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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02582684

Enrollment

122

Registered

2015-10-21

Start date

2015-12-08

Completion date

2017-09-26

Last updated

2018-05-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

HIV-1 Infection

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.

Interventions

DRUGDolutegravir

Participants were prescribed 50 mg of DTG orally daily

DRUGLamivudine

Participants were prescribed 300 mg of 3TC orally daily.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion 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.

Design outcomes

Primary

Measure	Time frame	Description
Virologic Status at Week 24	At 24 weeks after study entry	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).

Secondary

Measure	Time frame	Description
Virologic Status at Week 48	At 48 weeks after study entry	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).
Virologic Failure	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48	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/mL 1. Participants were evaluated for virologic failure regardless of whether on study treatment. 2. Confirmation was determined based on any two consecutive evaluations meeting the virologic failure definition regardless of the time between them. 3. 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.
Proportion of Participants With Plasma HIV-1 RNA < 50 Copies/mL - Missing = Failure	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48	Proportion of participants with HIV-1 RNA \< 50 copies/mL by week, ITT (Intention To Treat; missing/off study/off treatment = failure) population.
Proportion of Participants With Plasma HIV-1 RNA < 200 Copies/mL - Missing = Failure	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48	Proportion of participants with HIV-1 RNA \< 200 copies/mL by week, ITT (missing/off study/off treatment = failure) population.
Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL - Missing = Ignored	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48	Proportion of participants with HIV-1 RNA \< 50 copies/mL by week, ITT (missing = ignored) population.
Proportion of Participants With Plasma HIV-1 RNA <200 Copies/mL- ITT Missing = Ignored	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48	Proportion of participants with HIV-1 RNA \< 200 copies/mL by week, ITT (missing = ignored) population.
Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL- As Treated	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48	Proportion of participants with HIV-1 RNA \< 50 copies/mL by week, as treated population.
Virologic Status at Week 12	At 12 weeks after study entry	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).
CD4+ Cell Count	Baseline, weeks 4, 12, 24, and 48	CD4+ cell counts by study week.
Change in CD4+ Cell Count	Baseline, weeks 4, 12, 24, and 48	Change in CD4+ cell counts by study week. Change was calculated as value at the later visit minus the value at baseline.
Number of HIV-1 Drug Resistance Mutation Occurrences in Participants	at the time of virologic failure	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.
Fasting Lipids and Glucose	Baseline and week 48	Fasting lipids include: total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, and glucose. Fasting was set to be 8 hours prior to the sample collection.
Creatinine Clearance	Baseline, weeks 4, 12, 24, 32, 40 and 48	Creatinine clearance was estimated by the Cockcroft-Gault equation.
Number of Participants With Grade 3 of Higher Adverse Events	from study treatment dispensation through up to week 52 or until study discontinuation	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.
Proportion of Participants With Plasma HIV-1 RNA <200 Copies/mL- As Treated	Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48	Proportion of participants with HIV-1 RNA \< 200 copies/mL by week, as treated population.

Countries

Puerto Rico, United States

Participant flow

Pre-assignment details

A total of 122 participants were accrued.

Participants by arm

Arm	Count
Arm 1: DTG 50 MG + 3TC 300 mg Dolutegravir: Participants were prescribed 50 mg of DTG orally daily Lamivudine: Participants were prescribed 300 mg of 3TC orally daily.	120
Total	120

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Found to be ineligible after enrollment	2
Overall Study	Subject not able to get to clinic	10
Overall Study	Subject withdrew consent	1
Overall Study	Unable to contact subject/parent	4

