Safety and Efficacy of Dolutegravir/Lamivudine (DTG/3TC) in Therapy-naive Human Immunodeficiency Virus-1 (HIV-1) Infected Adolescents

ViiV Healthcare32 enrolled

Overview

First-line antiretroviral regimens are highly efficacious and generally well tolerated. However, as these regimens need to be taken life-long, there is growing concern about long-term toxicities associated with these regimens. Thus, there is great interest from participants and clinicians in unique regimens that might avoid such toxicities by minimizing the number of antiretrovirals without sacrificing long-term antiviral efficacy. DTG plus 3TC is a novel, well-tolerated first-line regimen for HIV-infected treatment- naive participants, limiting the risk of many common adverse reactions associated with other antiretroviral drugs. This study was designed to evaluate the efficacy and safety of DTG/3TC as an FDC in ART-naive HIV-1-infected adolescents who weighed at least 25 kilograms (kg). The study consisted of a Screening Phase (up to 28 days prior to the first dose of drug), followed by a Treatment Phase (up to 48 weeks). Participants who successfully completed 48 weeks of therapy and continued to receive benefit from DTG/3TC FDC were eligible to enter a 96-week Extension Phase. Study participants who successfully completed both the Treatment Phase through 48 weeks and the Extension Phase through 144 weeks and continued to receive benefit from this two-drug regimen were to continue receiving DTG/3TC FDC in a Continuation Phase (after Week 144) until DTG and 3TC were both locally approved for use as part of a dual regimen and the single entities of DTG and 3TC were available to participants (e.g., through public health services), or the DTG/3TC FDC tablet, if required by local regulations, was locally approved and available (e.g., commercially or through public health services), or the participant no longer derived clinical benefit, or the participant met a protocol-defined reason for discontinuation. All participants received the FDC of DTG/3TC (50/300 milligrams) once daily.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Eligibility

