PHI-05: Safety and Efficacy of Fixed Dose Combination Dolutegravir/Abacavir/Lamivudine FDC Initiated During Acute HIV Infection

Sponsor
University of North Carolina, Chapel Hill (Other)
Overall Status
Completed
CT.gov ID
NCT02384395
Collaborator
ViiV Healthcare (Industry)
40
2
1
72.5
20
0.3

Study Details

Study Description

Brief Summary

This is a multicenter, single arm, 96-week open-label study of the safety and virologic efficacy of fixed dose combination Dolutegravir/Lamivudine/Abacavir (DTG/3TC/ABC FDC) initiated during acute HIV infection (AHI).

Condition or Disease Intervention/Treatment Phase
  • Drug: Dolutegravir 50 mg
  • Drug: Lamivudine 300 mg
  • Drug: Abacavir 600 mg
N/A

Detailed Description

The study will be conducted at the University of North Carolina in Chapel Hill, NC and Duke University in Durham, NC. The investigators plan to enroll up to 44 participants who will be enrolled for 96 weeks and will receive DTG/3TC/ABC FDC.

The investigators propose to evaluate the efficacy and time to viral suppression with DTG/3TC/ABC FDC as initial therapy for acute HIV infection (AHI), as well as the feasibility of prompt administration using a rapid human leukocyte antigen-B57 (HLA-B57) screening antibody assay. In addition to validating the restriction of resting cell infection (RCI) by antiretroviral therapy (ART) including a DTG-based regimen initiated during AHI, the investigators will seek correlations between low RCI, residual gastrointestinal associated lymphoid tissue (GALT) HIV expression, and measures of immune activation. The investigators hypothesize that rapid reduction in plasma viremia with this regimen will limit the area under the pre-ART viral load curve, and thus reduce the latent reservoir size as measured by a viral outgrowth assay one to two years following ART start, and as compared with the latent reservoir size in acutely infected individuals started on regimens without an integrase inhibitor based regimen. In addition, the investigators will examine the longitudinal impact of the proposed integrase-based regimen initiated during the acute period on immune activation through week 96. If residual viral expression and persistent immune dysfunction is related to the burden of the latent viral reservoir (and presumably its periodic activation) these abnormalities should be ameliorated by early ART with rapid viral suppression. The investigators hypothesize that earlier treatment coupled with more rapid ART-mediated virus suppression will be associated with better long-term T cell function, specifically better T cell function after 2 years of durable HIV suppression.

Study Design

Study Type:
Interventional
Actual Enrollment :
40 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
IGHID 11417 - The Safety and Efficacy of Fixed Dose Combination Dolutegravir/Abacavir/Lamivudine FDC Initiated During Acute HIV Infection: Impact on the Latent HIV Reservoir and Long-Term Immunologic Effect
Study Start Date :
Sep 1, 2015
Actual Primary Completion Date :
Mar 6, 2020
Actual Study Completion Date :
Sep 17, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: DTG/3TC/ABC FDC

Dolutegravir (DTG 50 mg), abacavir sulfate (ABC 600 mg) and lamivudine (3TC 300 mg) formulated in a single tablet fixed dose combination (FDC) (DTG/ABC/3TC, GSK2619619), administered orally, once daily

Drug: Dolutegravir 50 mg
Initial therapy for AHI
Other Names:
  • DTG
  • Tivicay
  • Drug: Lamivudine 300 mg
    Initial therapy for AHI
    Other Names:
  • 3TC
  • Epivir
  • Drug: Abacavir 600 mg
    Initial therapy for AHI
    Other Names:
  • ABC
  • Ziagen
  • Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Viral Load Measurement <200 Copies/mL at Week 24 [Week 24]

      Total number of participants on study at Week 24 with an HIV-1 RNA level less than 200 copies/mL

    Secondary Outcome Measures

    1. Number of Participants With Grade 3 or Higher Adverse Event (AE) [Baseline through Week 96]

      Sign/symptom, lab toxicity, or clinical events, or Grade 3 or higher AE that is definitely, probably, or possibly related to study treatment

    2. Proportion of Treated Participants With HIV-1 RNA to <50 Copies/mL at Week 48 [Week 48]

      Proportion of participants completing Week 48 with an HIV-1 RNA level less than 50 copies/mL

    3. Median Change HIV-1 RNA Level Among Participants Completing Week 24 Visit [Baseline, Week 24]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    Inclusion Criteria

    1. Documentation of Acute HIV infection at or within 30 days of study entry.

    2. Men and women age ≥18 years.

    3. ART naive, defined as ≤14 days of antiretroviral treatment at any time prior to entry.

    The only exceptions are:
    • Pre-exposure prophylaxis (PrEP) and documented as HIV-1 negative at least 1 month prior to AHI diagnosis during PrEP, and

    • Post-exposure prophylaxis (PEP) provided the participant was documented as HIV-1 negative at least 3-6 months following completion of PEP treatment.