Baseline characteristics

Characteristic	Arm 1: DTG 50 MG + 3TC 300 mg
Age, Continuous Age	30 Years
Age, Customized Age Category 18-29 years	58 Participants
Age, Customized Age Category 30-39 years	29 Participants
Age, Customized Age Category 40-49 years	17 Participants
Age, Customized Age Category 50-59 years	12 Participants
Age, Customized Age Category >= 60 years	4 Participants
Baseline HIV-1 RNA	4.61 log10 copies/mL
Baseline HIV-1 RNA Category 100,000 - 200,000 copies/mL	23 Participants
Baseline HIV-1 RNA Category 10,000 - 99,999 copies/mL	48 Participants
Baseline HIV-1 RNA Category 1,000 - 9,999 copies/mL	34 Participants
Baseline HIV-1 RNA Category < 1,000 copies/mL	1 Participants
Baseline HIV-1 RNA Category > 200,000 copies/mL	14 Participants
CD4/CD8 Ratio	0.44 ratio
CD4 Count, Categorized 200-349 cells/mm^3	27 Participants
CD4 Count, Categorized <200 cells/mm^3	16 Participants
CD4 Count, Categorized 350-499 cells/mm^3	30 Participants
CD4 Count, Categorized 500-649 cells/mm^3	19 Participants
CD4 Count, Categorized 650-799 cells/mm^3	15 Participants
CD4 Count, Categorized >=800 cells/mm^3	11 Participants
CD4 Count, Categorized Missing	2 Participants
CD4 Count, Continuous	387 cells/mm^3
CD8 Count	871 cells/mm^3
Hepatitis C Antibody Status Negative	116 Participants
Hepatitis C Antibody Status Positive	4 Participants
Intravenous Drug Use Currently	2 Participants
Intravenous Drug Use Never	113 Participants
Intravenous Drug Use Previously	5 Participants
Post-exposure Prophylaxis or Pre-Exposure Prophylaxis History No	119 Participants
Post-exposure Prophylaxis or Pre-Exposure Prophylaxis History Yes	1 Participants
Race/Ethnicity, Customized Race/Ethnicity Asian, Pacific Islander	2 Participants
Race/Ethnicity, Customized Race/Ethnicity Black Non-Hispanic	48 Participants
Race/Ethnicity, Customized Race/Ethnicity Does not want to report	2 Participants
Race/Ethnicity, Customized Race/Ethnicity Hispanic (Regardless of Race)	32 Participants
Race/Ethnicity, Customized Race/Ethnicity More than one race	2 Participants
Race/Ethnicity, Customized Race/Ethnicity White Non-Hispanic	34 Participants
Region of Enrollment Puerto Rico	3 Participants
Region of Enrollment United States	117 Participants
Screening HIV-1 RNA	4.70 log10 copies/mL
Sex: Female, Male Female	16 Participants
Sex: Female, Male Male	104 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 122
other Total, other adverse events	75 / 122
serious Total, serious adverse events	3 / 122

Outcome results

Primary

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).

Time frame: At 24 weeks after study entry

Population: All eligible participants enrolled.

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Arm 1: DTG 50 MG + 3TC 300 mg	Virologic Status at Week 24	Virologic success	108 Participants
Arm 1: DTG 50 MG + 3TC 300 mg	Virologic Status at Week 24	Virologic non-success	5 Participants
Arm 1: DTG 50 MG + 3TC 300 mg	Virologic Status at Week 24	No virologic data in window	7 Participants

95% CI: [0.83, 0.95]

Secondary

CD4+ Cell Count

CD4+ cell counts by study week.

Time frame: Baseline, weeks 4, 12, 24, and 48

Population: All eligible participants enrolled with CD4 count results available at a given visit.

Arm	Measure	Group	Value (MEDIAN)
Arm 1: DTG 50 MG + 3TC 300 mg	CD4+ Cell Count	Week 0	387 cells/mm^3
Arm 1: DTG 50 MG + 3TC 300 mg	CD4+ Cell Count	Week 4	473 cells/mm^3
Arm 1: DTG 50 MG + 3TC 300 mg	CD4+ Cell Count	Week 12	520 cells/mm^3
Arm 1: DTG 50 MG + 3TC 300 mg	CD4+ Cell Count	Week 24	582 cells/mm^3
Arm 1: DTG 50 MG + 3TC 300 mg	CD4+ Cell Count	Week 48	579 cells/mm^3

Secondary

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.

Time frame: Baseline, weeks 4, 12, 24, and 48

Population: All eligible participants enrolled with CD4 cell count results available at baseline and the given visit.

