CompletedNCT01302847Updated Dec 12, 2024Results posted

Safety of and Immune Response to Dolutegravir in HIV-1 Infected Infants, Children, and Adolescents

A Phase 1/2 interventional study of DTG film-coated tablets and DTG granules for suspension in HIV Infections, sponsored by National Institute of Allergy and Infectious Diseases (NIAID). Completed at 33 sites in 8 countries. Open to participants aged 4 Weeks to 17 Years. Per ClinicalTrials.gov, last updated 2024-12-12.

Sponsored by National Institute of Allergy and Infectious Diseases (NIAID) · Phase 1/2, Interventional, and Treatment

Phase: Phase 1/2
Study type: Interventional
Enrollment: 181
Allocation: Non-randomized
Ages: 4 Weeks to 17 Years
Sex: All

Study summary

Dolutegravir (DTG) is an HIV drug in the integrase inhibitor drug class. This study evaluated the pharmacokinetics (PK), safety, tolerability of and immune response to DTG when used concurrently with optimized background therapy (OBT) in HIV-1 infected infants, children, and adolescents.

Read the detailed description

DTG is an HIV medicine in the integrase inhibitor drug class. The purpose of this study was to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of DTG when used concurrently with OBT in HIV-1 infected infants, children, and adolescents.

Participants in this study were evaluated for PK, safety and tolerability through 48 weeks, followed by additional long-term study follow-up that lasted for approximately 144 weeks (3 years), for a total of 192 weeks on study. This study had two stages. Stage I provided pharmacokinetics, short-term tolerability and safety data on DTG on a limited number of participants to permit dose selection for further study in Stage II. Once a Stage I dose was accepted, enrollment to Stage II began to complete enrollment to the cohort. Stage II provided longer-term safety and antiviral activity data among a larger number of participants.

Infants, children and adolescents with HIV-1, aged ≥ 4 weeks to \< 18 years enrolled in the age and formulation cohorts specified below:

Cohort I: Adolescents ≥ 12 to \<18 years of age (film-coated tablets)
Cohort IIA: Children ≥ 6 to \<12 years of age (film-coated tablets)
Cohort IIB: Children ≥ 6 to \<12 years of age (granules for suspension)
Cohort III: Children ≥ 2 to \< 6 years of age (granules for suspension)
Cohort IV: Children ≥ 6 months to \< 2 years of age (granules for suspension)
Cohort III-DT: Children ≥ 2 to \< 6 years of age (dispersible tablets)
Cohort IV-DT: Children ≥ 6 months to \< 2 years of age (dispersible tablets)
Cohort V-DT: Infants ≥ 4 weeks to \< 6 months (dispersible tablets)

Cohorts were opened sequentially according by age group (starting with the older age group), DTG formulation, and study stage, i.e. Initial study enrollment was for Cohort I and progressed to Cohort IIA once Cohort I Stage I met the PK and safety criteria, followed by opening of Cohort IIB. Each cohort enrolled in two sequential stages: Stage I and II (the only exception is Cohort IIB, which only enrolled through Stage I). Sequential enrollment for Cohort III and IV proceeded in the same manner. Cohort V never enrolled because of the recommended changes in dosing and inclusion of enrollment weight band in the criteria for dose finding.

Stage I participants had physical examinations and had blood draws for safety assessments at study visits: Day 0; Day 5 (+5 days); and Weeks 4, 8, 12, 16, 24, 32, 40, and 48. Stage I participants also had intensive PK sampling with blood samples collected at time 0 (pre-dose), and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing. Once a Stage I treatment dose was accepted, enrollment to Stage II began to complete enrollment to the cohort. Stage II participants had physical examinations and blood draws for safety assessment at study visits: Day 0; Day 10; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48. Blood, plasma, and urine were collected and tested to measure immune response. Females of childbearing potential underwent pregnancy testing at screening and at every study visit.

After 48 weeks, all Stage I and Stage II participants entered the long-term study follow-up and continued to receive DTG. During this time, participants had safety and/or antiviral activity assessments every 12 weeks for up to 3 years.

The study was able to determine a proposed dose (i.e. optimal dose) for Cohorts I, IIA, III-DT, IV-DT, and V-DT but not for Cohorts IIB, III, and IV. Participants on the proposed dose had intensive PK sampling between days 5 and10 of DTG initiation with blood samples collected at time 0 (pre-dose), and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing.

The study is closed to accrual and study follow-up was completed on Oct 18, 2023.

Conditions studied

HIV Infections

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HIV Infections 4,340

Keywords

Integrase Inhibitors
Infant
Child
Adolescent

In context

HIV Infections

4,340 studies on the registry are indexed under HIV Infections; 240 are open to participants now.

This study's enrollment of 181 is above the median of 83 across 3,312 interventional studies indexed under HIV Infections.

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Lead sponsor

National Institute of Allergy and Infectious Diseases (NIAID) is the lead sponsor of 2,445 studies on the registry; 182 are open to participants now.

Of its 402 completed or terminated interventional studies of FDA-regulated products, 300 (75%) have results posted.