    1. Lab values obtained within 30 days prior to study entry:
    • Absolute neutrophil count >500/mm^3

    • Hemoglobin > 8.5 g/dL for men and > 8.0 g/dL for women

    • Platelet count >50,000/mm^3

    • Lipase ≤ 3 X upper limit of normal (ULN), single repeat test is allowed to determine eligibility

    • Calculated creatinine clearance (CrCl, Cockcroft-Gault formula) ≥ 50 mL/min:

    CrCl = (140-age) x body weight (kg) (x 0.85 if female) Serum creatinine [mg/dL] x (72)

    1. Testing for HBsAg is pending. Note: Participants who test positive for HBsAg will be terminated from the study prior to starting study treatment.

    2. Testing for HLA-B57 and/or HLA-B5701 is pending. Note: Participants who test positive for HLA-B5701 will be terminated from the study prior to starting study treatment.

    3. A female is eligible to enter and participate in the study if she:

    • Is of non-childbearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and ≥ 45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy; or,

    • Is of child-bearing potential, with a negative pregnancy test at screening and at enrollment, who agrees to use one of the methods of contraception listed below.

    • Complete abstinence from intercourse from 2 weeks prior to administration of study medication, throughout the study, and for at least 2 weeks after discontinuation of all study medication;

    • Double barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide);

    • Approved hormonal contraception - used alone is not considered a sufficient form of contraception for the study see Protocol Appendix 1 for a listing of examples of approved hormonal contraception;

    • Any intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year; see Protocol Appendix 2 for a listing of IUDs meeting this criterion;

    • Male partner sterilization confirmed prior to the female participant's entry into the study, and this male is the sole partner for that patient;

    • Any other method with published data showing that the expected failure rate is <1% per year.

    • Any contraception method must be used consistently, in accordance with the approved product label and for at least 2 weeks after discontinuation of the study medication.

    1. Females who meet the post-menopausal definition, noted in inclusion criterion 7, will have a follicle stimulation hormone (FSH) test to verify menopause,

    2. Ability and willingness of participant to give written informed consent.

    Exclusion Criteria

    1. Alanine Transaminase (ALT) ≥ 5 times Upper Limit of Normal (≥5xULN)

    2. Aspartate Aminotransferase (AST) ≥ 3x ULN

    3. Bilirubin ≥1.5x ULN (with >35% direct bilirubin)

    4. Weight <40 kg

    5. Women who are breast-feeding.

    6. Women with a positive pregnancy test on enrollment or prior to study drug administration.

    7. Women and men of child bearing potential unwilling to agree to use an effective methods of contraception required by the study.

    8. History or presence of allergy to the study drugs or their components.

    9. Requires or is anticipated to require any of the prohibited concomitant therapy: barbiturates, dofetilide, fampridine (dalfampridine), modafinil, oxcarbazepine, pioglitazone, pilsicainide, pimozide, rifampin, rifapentine, phenytoin, phenobarbital, carbamazepine, and St. John's wort.

    • Dofetilide, fampridine, and pilsicainide are prohibited, as DTG may inhibit its renal tubular secretion resulting in increased dofetilide concentrations and potential for toxicity.
    1. Unable to discontinue any current medications that are excluded during study treatment.

    2. Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), radiation therapy, HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry.

    • Prednisone at a daily dose of 10 mg or less (physiologic replacement dose) is permitted.
    1. Treatment with radiation therapy or cytotoxic chemotherapeutics agents within 28 days prior to screening or has an anticipated need for these agents during the study.

    2. Administration of an HIV-1 immunotherapeutic vaccine within 90 days prior to screening.

    3. Prior treatment with any other experimental drug for any indication (within 30 days of initiating study treatment).

    4. Difficulty swallowing capsules/tablets.

    5. Inability to communicate effectively with study personnel.

    6. Incarceration; prisoner recruitment and participation are not permitted.

    7. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements or confound the analysis of study endpoints.

    8. Any condition (including but not limited to alcohol and drug use) or any active clinically significant disease or findings during screening of medical history or physical examination, which, in the opinion of the Investigator would interfere with patient safety or compliance.

    9. Serious illness requiring systemic treatment and/or hospitalization until patient either completes therapy or is clinically stable on therapy, in the opinion of the site investigator, for at least 7 days prior to study entry.

    Note: Oral candidiasis, vaginal candidiasis, mucocutaneous herpes simplex, and other minor illnesses (as judged by the site investigator) have no restriction.