Sex: ALLMin age: 12 YearsMax age: 17 Years

Medical Language ↔ Plain English

Inclusion Criteria: * HIV-1-infected adolescents were 12 to \<18 years of age at the time of signing the informed consent form. * Weight was \>25 kg at the time of signing the informed consent form. * Screening plasma HIV-1 RNA was between 1,000 and =500,000 c/mL. * Participants were antiretroviral-naive (defined as having had no prior therapy with any antiretroviral agent for the treatment of HIV following a diagnosis of HIV-1 infection). Participants who had received ART for prevention of mother-to-child transmission of HIV in the first 3 months of life were allowed. Participants who had received HIV post-exposure prophylaxis (PEP) or pre-exposure prophylaxis (PrEP) in the past were allowed as long as the last PEP/PrEP dose was = 6 months before HIV diagnosis or there was documented HIV seronegativity at least 2 months after the last prophylactic dose and prior to the date of HIV diagnosis. * Male and female participants were included. A female participant was eligible to participate if she was not pregnant (as confirmed by a negative serum human chorionic gonadotropin \[hCG\] test at Screening and a negative urine hCG test before Enrollment) and not lactating. Female participants of child-bearing potential who were engaging in sexual activity that could have led to pregnancy had to agree to use one birth-control method from 28 days prior to the first dose of study medication until 4 weeks after the last dose of study medication (and completion of the follow-up visit). Condoms were additionally recommended, as appropriate use was the only contraceptive method effective in preventing HIV-1 transmission. The investigator was responsible for ensuring that participants understood how to properly use these contraceptive methods. All participants in the study were also counseled on safer sexual practices, including the use and benefit/risk of effective barrier methods (e.g., male condoms), as well as on the risk of HIV transmission to an uninfected partner. * The participant's parent(s) or legal guardian, or the participant, was capable of giving signed informed consent. Exclusion Criteria: * Females who were breastfeeding or who planned to become pregnant or breastfeed during the study were excluded. * Any evidence of active Centers for Disease Control and Prevention (CDC) Stage 3 and/or Category C or World Health Organization (WHO) Stage 4 disease-except cutaneous Kaposi's sarcoma not requiring systemic therapy-and historical or current CD4 cell counts \<200 cells/mm³ or CD4 percent \<15 percent resulted in exclusion. * Participants with severe hepatic impairment (Class C) as determined by the Child-Pugh classification were excluded. * Participants with unstable liver disease (defined by ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), cirrhosis, or known biliary abnormalities (except Gilbert's syndrome or asymptomatic gallstones) were excluded. * Evidence of hepatitis B virus (HBV) infection at Screening led to exclusion as follows: participants positive for HBsAg were excluded; participants negative for anti-HBs but positive for anti-HBc (negative HBsAg) and positive for HBV DNA were excluded. Participants positive for anti-HBc (negative HBsAg) and anti-HBs (past and/or current evidence) were immune to HBV and were not excluded. * Participants with an anticipated need for any HCV therapy during the first 48 weeks of the study-and for any HCV therapy based on interferon or drugs with potential adverse drug-drug interactions with study treatment throughout the entire study period-were excluded. * Untreated syphilis infection (positive rapid plasma reagin \[RPR\] at Screening without clear documentation of treatment) resulted in exclusion. Participants who were at least 24 hours post-completed treatment were eligible. * Participants with a history of sensitivity to any study medication or its components, or to drugs of the same class, or a history of drug or other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicated participation, were excluded. * Participants with ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, resected non-invasive cutaneous squamous cell carcinoma, or cervical, anal, or penile intraepithelial neoplasia were excluded. Other localized malignancies required agreement between the investigator and Study Medical Monitor for inclusion. * Participants who, in the investigator's judgment, posed a significant suicide risk were excluded. A recent history of suicidal behavior and/or suicidal ideation could have been considered evidence of serious suicide risk. * Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening resulted in exclusion. * Treatment with radiation therapy, cytotoxic chemotherapeutic agents, or any systemic immune suppressant within 28 days of Screening resulted in exclusion. * Treatment with any agent with documented activity against HIV-1 in vitro within 28 days of the first study dose resulted in exclusion. * Receipt of any prohibited medication, and inability or unwillingness to switch to an alternative medication, resulted in exclusion. * Exposure to an experimental drug or vaccine within 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent (whichever was longer) prior to the first study dose resulted in exclusion. * Any evidence of pre-existing viral resistance based on any major resistance-associated mutation in Screening or historical results led to exclusion. * Any verified Grade 4 laboratory abnormality led to exclusion. A single repeat test during Screening was allowed to verify results. * Any acute laboratory abnormality at Screening that, in the Investigator's opinion, would have precluded participation in the study of an investigational compound resulted in exclusion. * ALT \>5× the upper limit of normal (ULN), or ALT \>5× ULN with bilirubin \>1.5× ULN (with \>35 percent direct bilirubin), resulted in exclusion. * Creatinine clearance \<50 mL/min/1.73 m² using the Schwartz equation resulted in exclusion. * Children who were wards of the state or government were excluded.

Outcomes

Primary Outcomes

Percentage of Participants With Plasma Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Less Than 50 Copies Per Milliliter (c/mL) at Week 48

Percentage of participants with plasma HIV-1 RNA \<50 c/mL was assessed at Week 48 according to the Food and Drug Administration (FDA) snapshot algorithm.

Time frame: Week 48

Secondary Outcomes

Percentage of Participants With Plasma HIV-1 RNA <200 c/mL at Week 24

Percentage of participants with plasma HIV-1 RNA \<200 c/mL was assessed at Week 24 according to the FDA snapshot algorithm.

Time frame: Week 24

Percentage of Participants With Plasma HIV-1 RNA <200 c/mL at Week 96

Percentage of participants with plasma HIV-1 RNA \<200 c/mL was assessed at Week 96 according to the FDA snapshot algorithm.

Time frame: Week 96

Percentage of Participants With Plasma HIV-1 RNA <200 c/mL at Week 144

Percentage of participants with plasma HIV-1 RNA \<200 c/mL was assessed at Week 144 according to the FDA snapshot algorithm.