Browse National Institute of Allergy and Infectious Diseases (NIAID) studies →

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 4 Weeks to 17 Years
Sexes eligible: All
Accepts healthy volunteers: No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

Confirmed HIV-1 infection, defined as positive results from two samples collected at different time points (see protocol for more information)
Participant belonged to one of the ARV exposure groups below:
1. ARV-treatment experienced (not including receipt of ARVs as prophylaxis or for prevention of perinatal transmission)
  - Previously took ARVs for treatment, but not taking ARVs at study screening.
  - Had been off treatment for greater than or equal to 4 weeks prior to screening, OR
  - At screening, taking ARVs for treatment but failing.
  - Was on an unchanged, failing therapeutic regimen within the 4 to 12 weeks prior to screening (less than or equal to 1 log drop in HIV-1 RNA within the 4 to 12 weeks prior to screening). OR
  - For participants less than 2 years of age, initiated ARVs for treatment less than 4 weeks prior to screening.
2. ARV treatment naive (no exposure to ARVs for treatment; could have received ARVs for prophylaxis or prevention of perinatal transmission)
If an infant had received nevirapine (NVP) as prophylaxis to prevent perinatal transmission, he or she did not receive NVP for at least 14 days prior to enrollment into Stage I or II.
HIV-1 RNA viral load greater than 1,000 copies/mL of plasma at screening.
Demonstrated ability or willingness to swallow assigned study medications.
Parent or legal guardian were able and willing to provide signed informed consent.
Female participants of reproductive potential, defined as having reached menarche, and who were engaging in sexual activity that could lead to pregnancy, agreed to use two contraceptive methods while on study and for two weeks after stopping study drug.
Males engaging in sexual activity that could lead to HIV-1 transmission agreed to use a condom.
Agreed to stay on optimized background therapy (OBT) while on study:
- Participants who at screening were greater than or equal to 2 years of age and ARV-treatment experienced, had at screening at least one fully active drug for the OBT.
- Participants who were greater than or equal to 2 years of age and ARV-treatment naïve, had genotype testing at screening/entry even with results pending.
- Participants less than 2 years of age (either ARV-treatment experienced or ARV treatment naïve), had genotype testing at screening/entry even with results pending.

Exclusion criteria

Exclusion Criteria:

Presence of any active AIDS-defining opportunistic infection
At enrollment, participant less than 3.0 kg
Known Grade 3 or greater of any of the following laboratory toxicities within 30 days prior to study entry: neutrophil count, hemoglobin, platelets, aspartate aminotransferase (AST), alanine transaminase (ALT), lipase, serum creatinine and total bilirubin. A single repeat within the 30 days is allowed for eligibility determination. NOTE: Grade 3 total bilirubin was allowable, if the participant was on atazanavir (ATV).
ANY known Grade 4 laboratory toxicities within 30 days prior to study entry. NOTE: Grade 4 total bilirubin was allowable, if the participant was on ATV.
The following liver toxicities within 30 days prior to study entry: ALT greater than 3x the upper limit of normal (ULN) AND direct bilirubin was greater than 2x ULN
Any prior history of malignancy, with the exception of localized malignancies such as squamous cell or basal cell carcinoma of the skin
Clinical or symptomatic evidence of pancreatitis, as determined by the clinician
Use of any disallowed medications at time of screening (see the protocol for a complete list of disallowed medications)
Known history of exposure to integrase inhibitor treatment by the participant or participant's mother prior to delivery/cessation of breastfeeding
Known resistance to an integrase inhibitor
Women who were pregnant or breastfeeding
At screening/entry, participating in or had participated in a study with a compound or device that was not commercially available within 30 days of signing informed consent, unless permission from both Protocol Teams was granted
Participant was unlikely to adhere to the study procedures, keep appointments, or was planning to relocate during the study to a non-IMPAACT study site
Any clinically significant diseases (other than HIV infection) or clinically significant findings during the screening medical history or physical examination that, in the investigator's opinion, would compromise the outcome of this study
At screening/entry had used, or anticipated using, chronic systemic immunosuppressive agents or systemic interferon (e.g., for treatment of hepatitis C virus [HCV] infection) within 30 days prior to beginning DTG study treatment. Systemic corticosteroids (e.g., prednisone or equivalent up to 2 mg/kg/day) for replacement therapy or short courses (less than or equal to 30 days) were permitted. (See protocol for more information on disallowed medications.)
Any condition that in the opinion of the site investigator, placed the participant at an unacceptable risk of injury or render the participant unable to meet the requirements of the protocol.
Active tuberculosis (TB) disease and/or requirement for treatment that included rifampin at the time of the screening visit. However, participants who needed rifampin treatment while on DTG were allowed to continue in P1093 provided the DTG dose was adjusted according to the protocol.