    1. A life expectancy less than twelve months.

    2. Acute viral hepatitis, including, but not limited to, hepatitis A, B, or C.

    3. History of myocardial infarction or diagnosis of coronary artery disease.

    4. History of ongoing or clinically relevant pancreatitis within the previous 6 months.

    5. Chronic hepatitis C infection with an anticipated need for treatment during the study period (through week 96).

    6. Chronic hepatitis B infection (see inclusion criterion 5).

    7. Evidence for moderate to severe hepatic impairment (as defined by the presence of cirrhosis, ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice or Child-Pugh class B or greater hepatic impairment).

    8. Evidence of biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

    9. Any verified grade 4 laboratory abnormality with exception of ALT as defined in exclusion criterion 1

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of North Carolina Chapel Hill North Carolina United States 27599
    2 Duke University Health System Durham North Carolina United States 27710

    Sponsors and Collaborators

    • University of North Carolina, Chapel Hill
    • ViiV Healthcare

    Investigators

    • Principal Investigator: Cindy Gay, MD, MPH, University of North Carolina

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    Responsible Party:
    University of North Carolina, Chapel Hill
    ClinicalTrials.gov Identifier:
    NCT02384395
    Other Study ID Numbers:
    • 14-0549
    First Posted:
    Mar 10, 2015
    Last Update Posted:
    Nov 22, 2021
    Last Verified:
    Oct 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by University of North Carolina, Chapel Hill
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title DTG/3TC/ABC FDC
    Arm/Group Description Dolutegravir (DTG 50 mg), abacavir sulfate (ABC 600 mg) and lamivudine (3TC 300 mg) formulated in a single tablet fixed dose combination (FDC) (DTG/ABC/3TC, GSK2619619), administered orally, once daily initiated during acute HIV infection.
    Period Title: Overall Study
    STARTED 40
    Enrolled 40
    Initiated Treatment 37
    Completed Week 24 34
    Completed Week 48 33
    Completed Week 96 30
    COMPLETED 30
    NOT COMPLETED 10

    Baseline Characteristics

    Arm/Group Title DTG/3TC/ABC FDC
    Arm/Group Description Dolutegravir (DTG 50 mg), abacavir sulfate (ABC 600 mg) and lamivudine (3TC 300 mg) formulated in a single tablet fixed dose combination (FDC) (DTG/ABC/3TC, GSK2619619), administered orally, once daily initiated during acute HIV infection.
    Overall Participants 37
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    26
    Sex: Female, Male (Count of Participants)
    Female
    1
    2.7%
    Male
    36
    97.3%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    6
    16.2%
    Not Hispanic or Latino
    31
    83.8%
    Unknown or Not Reported
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    24
    64.9%
    White
    13
    35.1%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (Count of Participants)
    United States
    37
    100%
    Baseline CD4 Count (cells/mm^3) [Median (Full Range) ]
    Median (Full Range) [cells/mm^3]
    478
    Baseline HIV-1 RNA PCR Level (copies/mL) [Median (Full Range) ]
    Median (Full Range) [copies/mL]
    382000

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Viral Load Measurement <200 Copies/mL at Week 24
    Description Total number of participants on study at Week 24 with an HIV-1 RNA level less than 200 copies/mL
    Time Frame Week 24

    Outcome Measure Data

    Analysis Population Description
    Excludes 3 participants who terminated prior to Week 24
    Arm/Group Title DTG/3TC/ABC FDC
    Arm/Group Description Dolutegravir (DTG 50 mg), abacavir sulfate (ABC 600 mg) and lamivudine (3TC 300 mg) formulated in a single tablet fixed dose combination (FDC) (DTG/ABC/3TC, GSK2619619), administered orally, once daily initiated during acute HIV infection.
    Measure Participants 34
    Count of Participants [Participants]
    34
    91.9%
    2. Secondary Outcome
    Title Number of Participants With Grade 3 or Higher Adverse Event (AE)
    Description Sign/symptom, lab toxicity, or clinical events, or Grade 3 or higher AE that is definitely, probably, or possibly related to study treatment
    Time Frame Baseline through Week 96

    Outcome Measure Data

    Analysis Population Description
    Two participants had data collected outside of Week 96 window
    Arm/Group Title DTG/3TC/ABC FDC
    Arm/Group Description Dolutegravir (DTG 50 mg), abacavir sulfate (ABC 600 mg) and lamivudine (3TC 300 mg) formulated in a single tablet fixed dose combination (FDC) (DTG/ABC/3TC, GSK2619619), administered orally, once daily initiated during acute HIV infection.
    Measure Participants 37
    Count of Participants [Participants]
    1
    2.7%
    3. Secondary Outcome
    Title Proportion of Treated Participants With HIV-1 RNA to <50 Copies/mL at Week 48
    Description Proportion of participants completing Week 48 with an HIV-1 RNA level less than 50 copies/mL
    Time Frame Week 48

