Dolutegravir Plus Lamivudine Dual Therapy in Treatment Naïve HIV-1 Patients

A Study to Evaluate Dolutegravir Plus Lamivudine Dual Therapy for the Treatment of Naïve HIV-1-infected Participants

This study was done to see if the combination of two anti-HIV medicines, dolutegravir (DTG, Tivicay) and lamivudine (3TC, Epivir) taken once a day, provide a safe, effective, and well-tolerated treatment for HIV. DTG is a type of HIV medicine called an integrase inhibitor; 3TC is a type of HIV medicine called a reverse transcriptase inhibitor. DTG works by blocking integrase and 3TC works by blocking reverse transcriptase, two HIV proteins (enzymes). This prevents HIV from multiplying and lowers the viral load (amount of HIV in the blood). Both DTG and 3TC are currently part of Food and Drug Administration (FDA) recommended regimens along with a third active drug. Since some HIV medicines have side effects and are costly, there is interest in whether HIV can be successfully controlled with fewer than three HIV drugs.

Study Overview

• Status: Completed
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: Dolutegravir; Drug: Lamivudine

Detailed Description

This study was a phase II, single-arm, open-label pilot study designed to estimate the efficacy of dolutegravir (DTG) plus lamivudine (3TC) as initial combination ART (antiretroviral therapy) in HIV-1 infected treatment naive participants. The target enrollment was 120 participants with a cap of N=90 participants with screening HIV-1 RNA <= 100,000 copies/mL. The study aimed to enroll >= 20% women. The expected follow-up for each participant was 52 weeks.

Visits occurred at screening, entry, and weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52 from study entry. All signs/symptoms within 30 days prior to entry were recorded. Subsequently, grade 2 or higher rash and all other grade 3 or higher signs and symptoms were recorded. All participants underwent routine monitoring including plasma HIV-1 RNA levels, CD4+ cell count, hematology, chemistry, urinalysis, and pregnancy testing (for women of reproductive potential).

Population-based protease (PR), reverse transcriptase (RT) and integrase genotyping were done at the time of confirmed virologic failure. Plasma samples were stored for potential future studies to assess the impact of adherence, drug-resistant minority viral variants, and DTG exposure on virologic and CD4+ cell count responses to DTG plus 3TC. All participants also underwent UGT1A1 genotyping.

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 2

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00935
    • Puerto Rico-AIDS CRS (5401)
• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA CARE Center CRS (601)
    • Los Angeles, California, United States, 90033
      • University of Southern California CRS (1201)
    • San Diego, California, United States, 92103
      • Ucsd, Avrc Crs (701)
    • Torrance, California, United States, 90502
      • Harbor-UCLA Med. Ctr. CRS (603)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital CRS (6101)
  • Florida
    • Miami, Florida, United States, 33136
      • Univ. of Miami AIDS CRS (901)
  • 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 York
    • New York, New York, United States, 10011
      • Cornell CRS (7804)
    • New York, New York, United States, 10032
      • Columbia Physicians and Surgeons CRS (30329)
    • New York, New York, United States, 10011
      • Weill Med. College of Cornell Univ., The Cornell CTU -Chelsea (7803)
    • Rochester, New York, United States, 14642
      • University of Rochester Adult HIV Therapeutic Strategies Network CRS (31787)
  • 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
      • Hosp. of the Univ. of Pennsylvania CRS (6201)
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • The Miriam Hospital ACTG CRS (2951)
  • Tennessee
    • Nashville, Tennessee, United States, 37204
      • Vanderbilt Therapeutics CRS (3652)
  • Texas
    • Dallas, Texas, United States, 75208
      • 31443 Trinity Health and Wellness Center CRS
    • Houston, Texas, United States, 77030
      • Houston AIDS Research Team CRS (31473)

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

NOTE: Further information on the eligibility criteria can be found in the study protocol.

Inclusion Criteria:

• HIV-1 infection.
• Plasma HIV-1 RNA ≥1000 copies/mL and <500,000 copies/mL obtained within 90 days prior to study entry.
• No evidence of any RT, any integrase, or major protease resistance mutation (according to the 2014 IAS-USA drug resistance mutations list, available at https://www.iasusa.org/sites/default/files/tam/22-3-642.pdf) based on pre-ARV (antiretroviral) treatment genotype performed any time prior to study entry.
• ARV treatment drug-naive (defined as no previous ARV treatment at any time prior to study entry, with the exception of successful post-exposure prophylaxis (PEP) or pre-exposure prophylaxis (PrEP).