Study design

Phase: Phase 1 / Phase 2
Primary purpose: Treatment
Allocation: Non-randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 181 participants (actual)

Study arms

Experimental
Cohort I
Adolescents 12 to younger than 18 years of age who received DTG film-coated tablets
Drug: DTG film-coated tablets
Experimental
Cohort IIA
Children 6 to younger than 12 years of age who received DTG film-coated tablets
Drug: DTG film-coated tablets
Experimental
Cohort IIB
Children 6 to younger than 12 years of age who received DTG granules for suspension
Drug: DTG granules for suspension
Experimental
Cohort III
Children 2 to younger than 6 years of age who received DTG granules for suspension
Drug: DTG granules for suspension
Experimental
Cohort IV
Children 6 months to younger than 2 years of age who received DTG granules for suspension
Drug: DTG granules for suspension
Experimental
Cohort III-DT
Children 2 to younger than 6 years of age who received DTG dispersible tablets
Drug: DTG dispersible tablets
Experimental
Cohort IV-DT
Children 6 months to younger than 2 years of age who received DTG dispersible tablets
Drug: DTG dispersible tablets
Experimental
Cohort V-DT
Infants 4 weeks to younger than 6 months of age who received DTG dispersible tablets
Drug: DTG dispersible tablets

Interventions

DrugDTG film-coated tablets
DTG film-coated tablets initial starting dose at \~1 mg/kg with a maximum dose of 50 mg; orally once daily. Participants weighing ≥ 35kg received the proposed dose of 50 mg of DTG film-coated tablets.
DrugDTG granules for suspension
DTG granules for suspension initial starting dose at \~0.64 mg/kg with a maximum dose of 32 mg; orally once daily.
DrugDTG dispersible tablets
DTG dispersible tablets initial starting dose of \~0.8 mg/kg with a maximum dose of 30 mg; orally once daily. The proposed weight-band dosing was: Weight band 3 to \<6 kg: 5 mg DTG dispersible tablets; Weight band 6 to \<10 kg: 15 mg DTG dispersible tablets; Weight band 10 to \<14 kg: 20 mg DTG dispersible tablets; Weight band 14 to \<20 kg: 25 mg DTG dispersible tablets; Weight band ≥20 kg: 30 mg DTG dispersible tablets.
DrugDTG dispersible tablets
DTG dispersible tablets initial starting dose of \~1.25 mg/kg with a maximum dose of 30 mg; orally once daily. The proposed weight-band dosing was: Weight band 3 to \<6 kg: 5 mg DTG dispersible tablets; Weight band 6 to \<10 kg: 15 mg DTG dispersible tablets; Weight band 10 to \<14 kg: 20 mg DTG dispersible tablets; Weight band 14 to \<20 kg: 25 mg DTG dispersible tablets; Weight band ≥20 kg: 30 mg DTG dispersible tablets.
DrugDTG dispersible tablets
DTG dispersible tablets initial starting dose of \~1.25 mg/kg with a maximum dose of 30 mg; orally once daily. The proposed weight-band dosing was: Weight band 3 to \<6 kg: 5 mg DTG dispersible tablets; Weight band 6 to \<10 kg: 15 mg DTG dispersible tablets.

What researchers measure

Primary outcomes

Percentage of Participants With Grade 3 or Higher Adverse Events (AEs)
All grade 3 or higher signs/symptoms, diagnoses, and laboratory AEs were included. AE grading was based on DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, August 2009). A 2-sided 95% Confidence Interval (CI) was calculated for the percentage using the binominal exact method.
Time frame: From treatment initiation through Weeks 24 and 48
Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug
All grade 3 or higher signs/symptoms, diagnoses, and laboratory AEs were included. AE grading was based on DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, August 2009). A 2-sided 95% Confidence Interval (CI) was calculated for the percentage using the binominal exact method.
Time frame: From treatment initiation through Weeks 24 and 48
Number of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events (AEs) Assessed as Related to Study Drug
Number of participants with permanent discontinuation of study drug due to AEs assessed by the site investigator as related to the study drug.
Time frame: From treatment initiation through Weeks 24 and 48
Number of Participants Who Died
Number of participants who died were summarized
Time frame: From treatment initiation through Weeks 24 and 48
PK Parameter: Area-under-the-curve From 0 to 24 Hours (AUC0-24)
Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). AUC0-24 was determined using linear up-log down estimation in WinNonlin.
Time frame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing