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title DTG/3TC/ABC FDC
    Arm/Group Description Dolutegravir (DTG 50 mg), abacavir sulfate (ABC 600 mg) and lamivudine (3TC 300 mg) formulated in a single tablet fixed dose combination (FDC) (DTG/ABC/3TC, GSK2619619), administered orally, once daily initiated during acute HIV infection.
    Measure Participants 33
    Number (95% Confidence Interval) [proportion of participants]
    0.88
    2.4%
    4. Secondary Outcome
    Title Median Change HIV-1 RNA Level Among Participants Completing Week 24 Visit
    Description
    Time Frame Baseline, Week 24

    Outcome Measure Data

    Analysis Population Description
    Excludes 3 participants who terminated prior to Week 24
    Arm/Group Title DTG/3TC/ABC FDC
    Arm/Group Description Dolutegravir (DTG 50 mg), abacavir sulfate (ABC 600 mg) and lamivudine (3TC 300 mg) formulated in a single tablet fixed dose combination (FDC) (DTG/ABC/3TC, GSK2619619), administered orally, once daily initiated during acute HIV infection.
    Measure Participants 34
    Median (Full Range) [copies/mL]
    -590211

    Adverse Events

    Time Frame From the time of signing informed consent throughout treatment, a total of approximately 96 weeks.
    Adverse Event Reporting Description
    Arm/Group Title DTG/3TC/ABC FDC
    Arm/Group Description Dolutegravir (DTG 50 mg), abacavir sulfate (ABC 600 mg) and lamivudine (3TC 300 mg) formulated in a single tablet fixed dose combination (FDC) (DTG/ABC/3TC, GSK2619619), administered orally, once daily initiated during acute HIV infection.
    All Cause Mortality
    DTG/3TC/ABC FDC
    Affected / at Risk (%) # Events
    Total 0/37 (0%)
    Serious Adverse Events
    DTG/3TC/ABC FDC
    Affected / at Risk (%) # Events
    Total 5/37 (13.5%)
    Eye disorders
    Anterior Uveitis 1/37 (2.7%) 1
    Gastrointestinal disorders
    Abdominal Pain 1/37 (2.7%) 1
    Diarrhea 1/37 (2.7%) 1
    General disorders
    Chest Pain associated with Back Pain 1/37 (2.7%) 1
    Infections and infestations
    Acute Bronchitis 1/37 (2.7%) 1
    Left Scrotal Cellulitis 1/37 (2.7%) 1
    Left Scrotal Abscess 1/37 (2.7%) 1
    Investigations
    Elevated Alanine Aminotransferase (ALT) 1/37 (2.7%) 1
    Elevated Aspartate Aminotransferase (AST) 1/37 (2.7%) 1
    Metabolism and nutrition disorders
    Diabetic Ketoacidosis without coma associated with T1DM 1/37 (2.7%) 1
    Musculoskeletal and connective tissue disorders
    Back Pain 1/37 (2.7%) 1
    Psychiatric disorders
    Acute Stress Reaction 1/37 (2.7%) 1
    Depression 1/37 (2.7%) 1
    Respiratory, thoracic and mediastinal disorders
    Exacerbation of Asthma 1/37 (2.7%) 1
    Other (Not Including Serious) Adverse Events
    DTG/3TC/ABC FDC
    Affected / at Risk (%) # Events
    Total 21/37 (56.8%)
    Gastrointestinal disorders
    Nausea 7/37 (18.9%) 8
    Vomiting 2/37 (5.4%) 3
    General disorders
    IV Infiltration During Leukapheresis 4/37 (10.8%) 5
    Injury, poisoning and procedural complications
    Citrate Sensitivity 2/37 (5.4%) 4
    Elevated BP During Leukapheresis 13/37 (35.1%) 16
    Investigations
    ALT Increased 3/37 (8.1%) 3
    Creatinine Clearance Decreased 7/37 (18.9%) 8
    Nervous system disorders
    Headache 3/37 (8.1%) 3

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Cynthia Gay, MD, MPH
    Organization University of North Carolina at Chapel Hill
    Phone 919-966-6712
    Email cynthia_gay@med.unc.edu
    Responsible Party:
    University of North Carolina, Chapel Hill
    ClinicalTrials.gov Identifier:
    NCT02384395
    Other Study ID Numbers:
    • 14-0549
    First Posted:
    Mar 10, 2015
    Last Update Posted:
    Nov 22, 2021
    Last Verified:
    Oct 1, 2021