Clinical trial NCT02582684: Dolutegravir Plus Lamivudine Dual Therapy in Treatment Naïve HIV-1 Patients
Official title: A Study to Evaluate Dolutegravir Plus Lamivudine Dual Therapy for the Treatment of Naïve HIV-1-infected Participants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV-1 Infection
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2015-10-21
Enrollment: 122
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Virologic Status at Week 24
timeFrame: At 24 weeks after study entry
Secondary outcomes:
measure: Virologic Status at Week 12
timeFrame: At 12 weeks after study entry
measure: Virologic Status at Week 48
timeFrame: At 48 weeks after study entry
measure: Virologic Failure
timeFrame: Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
measure: Proportion of Participants With Plasma HIV-1 RNA < 50 Copies/mL - Missing = Failure
timeFrame: Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
measure: Proportion of Participants With Plasma HIV-1 RNA < 200 Copies/mL - Missing = Failure
timeFrame: Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
measure: Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL - Missing = Ignored
timeFrame: Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
measure: Proportion of Participants With Plasma HIV-1 RNA <200 Copies/mL- ITT Missing = Ignored
timeFrame: Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
measure: Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL- As Treated
timeFrame: Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
measure: Proportion of Participants With Plasma HIV-1 RNA <200 Copies/mL- As Treated
timeFrame: Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48
measure: CD4+ Cell Count
timeFrame: Baseline, weeks 4, 12, 24, and 48
measure: Change in CD4+ Cell Count
timeFrame: Baseline, weeks 4, 12, 24, and 48
measure: Number of HIV-1 Drug Resistance Mutation Occurrences in Participants
timeFrame: at the time of virologic failure
measure: Fasting Lipids and Glucose
timeFrame: Baseline and week 48
measure: Creatinine Clearance
timeFrame: Baseline, weeks 4, 12, 24, 32, 40 and 48
measure: Number of Participants With Grade 3 of Higher Adverse Events
timeFrame: from study treatment dispensation through up to week 52 or until study discontinuation
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California CRS (1201)
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS (601)
state: California
city: San Diego
country: United States
facility: Ucsd, Avrc Crs (701)
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Med. Ctr. CRS (603)
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS (6101)
state: Colorado
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS (901)
state: Florida
city: Atlanta
country: United States
facility: The Ponce de Leon Center CRS (5802)
state: Georgia
city: Chicago
country: United States
facility: Northwestern University CRS (2701)
state: Illinois
city: Chicago
country: United States
facility: Rush Univ. Med. Ctr. ACTG CRS (2702)
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS (101)
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hosp. ACTG CRS (107)
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University CRS (2101)
state: Missouri
city: New York
country: United States
facility: Cornell CRS (7804)
state: New York
city: New York
country: United States
facility: Weill Med. College of Cornell Univ., The Cornell CTU -Chelsea (7803)
state: New York
city: New York
country: United States
facility: Columbia Physicians and Surgeons CRS (30329)
state: New York
city: Rochester
country: United States
facility: University of Rochester Adult HIV Therapeutic Strategies Network CRS (31787)
state: New York
city: Chapel Hill
country: United States
facility: 3201 Chapel Hill CRS
state: North Carolina
city: Greensboro
country: United States
facility: Greensboro CRS (3203)
state: North Carolina
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS (2401)
state: Ohio
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS (2301)
state: Ohio
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS (6201)
state: Pennsylvania
city: Providence
country: United States
facility: The Miriam Hospital ACTG CRS (2951)
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt Therapeutics CRS (3652)
state: Tennessee
city: Dallas
country: United States
facility: 31443 Trinity Health and Wellness Center CRS
state: Texas
city: Houston
country: United States
facility: Houston AIDS Research Team CRS (31473)
state: Texas
city: San Juan
country: Puerto Rico
facility: Puerto Rico-AIDS CRS (5401)
Study officials:
affiliation: Weill Medical College of Cornell University
name: Roy Gulick, MD, MPH
role: STUDY_CHAIR
affiliation: Northwestern University
name: Babafemi Taiwo, MBBS
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.