Secondary outcomes

Percentage of Participants With Grade 3 or Higher Adverse Events (AEs)
Percentage and exact 95% Confidence Interval (CI) of participants with Grade 3 or higher AEs. AEs were graded based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004, Clarification August 2009 (see References). All grade 3 or higher signs, symptoms, and laboratory toxicities were included.
Time frame: From treatment initiation through Week 192. AEs after that time were censored.
Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug
Percentage and exact 95% Confidence Interval (CI) of participants with Grade 3 or higher AEs assessed by the site investigator as related to the study drug.
Time frame: From treatment initiation through Week 192. AEs after that time were censored.
Number of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events (AEs) Assessed as Related to Study Drug
Number of participants with permanent discontinuation of study drug due to AEs assessed by the site investigator as related to the study drug.
Time frame: From treatment initiation through Week 192. AEs after that time were censored.
Number of Participants Who Died
Number of participants who died were summarized.
Time frame: From treatment initiation through Week 192. AEs after that time were censored.
Percentage of Participants With Plasma HIV-1 RNA Less Than 400 Copies/ml
Virologic responses were assessed at weeks 24 and 48 as percentages of participants and exact 95% Confidence Interval (CI). The virologic response or virologic failure was defined and calculated according to FDA's Snapshot algorithm.
Time frame: Week 24 and Week 48
Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/ml
Virologic responses were assessed at weeks 24 and 48 as percentages of participants and exact 95% Confidence Interval (CI), The virologic response or virologic failure was defined and calculated according to FDA's Snapshot algorithm.
Time frame: Week 24 and Week 48
PK Parameter: Plasma Concentration Observed at End of 24 Hour Dosing Interval (C24h)
Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). C24h was taken directly from the observed concentration-time data or estimated using the elimination rate constant.
Time frame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
PK Parameter: Plasma Concentration Observed Immediately to Dosing of 24 Hour Dosing Interval (C0h)
Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). C0h was taken directly from the observed concentration-time data.
Time frame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
PK Parameter: Minimum Plasma Concentration (Cmin)
Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ) and were performed in real-time. Cmin was taken directly from the observed concentration-time data.
Time frame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
PK Parameter: Maximum Plasma Concentration (Cmax)
Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). Cmax was taken directly from the observed concentration-time data.
Time frame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
PK Parameter: Apparent Clearance (CL/F)
Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). CL/F was calculated as Dose/AUC.
Time frame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
PK Parameter: Apparent Volume of Distribution (Vz/F)
Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). Vz/F was calculated as Dose/(ke x AUC).
Time frame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
PK Parameter: Terminal Half-life (t1/2)
Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). t1/2 was calculated as ln(2)/ke.
Time frame: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
Summary of Changes in CD4 Count From Baseline
The median differences between CD4 count at Week 24 and 48 minus at the Day 0 (baseline), and Interquartile Ranges (IQRs) are presented.
Time frame: Measured at Day 0, Week 24, and Week 48
Summary of Changes in CD4 Percent From Baseline
The median differences between CD4 percent at Week 24 and 48 minus at the Day 0 (baseline), and Interquartile Ranges (IQRs) are presented.
Time frame: Measured at Day 0, Week 24, and Week 48
Summary of Changes in CD8 Count From Baseline
The median differences between CD8 count at Week 24 and 48 minus at the Day 0 (baseline), and Interquartile Ranges (IQRs) are presented.
Time frame: Measured at Day 0, Week 24, and Week 48
Summary of Changes in CD8 Percent From Baseline
The median differences between CD8 percent at Week 24 and 48 minus at the Day 0 (baseline), and Interquartile Ranges (IQRs) are presented.
Time frame: Measured at Day 0, Week 24, and Week 48
Genotypic Measures of Resistance to Integrase
Genes were sequenced and compared to a reference sequence to identify mutations
Time frame: At baseline
Genotypic Measures of Resistance to Integrase
Genes were sequenced and compared to a reference sequence to identify mutations
Time frame: at virological failure visit at or prior to Week 192
Genotypic Measures of Resistance to Protease
Genes were sequenced and compared to a reference sequence to identify mutations
Time frame: at baseline
Genotypic Measures of Resistance to Protease
Genes were sequenced and compared to a reference sequence to identify mutations
Time frame: at virological failures at or prior to Week 192
Genotypic Measures of Resistance to Reverse Transcriptase
Genes were sequenced and compared to a reference sequence to identify mutations
Time frame: at baseline
Genotypic Measures of Resistance to Reverse Transcriptase
Genes were sequenced and compared to a reference sequence to identify mutations
Time frame: at virologic failure at or prior to Week 192
Phenotypic Measures of Resistance
The participant viral culture is considered to be reduced susceptibility if more DTG is needed to inactivate 50% of the participant viral culture compared to the control viral specimen
Time frame: Whenever virological failures took place from baseline to week 192
Worst Case CDC HIV Classification Status
Disease progression as measured by change from baseline to the worst case CDC HIV classification status
Time frame: From baseline through Week 192

Results

Posted Mar 22, 2022

Participant flow

Participants were enrolled from April 20, 2011 to February 19, 2020. Participants were recruited from 9 countries in North America, South America, Africa, and Asia.

Participant flow — Overall Study
Milestone	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
Started	23	23	15	17	7	36	35	25
Completed	10	16	14	15	5	31	30	20
Not completed	13	7	1	2	2	5	5	5
Withdrew: Death	0	1	0	0	0	1	1	0
Withdrew: Pregnancy	2	0	0	0	0	0	0	0
Withdrew: Virologic failure	0	2	0	2	1	3	1	2
Withdrew: Severe debilitation, unable to continue	0	0	0	0	0	1	1	0
Withdrew: Not able to get to clinic	1	1	0	0	0	0	0	0
Withdrew: Site closing	2	2	0	0	0	0	0	0
Withdrew: Withdrawal by subject	1	0	0	0	1	0	0	1
Withdrew: Not willing to adhere to requirements	5	0	1	0	0	0	0	2
Withdrew: Site unable to contact participant	2	1	0	0	0	0	2	0

Outcome measures

PrimaryPercentage of Participants With Grade 3 or Higher Adverse Events (AEs)

All grade 3 or higher signs/symptoms, diagnoses, and laboratory AEs were included. AE grading was based on DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, August 2009). A 2-sided 95% Confidence Interval (CI) was calculated for the percentage using the binominal exact method.