Time frame: Week 144

Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 24

Percentage of participants with plasma HIV-1 RNA \<50 c/mL was assessed at Week 24 according to the FDA snapshot algorithm.

Time frame: Week 24

Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 96

Percentage of participants with plasma HIV-1 RNA \<50 c/mL was assessed at Week 96 according to the FDA snapshot algorithm.

Time frame: Week 96

Percentage of Participants With Plasma HIV-1 RNA <50 c/mL at Week 144

Percentage of participants with plasma HIV-1 RNA \<50 c/mL was assessed at Week 144 according to the FDA Snapshot algorithm.

Time frame: Week 144

Percentage of Participants With Plasma HIV-1 RNA <200 c/mL at Week 48

Percentage of participants with plasma HIV-1 RNA \<200 c/mL was assessed at Week 48 according to the FDA snapshot algorithm.

Time frame: Week 48

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Through 144 Weeks

An adverse event is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A serious adverse event is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment.

Time frame: Up to 144 weeks

Number of Participants With AEs Through 144 Weeks by Severity

The Division of Acquired Immunodeficiency Syndrome (DAIDS) criteria for grading the severity of adult and pediatric adverse events was used to assess severity. Grades were defined based on numeric criteria as follows: Grade 1 - mild; Grade 2 - moderate; Grade 3 - severe or medically significant; Grade 4 - life-threatening consequences; Grade 5 - death. A higher grade indicates a greater severity.

Time frame: Up to 144 weeks

Number of Participants With Abnormal Findings for Hematology Parameters Through 144 Weeks

Blood samples were collected from participants for analysis of hematology parameters including hemoglobin, leukocytes and neutrophils. The DAIDS criteria for grading the severity of adult and pediatric adverse events was used to assess severity. Grades were defined based on numeric criteria as follows: Grade 0 - no abnormality; Grade 1 - mild; Grade 2 - moderate; Grade 3 - severe or medically significant; Grade 4 - life-threatening consequences.

Time frame: Up to 144 weeks

Number of Participants With Abnormal Findings for Clinical Chemistry Parameters Through 144 Weeks

Blood samples were collected from participants for analysis of clinical chemistry parameters including potassium, aspartate aminotransferase, creatinine, alanine aminotransferase (ALT), carbon dioxide, alkaline phosphatase, bilirubin, direct bilirubin, sodium, GFR from creatinine adjusted for BSA, calcium, and creatine kinase. Grades were defined based on numeric criteria as follows: Grade 0 - no abnormality; Grade 1 - mild; Grade 2 - moderate; Grade 3 - severe or medically significant; Grade 4 - life-threatening consequences.

Time frame: Up to 144 weeks

Number of Participants With Abnormal Findings for Fasting Lipids Through 144 Weeks

Lipid assessments including cholesterol, low density lipoprotein (LDL) cholesterol, LDL Cholesterol Calculation, LDL Cholesterol Direct, and triglycerides were performed. Grades were defined based on numeric criteria as follows: Grade 0 - no abnormality; Grade 1 - mild; Grade 2 - moderate; Grade 3 - severe or medically significant; Grade 4 - life-threatening consequences.

Time frame: Up to 144 weeks

Number of Participants With Abnormal Findings for Urinalysis Parameters Through 144 Weeks

Urine samples were collected from participants for the analysis of urinalysis parameters including urinary glucose, urinary protein, and urine erythrocytes. Grades were defined based on numeric criteria as follows: Grade 0 - no abnormality; Grade 1 - mild; Grade 2 - moderate; Grade 3 - severe or medically significant; Grade 4 - life-threatening consequences.

Time frame: Up to 144 weeks

Number of Participants Who Discontinue Treatment Due to Adverse Events Through 144 Weeks

Time frame: Up to 144 weeks

Number of Participants With Adverse Events and Serious Adverse Events Through 96 Weeks

Time frame: Up to 96 weeks

Number of Participants With Severity of Adverse Events Through 96 Weeks

AEs were evaluated by the investigator and graded according to the DAIDS toxicity scales as follows: Grade 1 - mild; Grade 2 - moderate; Grade 3 - severe or medically significant; Grade 4 - life-threatening consequences; Grade 5 - death. The higher the grade, the more severe the symptoms.