Arm	Measure	Group	Value (MEDIAN)
Arm 1: DTG 50 MG + 3TC 300 mg	Change in CD4+ Cell Count	Change from Baseline to Week 48	182 cells/mm^3
Arm 1: DTG 50 MG + 3TC 300 mg	Change in CD4+ Cell Count	Change from Baseline to Week 4	78 cells/mm^3
Arm 1: DTG 50 MG + 3TC 300 mg	Change in CD4+ Cell Count	Change from Baseline to Week 12	122 cells/mm^3
Arm 1: DTG 50 MG + 3TC 300 mg	Change in CD4+ Cell Count	Change from Baseline to Week 24	167 cells/mm^3

Secondary

Creatinine Clearance

Creatinine clearance was estimated by the Cockcroft-Gault equation.

Time frame: Baseline, weeks 4, 12, 24, 32, 40 and 48

Population: All eligible participants enrolled with creatinine clearance results available at a given time point.

Arm	Measure	Group	Value (MEDIAN)
Arm 1: DTG 50 MG + 3TC 300 mg	Creatinine Clearance	Week 4	112.9 mL/min
Arm 1: DTG 50 MG + 3TC 300 mg	Creatinine Clearance	Week 12	112.0 mL/min
Arm 1: DTG 50 MG + 3TC 300 mg	Creatinine Clearance	Week 24	114.7 mL/min
Arm 1: DTG 50 MG + 3TC 300 mg	Creatinine Clearance	Week 32	115.5 mL/min
Arm 1: DTG 50 MG + 3TC 300 mg	Creatinine Clearance	Week 40	112.7 mL/min
Arm 1: DTG 50 MG + 3TC 300 mg	Creatinine Clearance	Week 0	126.0 mL/min
Arm 1: DTG 50 MG + 3TC 300 mg	Creatinine Clearance	Week 48	114.4 mL/min

Secondary

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.

Time frame: Baseline and week 48

Population: All eligible participants enrolled with lipids results available at a given time point.

Arm	Measure	Group	Value (MEDIAN)
Arm 1: DTG 50 MG + 3TC 300 mg	Fasting Lipids and Glucose	Baseline Glucose	84 mg/dL
Arm 1: DTG 50 MG + 3TC 300 mg	Fasting Lipids and Glucose	Week 48 Glucose	86 mg/dL
Arm 1: DTG 50 MG + 3TC 300 mg	Fasting Lipids and Glucose	Baseline Total Cholesterol	151 mg/dL
Arm 1: DTG 50 MG + 3TC 300 mg	Fasting Lipids and Glucose	Week 48 Total Cholesterol	154 mg/dL
Arm 1: DTG 50 MG + 3TC 300 mg	Fasting Lipids and Glucose	Baseline LDL Cholesterol	85 mg/dL
Arm 1: DTG 50 MG + 3TC 300 mg	Fasting Lipids and Glucose	Week 48 LDL Cholesterol	86 mg/dL
Arm 1: DTG 50 MG + 3TC 300 mg	Fasting Lipids and Glucose	Baseline HDL Cholesterol	39 mg/dL
Arm 1: DTG 50 MG + 3TC 300 mg	Fasting Lipids and Glucose	Week 48 HDL Cholesterol	46 mg/dL
Arm 1: DTG 50 MG + 3TC 300 mg	Fasting Lipids and Glucose	Baseline Triglycerides	91 mg/dL
Arm 1: DTG 50 MG + 3TC 300 mg	Fasting Lipids and Glucose	Week 48 Triglycerides	98 mg/dL

Secondary

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.

Time frame: at the time of virologic failure

Population: Of the enrolled eligible participants, those with virologic failures had resistance testing done.

Arm	Measure	Group	Value (NUMBER)
Arm 1: DTG 50 MG + 3TC 300 mg	Number of HIV-1 Drug Resistance Mutation Occurrences in Participants	NRTI mutation	1 number of mutation occurrences
Arm 1: DTG 50 MG + 3TC 300 mg	Number of HIV-1 Drug Resistance Mutation Occurrences in Participants	NNRTI mutation	1 number of mutation occurrences
Arm 1: DTG 50 MG + 3TC 300 mg	Number of HIV-1 Drug Resistance Mutation Occurrences in Participants	INI mutation	1 number of mutation occurrences

Secondary

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.

Time frame: from study treatment dispensation through up to week 52 or until study discontinuation

Population: All eligible participants enrolled.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Arm 1: DTG 50 MG + 3TC 300 mg	Number of Participants With Grade 3 of Higher Adverse Events	16 Participants

Secondary