Time frame:: From treatment initiation through Weeks 24 and 48
Reported as:: Number · percentage of participants

Percentage of Participants With Grade 3 or Higher Adverse Events (AEs)
percentage of participants	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
Through Week 24	4.3 (0.1 to 22.0)	8.7 (1.1 to 28.0)	6.7 (0.2 to 32.0)	29.4 (10.3 to 56.0)	57.1 (18.4 to 90.1)	38.9 (23.1 to 56.5)	42.9 (26.3 to 60.7)	60 (38.7 to 78.9)
Through Week 48	8.7 (1.1 to 28.0)	17.4 (5.0 to 38.8)	13.3 (1.7 to 40.5)	35.3 (14.2 to 61.7)	57.1 (18.4 to 90.1)	41.7 (25.5 to 59.2)	51.4 (34.0 to 68.6)	64 (42.5 to 82.0)

PrimaryPercentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug

Time frame:: From treatment initiation through Weeks 24 and 48
Reported as:: Number · percentage of participants

Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug
percentage of participants	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
Through Week 24	0 (0.0 to 14.8)	0 (0.0 to 14.8)	0 (0.0 to 21.8)	0 (0.0 to 19.5)	14.3 (0.4 to 57.9)	0 (0.0 to 9.7)	0 (0.0 to 10.0)	0 (0.0 to 13.7)
Through Week 48	0 (0.0 to 14.8)	0 (0.0 to 14.8)	0 (0.0 to 21.8)	0 (0.0 to 19.5)	14.3 (0.4 to 57.9)	0 (0.0 to 9.7)	0 (0.0 to 10.0)	0 (0.0 to 13.7)

PrimaryNumber of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events (AEs) Assessed as Related to Study Drug

Number of participants with permanent discontinuation of study drug due to AEs assessed by the site investigator as related to the study drug.

Time frame:: From treatment initiation through Weeks 24 and 48
Reported as:: Count of participants · Participants

Number of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events (AEs) Assessed as Related to Study Drug
Participants	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
Through Week 24	0	0	0	0	0	0	0	0
Through Week 48	0	0	0	0	0	0	0	0

PrimaryNumber of Participants Who Died

Number of participants who died were summarized

Time frame:: From treatment initiation through Weeks 24 and 48
Reported as:: Count of participants · Participants

Number of Participants Who Died
Participants	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
Through Week 24	0	0	0	0	0	1	1	0
Through Week 48	0	0	0	0	0	1	1	0

PrimaryPK Parameter: Area-under-the-curve From 0 to 24 Hours (AUC0-24)

Pharmacokinetic parameters were determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). AUC0-24 was determined using linear up-log down estimation in WinNonlin.

Time frame:: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
Reported as:: Mean · hr*mg/L

PK Parameter: Area-under-the-curve From 0 to 24 Hours (AUC0-24)
hr*mg/L	Cohort I	Cohort IIA	Cohort III-DT	Cohort IV-DT	Cohort V-DT
PK Parameter: Area-under-the-curve From 0 to 24 Hours (AUC0-24)	52.98 ± 23.11	68.33 ± 43.33	63.16 ± 37.77	82.67 ± 47.05	71.45 ± 28.21

SecondaryPercentage of Participants With Grade 3 or Higher Adverse Events (AEs)

Percentage and exact 95% Confidence Interval (CI) of participants with Grade 3 or higher AEs. AEs were graded based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004, Clarification August 2009 (see References). All grade 3 or higher signs, symptoms, and laboratory toxicities were included.

Time frame:: From treatment initiation through Week 192. AEs after that time were censored.
Reported as:: Number · percentage of participants

Percentage of Participants With Grade 3 or Higher Adverse Events (AEs)
percentage of participants	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
Percentage of Participants With Grade 3 or Higher Adverse Events (AEs)	34.8 (16.4 to 57.3)	30.4 (13.2 to 52.9)	20 (4.3 to 48.1)	52.9 (27.8 to 77.0)	57.1 (18.4 to 90.1)	58.3 (40.8 to 74.5)	51.4 (34.0 to 68.6)	64 (42.5 to 82.0)

SecondaryPercentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug

Percentage and exact 95% Confidence Interval (CI) of participants with Grade 3 or higher AEs assessed by the site investigator as related to the study drug.

Time frame:: From treatment initiation through Week 192. AEs after that time were censored.
Reported as:: Number · percentage of participants

Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug
percentage of participants	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
Percentage of Participants With Grade 3 or Higher Adverse Events (AEs) Assessed as Related to Study Drug	0 (0.0 to 14.8)	0 (0.0 to 14.8)	0 (0.0 to 21.8)	0 (0.0 to 19.5)	14.3 (0.4 to 57.9)	0 (0.0 to 9.7)	0 (0.0 to 10.0)	0 (0.0 to 13.7)

SecondaryNumber of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events (AEs) Assessed as Related to Study Drug

Number of participants with permanent discontinuation of study drug due to AEs assessed by the site investigator as related to the study drug.

Time frame:: From treatment initiation through Week 192. AEs after that time were censored.
Reported as:: Count of participants · Participants

Number of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events (AEs) Assessed as Related to Study Drug
Participants	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
Number of Participants With Permanent Discontinuation of Study Drug Due to Adverse Events (AEs) Assessed as Related to Study Drug	0	0	0	0	0	0	0	0

SecondaryNumber of Participants Who Died

Number of participants who died were summarized.