• The following laboratory values obtained within 45 days prior to study entry:

  • ANC (absolute neutrophil count) ≥750/mm^3
  • Hemoglobin ≥10.0 g/dL
  • Platelets ≥ 50,000/mm^3
  • Calculated creatinine clearance (CrCl) ≥50 mL/min, as estimated by the Cockcroft-Gault equation
  • AST (aspartate aminotransferase) <5 x ULN (upper limit of normal)
  • ALT (alanine aminotransferase) <5x ULN
  • Total bilirubin <1.5 x ULN
• Hepatitis B surface antigen negative within 45 days prior to study entry.
• For women with reproductive potential, negative serum or urine pregnancy test at screening and within 48 hours prior to study entry.
• If participating in sexual activity that could lead to pregnancy, female participants with reproductive potential must have agreed to use one form of contraceptive as listed in the protocol while receiving protocol-specified medications and for 30 days after stopping the medications.
• Ability and willingness of participant or legal representative to provide informed consent.

Exclusion Criteria:

• Serious illness requiring systemic treatment and/or hospitalization.
• Treatment within 30 days prior to study entry with immune modulators such as systemic steroids, interleukins, interferons, granulocyte colony-stimulating factor (G-CSF), erythropoietin, or any investigational therapy.
• Pregnancy or breastfeeding.
• Receipt of systemic cytotoxic chemotherapy or dofetilide.
• Known allergy/sensitivity to any of the study drugs or their formulations.
• Active drug or alcohol use or dependence that may interfere with adherence to study requirements, in the opinion of the site investigator.
• Active hepatitis C virus (HCV) treatment or anticipated need for treatment within study period.
• Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Severe hepatic impairment (Class C) as determined by Child-Pugh classification.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm 1: DTG 50 mg + 3TC 300 mg; Dolutegravir 50mg and Lamivudine 300mg, orally daily	Drug: Dolutegravir; Participants were prescribed 50 mg of DTG orally daily; Other Names: DTG; Drug: Lamivudine; Participants were prescribed 300 mg of 3TC orally daily.; Other Names: 3TC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Virologic Status at Week 24	Numbers of Participants With Virologic Success, Virologic Non-Success, and no Virologic Data at Week 24 Window are provided below. Virologic success is defined as HIV-1 RNA <50 copies/mL and on study treatment (FDA Snapshot definition).	At 24 weeks after study entry