Time frame: Up to 96 weeks

Number of Participants With Abnormal Findings for Hematology Parameters Through 96 Weeks

Blood samples were collected from participants for analysis of hematology parameters including hemoglobin, leukocytes and neutrophils. Grades were defined based on numeric criteria as follows: Grade 0 - no abnormality; Grade 1 - mild; Grade 2 - moderate; Grade 3 - severe or medically significant; Grade 4 - life-threatening consequences.

Time frame: Up to 96 weeks

Number of Participants With Abnormal Findings for Clinical Chemistry Parameters Through 96 Weeks

Blood samples were collected from participants for analysis of clinical chemistry parameters including potassium, aspartate aminotransferase, creatinine, alanine aminotransferase, carbon dioxide, alkaline phosphatase, bilirubin, sodium, GFR from creatinine adjusted for BSA, calcium, and creatine kinase. Grades were defined based on numeric criteria as follows: Grade 0 - no abnormality; Grade 1 - mild; Grade 2 - moderate; Grade 3 - severe or medically significant; Grade 4 - life-threatening consequences.

Time frame: Up to 96 weeks

Number of Participants With Abnormal Findings for Fasting Lipids Through 96 Weeks

Lipid assessments including cholesterol, LDL cholesterol, LDL cholesterol calculation, LDL cholesterol direct, and triglycerides were performed. Grades were defined based on numeric criteria as follows: Grade 0 - no abnormality; Grade 1 - mild; Grade 2 - moderate; Grade 3 - severe or medically significant; Grade 4 - life-threatening consequences.

Time frame: Up to 96 weeks

Number of Participants With Abnormal Findings for Urinalysis Parameters Through 96 Weeks

Urine samples will be collected from participants for the analysis of urinalysis parameters including urinary glucose, urinary protein, and urine erythrocytes. Grades were defined based on numeric criteria as follows: Grade 0 - no abnormality; Grade 1 - mild; Grade 2 - moderate; Grade 3 - severe or medically significant; Grade 4 - life-threatening consequences.

Time frame: Up to 96 weeks

Number of Participants Undergoing Viral Load Monitoring From Week 48 Through 144 Weeks

Viral load was defined as plasma HIV-RNA \<50 copies per mL. Viral load monitoring of participants was performed from Week 48 through 144 weeks.

Time frame: Weeks 48, 60, 72, 84, 96, 108, 120, 132, and 144

Change From Baseline in Cluster of Differentiation 4+ (CD4+) Cell Count at Weeks 24 and 48

Baseline value was defined as the latest pre-dose assessment with a non-missing value (Day 1). Change from Baseline was defined as post-dose visit value minus Baseline value.

Time frame: Baseline (Day 1) and Weeks 24 and 48

Change From Baseline in CD8+ Cell Count at Weeks 24 and 48

Baseline value was defined as the latest pre-dose assessment with a non-missing value (Day 1). Change from Baseline was defined as post-dose visit value minus Baseline value.

Time frame: Baseline (Day 1) and Weeks 24 and 48

Change From Baseline in Ratio of CD4+ and CD8+ at Weeks 24 and 48

Baseline value was defined as the latest pre-dose assessment with a non-missing value (Day 1). Change from Baseline was defined as post-dose visit value minus Baseline value.

Time frame: Baseline (Day 1) and Weeks 24 and 48

Number of Participants With Disease Progression From Week 24 Through Week 48

Participants with disease progression included incidences of HIV-associated conditions, Acquired Immuno Deficiency Syndrome (AIDS) and death. HIV-associated conditions were assessed according to the 2014 HIV infection by Centers for Disease Control and Prevention (CDC) classification system for HIV Infection in adults to evaluate the immune effects of DTG /3TC FDC.