Time frame:: From treatment initiation through Week 192. AEs after that time were censored.
Reported as:: Count of participants · Participants

Number of Participants Who Died
Participants	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
Number of Participants Who Died	0	1	0	0	0	1	1	0

SecondaryPercentage of Participants With Plasma HIV-1 RNA Less Than 400 Copies/ml

Virologic responses were assessed at weeks 24 and 48 as percentages of participants and exact 95% Confidence Interval (CI). The virologic response or virologic failure was defined and calculated according to FDA's Snapshot algorithm.

Time frame:: Week 24 and Week 48
Reported as:: Number · percentage of participants

Percentage of Participants With Plasma HIV-1 RNA Less Than 400 Copies/ml
percentage of participants	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
Week 24	82.6 (61.2 to 95)	78.3 (56.3 to 92.5)	100 (78.2 to 100)	88.2 (63.6 to 98.5)	71.4 (29 to 96.3)	86.1 (70.5 to 95.3)	88.6 (73.3 to 96.8)	68 (46.5 to 85.1)
Week 48	73.9 (51.6 to 89.8)	78.3 (56.3 to 92.5)	93.3 (68.1 to 99.8)	94.1 (71.3 to 99.9)	71.4 (29 to 96.3)	86.1 (70.5 to 95.3)	85.7 (69.7 to 95.2)	72 (50.6 to 87.9)

SecondaryPercentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/ml

Virologic responses were assessed at weeks 24 and 48 as percentages of participants and exact 95% Confidence Interval (CI), The virologic response or virologic failure was defined and calculated according to FDA's Snapshot algorithm.

Time frame:: Week 24 and Week 48
Reported as:: Number · percentage of participants

Percentage of Participants With Plasma HIV-1 RNA Less Than 50 Copies/ml
percentage of participants	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
Week 24	69.6 (47.1 to 86.8)	60.9 (38.5 to 80.3)	93.3 (68.1 to 99.8)	58.8 (32.9 to 81.6)	42.9 (9.9 to 81.6)	61.1 (43.5 to 76.9)	51.4 (34 to 68.6)	32 (14.9 to 53.5)
Week 48	60.9 (38.5 to 80.3)	69.6 (47.1 to 86.8)	93.3 (68.1 to 99.8)	64.7 (38.3 to 85.8)	42.9 (9.9 to 81.6)	69.4 (51.9 to 83.7)	65.7 (47.8 to 80.9)	36 (18 to 57.5)

SecondaryPK Parameter: Plasma Concentration Observed at End of 24 Hour Dosing Interval (C24h)

Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). C24h was taken directly from the observed concentration-time data or estimated using the elimination rate constant.

Time frame:: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
Reported as:: Mean · ng/mL

PK Parameter: Plasma Concentration Observed at End of 24 Hour Dosing Interval (C24h)
ng/mL	Cohort I	Cohort IIA	Cohort III-DT	Cohort IV-DT	Cohort V-DT
PK Parameter: Plasma Concentration Observed at End of 24 Hour Dosing Interval (C24h)	1145.36 ± 659.65	1475.46 ± 1139.52	1065.12 ± 1112.46	1488.24 ± 1175.44	1765.19 ± 929.97

SecondaryPK Parameter: Plasma Concentration Observed Immediately to Dosing of 24 Hour Dosing Interval (C0h)

Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). C0h was taken directly from the observed concentration-time data.

Time frame:: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
Reported as:: Mean · ng/mL

PK Parameter: Plasma Concentration Observed Immediately to Dosing of 24 Hour Dosing Interval (C0h)
ng/mL	Cohort I	Cohort IIA	Cohort III-DT	Cohort IV-DT	Cohort V-DT
PK Parameter: Plasma Concentration Observed Immediately to Dosing of 24 Hour Dosing Interval (C0h)	1429.09 ± 738.69	1508.44 ± 1271.93	944.22 ± 549.36	1584.29 ± 1388.27	1376.15 ± 1132.28

SecondaryPK Parameter: Minimum Plasma Concentration (Cmin)

Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ) and were performed in real-time. Cmin was taken directly from the observed concentration-time data.

Time frame:: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
Reported as:: Mean · ng/mL

PK Parameter: Minimum Plasma Concentration (Cmin)
ng/mL	Cohort I	Cohort IIA	Cohort III-DT	Cohort IV-DT	Cohort V-DT
PK Parameter: Minimum Plasma Concentration (Cmin)	1193.94 ± 668.76	1155.52 ± 1152.98	757.92 ± 439.83	1343.74 ± 1370.79	1213.68 ± 886.21

SecondaryPK Parameter: Maximum Plasma Concentration (Cmax)

Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). Cmax was taken directly from the observed concentration-time data.

Time frame:: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
Reported as:: Mean · ng/mL

PK Parameter: Maximum Plasma Concentration (Cmax)
ng/mL	Cohort I	Cohort IIA	Cohort III-DT	Cohort IV-DT	Cohort V-DT
PK Parameter: Maximum Plasma Concentration (Cmax)	3945.97 ± 1499.34	5111.10 ± 2459.92	5530.16 ± 2466.62	6256.67 ± 2508.57	4832.58 ± 1679.69

SecondaryPK Parameter: Apparent Clearance (CL/F)

Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). CL/F was calculated as Dose/AUC.