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Virologic Status at Week 12	Numbers of Participants With Virologic Success, Virologic Non-Success, and no Virologic Data at Week 12 Window are provided below. Virologic success is defined as HIV-1 RNA <50 copies/mL and on study treatment (FDA Snapshot definition).	At 12 weeks after study entry
Virologic Status at Week 48	Numbers of Participants With Virologic Success, Virologic Non-Success, and no Virologic Data at Week 48 Window are provided below. Virologic success is defined as HIV-1 RNA <50 copies/mL and on study treatment (FDA Snapshot definition).	At 48 weeks after study entry
Virologic Failure	Virologic failure is defined as follows: Weeks 16 or 20: confirmed plasma HIV-1 RNA > 400 copies/mL; Week 24 or later: confirmed plasma HIV-1 RNA > 200 copies/mLParticipants were evaluated for virologic failure regardless of whether on study treatment.Confirmation was determined based on any two consecutive evaluations meeting the virologic failure definition regardless of the time between them.Participants discontinuing the study (for any reason, including death and lost to follow-up) were considered virologic failures if their last measurement met the definition of virologic failure but no confirmatory measurement was obtained. All other participants' follow-up was censored immediately after the last available plasma HIV-1 RNA measurement.	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
Proportion of Participants With Plasma HIV-1 RNA < 50 Copies/mL - Missing = Failure	Proportion of participants with HIV-1 RNA < 50 copies/mL by week, ITT (Intention To Treat; missing/off study/off treatment = failure) population.	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
Proportion of Participants With Plasma HIV-1 RNA < 200 Copies/mL - Missing = Failure	Proportion of participants with HIV-1 RNA < 200 copies/mL by week, ITT (missing/off study/off treatment = failure) population.	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL - Missing = Ignored	Proportion of participants with HIV-1 RNA < 50 copies/mL by week, ITT (missing = ignored) population.	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
Proportion of Participants With Plasma HIV-1 RNA <200 Copies/mL- ITT Missing = Ignored	Proportion of participants with HIV-1 RNA < 200 copies/mL by week, ITT (missing = ignored) population.	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL- As Treated	Proportion of participants with HIV-1 RNA < 50 copies/mL by week, as treated population.	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
Proportion of Participants With Plasma HIV-1 RNA <200 Copies/mL- As Treated	Proportion of participants with HIV-1 RNA < 200 copies/mL by week, as treated population.	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
CD4+ Cell Count	CD4+ cell counts by study week.	Baseline, weeks 4, 12, 24, and 48
Change in CD4+ Cell Count	Change in CD4+ cell counts by study week. Change was calculated as value at the later visit minus the value at baseline.	Baseline, weeks 4, 12, 24, and 48
Number of HIV-1 Drug Resistance Mutation Occurrences in Participants	Number of HIV-1 drug resistance mutation occurrences participants with virologic failure and FDA snapshot non-successes. Participants that had one drug class resistance mutation may have one or more mutations.	at the time of virologic failure
Fasting Lipids and Glucose	Fasting lipids include: total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, and glucose. Fasting was set to be 8 hours prior to the sample collection.	Baseline and week 48
Creatinine Clearance	Creatinine clearance was estimated by the Cockcroft-Gault equation.	Baseline, weeks 4, 12, 24, 32, 40 and 48
Number of Participants With Grade 3 of Higher Adverse Events	Number of participants who experienced an AE (sign/symptom or laboratory abnormality) of Grade 3 or higher. The AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (see reference in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening.	from study treatment dispensation through up to week 52 or until study discontinuation

Collaborators and Investigators

• Sponsor: AIDS Clinical Trials Group
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Roy Gulick, MD, MPH, Weill Medical College of Cornell University; Study Chair: Babafemi Taiwo, MBBS, Northwestern University

Publications and helpful links

General Publications

• Nyaku AN, Zheng L, Gulick RM, Olefsky M, Berzins B, Wallis CL, Godfrey C, Sax PE, Acosta EP, Haas DW, Smith KY, Sha BE, Van Dam CN, Taiwo BO; ACTG A5353 Study Team. Dolutegravir plus lamivudine for initial treatment of HIV-1-infected participants with HIV-1 RNA <500 000 copies/mL: week 48 outcomes from ACTG 5353. J Antimicrob Chemother. 2019 May 1;74(5):1376-1380. doi: 10.1093/jac/dky564.
• Taiwo BO, Zheng L, Stefanescu A, Nyaku A, Bezins B, Wallis CL, Godfrey C, Sax PE, Acosta E, Haas D, Smith KY, Sha B, Van Dam C, Gulick RM. ACTG A5353: A Pilot Study of Dolutegravir Plus Lamivudine for Initial Treatment of Human Immunodeficiency Virus-1 (HIV-1)-infected Participants With HIV-1 RNA <500000 Copies/mL. Clin Infect Dis. 2018 May 17;66(11):1689-1697. doi: 10.1093/cid/cix1083.

Helpful Links

• DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0 November 2014
• FDA Snapshot Definition (refer to Appendix A in FDA Snapshot PDF)
• DAIDS Adverse Events Manual, Version 2.0 January 2010

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 8, 2015
• Primary Completion (ACTUAL): February 28, 2017
• Study Completion (ACTUAL): September 26, 2017

Study Registration Dates

• First Submitted: October 20, 2015
• First Submitted That Met QC Criteria: October 20, 2015
• First Posted (ESTIMATE): October 21, 2015

Study Record Updates

• Last Update Posted (ACTUAL): May 9, 2018
• Last Update Submitted That Met QC Criteria: April 10, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Lamivudine; Dolutegravir
• Other Study ID Numbers: ACTG A5353; 2UM1AI068636 (U.S. NIH Grant/Contract)