP1B); Tumor Necrosis Factor alpha (TNFa)	At 48 weeks
Proportion of Participants With Undetectable Cell-associated HIV-1 DNA (CAHD) Prior to ART Initiation	Proportion of participants with 0 copies of CAHD per million CD4+ blood-derived CD4+ T-cells (assayed by quantitative PCR [qPCR]), assessed separately and jointly by integrase and gag assays. In order for a participant to be considered as having 0 copies of CAHD for joint assays, the participant must be found to have an undetectable CAHD result from both integrase and gag assays. If all participants in both arms had undetectable CAHD then the statistical test was not performed.	At week 0

Collaborators and Investigators

• Sponsor: AIDS Clinical Trials Group
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• Crowell TA, Ritz J, Coombs RW, Zheng L, Eron JJ, Mellors JW, Dragavon J, van Zyl GU, Lama JR, Ruxrungtham K, Grinsztejn B, Arduino RC, Fox L, Ananworanich J, Daar ES; AIDS Clinical Trials Group A5354/EARLIER (Early ART to Limit Infection and Establishment of Reservoir) Study Team. Novel Criteria for Diagnosing Acute and Early Human Immunodeficiency Virus Infection in a Multinational Study of Early Antiretroviral Therapy Initiation. Clin Infect Dis. 2021 Aug 2;73(3):e643-e651. doi: 10.1093/cid/ciaa1893.

Helpful Links

• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010
• The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.1, July 2017

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 1, 2017
• Primary Completion (ACTUAL): December 2, 2020
• Study Completion (ANTICIPATED): April 30, 2025

Study Registration Dates

• First Submitted: August 4, 2016
• First Submitted That Met QC Criteria: August 4, 2016
• First Posted (ESTIMATE): August 9, 2016

Study Record Updates

• Last Update Posted (ACTUAL): February 6, 2023
• Last Update Submitted That Met QC Criteria: February 2, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Communicable Diseases; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Integrase Inhibitors; Tenofovir; Emtricitabine; Emtricitabine tenofovir alafenamide; Cobicistat; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Anti-Retroviral Agents; Elvitegravir
• Other Study ID Numbers: ACTG A5354; 2UM1AI068636 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No