Time frame:: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
Reported as:: Mean · L/h

PK Parameter: Apparent Clearance (CL/F)
L/h	Cohort I	Cohort IIA	Cohort III-DT	Cohort IV-DT	Cohort V-DT
PK Parameter: Apparent Clearance (CL/F)	1.29 ± 1.03	1.11 ± 0.92	0.49 ± 0.31	0.23 ± 0.11	0.11 ± 0.05

SecondaryPK Parameter: Apparent Volume of Distribution (Vz/F)

Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). Vz/F was calculated as Dose/(ke x AUC).

Time frame:: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
Reported as:: Mean · L

PK Parameter: Apparent Volume of Distribution (Vz/F)
L	Cohort I	Cohort IIA	Cohort III-DT	Cohort IV-DT	Cohort V-DT
PK Parameter: Apparent Volume of Distribution (Vz/F)	21.95 ± 13.71	19.11 ± 16.51	5.75 ± 3.66	3.19 ± 1.50	2.37 ± 1.04

SecondaryPK Parameter: Terminal Half-life (t1/2)

Determined from plasma concentration-time profiles using non-compartmental methods (Phoenix WinNonlin 8.0 or current, Certara, Princeton, NJ). t1/2 was calculated as ln(2)/ke.

Time frame:: One intensive PK visit between 5 and 10 days of DTG initiation. At intensive PK visit, blood samples were drawn pre-dose and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing
Reported as:: Mean · h

PK Parameter: Terminal Half-life (t1/2)
h	Cohort I	Cohort IIA	Cohort III-DT	Cohort IV-DT	Cohort V-DT
PK Parameter: Terminal Half-life (t1/2)	13.21 ± 5.51	12.22 ± 2.63	9.10 ± 3.40	9.93 ± 2.58	16.85 ± 8.22

SecondarySummary of Changes in CD4 Count From Baseline

The median differences between CD4 count at Week 24 and 48 minus at the Day 0 (baseline), and Interquartile Ranges (IQRs) are presented.

Time frame:: Measured at Day 0, Week 24, and Week 48
Reported as:: Median · cells/mm^3

Summary of Changes in CD4 Count From Baseline
cells/mm^3	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
From baseline to Week 24	63 (-56 to 180)	209 (30 to 403)	268 (142 to 372)	199 (-59 to 644)	472 (-20 to 883)	249 (47 to 535)	110 (-284 to 434)	441 (-114 to 1023)
From baseline to Week 48	84 (-81 to 238)	387 (49 to 575)	246 (160 to 466)	134.5 (-183.5 to 569.5)	577 (135 to 777)	191 (-202 to 541)	-1 (-449 to 577)	721 (-114 to 972)

SecondarySummary of Changes in CD4 Percent From Baseline

The median differences between CD4 percent at Week 24 and 48 minus at the Day 0 (baseline), and Interquartile Ranges (IQRs) are presented.

Time frame:: Measured at Day 0, Week 24, and Week 48
Reported as:: Median · Percentage of total lymphocytes

Summary of Changes in CD4 Percent From Baseline
Percentage of total lymphocytes	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
From baseline to Week 24	4.9 (1 to 8)	8 (5 to 11)	6 (3.3 to 9.1)	6 (4.5 to 9)	5.7 (3.9 to 8.1)	6.1 (3.4 to 10.9)	6 (2.5 to 12)	5.1 (1 to 10)
From baseline to Week 48	4.7 (0 to 9.4)	9 (7 to 14)	9.2 (5 to 11.9)	5.6 (1.5 to 11)	9.9 (8.5 to 10)	9.1 (4.4 to 13.4)	8.8 (0.7 to 14)	9.7 (4.1 to 11)

SecondarySummary of Changes in CD8 Count From Baseline

The median differences between CD8 count at Week 24 and 48 minus at the Day 0 (baseline), and Interquartile Ranges (IQRs) are presented.

Time frame:: Measured at Day 0, Week 24, and Week 48
Reported as:: Median · cells/mm^3

Summary of Changes in CD8 Count From Baseline
cells/mm^3	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
From baseline to Week 24	-36 (-371 to 30)	-147 (-804 to 30)	-43 (-247 to 151)	-282 (-533 to 176)	223 (-592 to 668)	-395 (-732 to 69)	-813 (-2013 to -65)	-210 (-1206 to 910)
From baseline to Week 48	-52.5 (-365 to 105)	-117 (-607 to 131)	-126 (-302 to 166)	-431.5 (-782 to -169.5)	-376 (-411 to 21)	-464 (-1013 to -94)	-1242 (-2433 to -280)	-442 (-1435 to 870)

SecondarySummary of Changes in CD8 Percent From Baseline

The median differences between CD8 percent at Week 24 and 48 minus at the Day 0 (baseline), and Interquartile Ranges (IQRs) are presented.

Time frame:: Measured at Day 0, Week 24, and Week 48
Reported as:: Median · Percentage of total lymphocytes

Summary of Changes in CD8 Percent From Baseline
Percentage of total lymphocytes	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
From baseline to Week 24	-5 (-9.7 to -2.3)	-10 (-17.4 to -6)	-7 (-9.2 to -4)	-6.8 (-9.9 to 2.5)	-2 (-4.1 to 3.5)	-3 (-9 to 0.1)	-4.2 (-9.9 to -1.3)	-4 (-10.2 to 2)
From baseline to Week 48	-6 (-12 to -2.4)	-11.4 (-22 to -7)	-8 (-15 to -5)	-6.5 (-14.5 to -3)	-1.8 (-4 to 0.3)	-6.5 (-10 to -1.9)	-9 (-15.2 to -4.9)	-3.5 (-11.5 to 1.7)

SecondaryGenotypic Measures of Resistance to Integrase

Genes were sequenced and compared to a reference sequence to identify mutations

Time frame:: At baseline
Reported as:: Count of participants · Participants

Genotypic Measures of Resistance to Integrase
Participants	All VF Participants
A128T	2
Gene not found	3
L74I	7
L74I,S230N	1
S230N	1
T97A	1
V151I	1
None	40

SecondaryGenotypic Measures of Resistance to Integrase

Genes were sequenced and compared to a reference sequence to identify mutations

Time frame:: at virological failure visit at or prior to Week 192
Reported as:: Count of participants · Participants

Genotypic Measures of Resistance to Integrase
Participants	All VF Participants
A128T	1
A128T,S153AFSV	1
E138AEKT,E138T,S147G,S147GS,R263K,R263KR	1
E138K,Q148K	1
E157Q	1
E92EG,T97A,N155H,N155HN	1
E92EQ,G118GR	1
H51HY	1
L74I	4
L74I,G118R	1
L74I,S230N	1
L74M,G118R	1
R263K	1
S230N	1
T66I,G118R,E138A	1
T66I,L74I,G118R	1
T97A,G118R,E138EK,S147G,V151I,N155H	1
missing	11
None	25

SecondaryGenotypic Measures of Resistance to Protease

Genes were sequenced and compared to a reference sequence to identify mutations

Time frame:: at baseline
Reported as:: Count of participants · Participants

Genotypic Measures of Resistance to Protease
Participants	All VF Participants
A71T	1
D30N,A71T,N88D	1
D30N,M46I,Q58EQ,A71T,N88D	1
I84V	1
K20I	2
K20I,V82I	1
K20R	8
K20R,A71T	1
K20R,L33F,M46I,I50V,I54V,T74P,V82A	1
K20R,T74S	1
K20R,T74S,V82A	1
K20T,V82I	1
K43T,A71T,V82A	1
L10I,K20KR,M46LM,I54IL,A71AV,V82AFSV	3
L10I	1
L10V	2
T74S	3
None	26

SecondaryGenotypic Measures of Resistance to Protease

Genes were sequenced and compared to a reference sequence to identify mutations

Time frame:: at virological failures at or prior to Week 192
Reported as:: Count of participants · Participants

Genotypic Measures of Resistance to Protease
Participants	All VF Participants
A71T	2
D30N,A71T,N88D	1
D30N,M46I,Q58E,Q58EQ,A71T,N88D	1
I84V	1
K20I	1
K20R	7
K20R,T74S	1
K20R,T74S,V82A	1
K20T,V82I	1
L10I	6
L10I,K20R	1
L10I,K43T,I54V,A71T,V82A	1
L10I,L10IV	1
L10IL,K20KR,L33FL,M46IM,I50IV,I54IV,T74PT,V82AV	1
L10V	2
L10V,K20IV,K20V	1
T74S	3
V11IV,K20I,V82I	1
missing	8
None	15

SecondaryGenotypic Measures of Resistance to Reverse Transcriptase

Genes were sequenced and compared to a reference sequence to identify mutations

Time frame:: at baseline
Reported as:: Count of participants · Participants

Genotypic Measures of Resistance to Reverse Transcriptase
Participants	All VF Participants
A62V,K65R,S68G,K70R,V75I,F77L,K101Q,K103N,F116Y,Q151M,P225H	1
D67DN,K238R	1
D67DN,V179I,V179IV,M184V,K219Q,N348I	1
E138A	1
E44D,K103N,M184V	1
K103N	4
K103N,M184V	1
K103N,M184V,M184MV	1
K103N,P225H	1
K103N,V179I	1
K103N,V179I,M184V	1
K103N,Y181C	1
K103S,V179I,G190A,Y318F	1
K65R,V106M,G190A	1
K70KR,T215F,T215FIST,K238R	1
L74LV,Y181CY,M184V	1
L74V,K103N,E138G,M184V,M230L	1
L74V,V106M,Y181C	1
M184V	2
M184V,H221Y	1
M184V,K238R	1
M41L,D67N,T69N,K70R,L74I,A98G,M184V,T215F,K219Q,K238R	1
M41L,K101E,V179I,M184V,G190A,T215F	1
M41L,T215L	1
S68G,K103N,E138Q,M184V,Y318F	1
S68G,V106I,K238R	1
S68G,V90I,K103N,V179I	1
T69D	1
V118I,E138A	1
V118IV,V179I,M184V	1
V179E,P225H	1
V179I	1
V179I,M184V	2
V179I,M184V,G190A,K219R	1
V179I,M184V,K238R	1
V179I,M184V,Y188L	1
V179S	1
V75M,K103N	1
V90I	2
Y181C	1
None	10

SecondaryGenotypic Measures of Resistance to Reverse Transcriptase

Genes were sequenced and compared to a reference sequence to identify mutations

Time frame:: at virologic failure at or prior to Week 192
Reported as:: Count of participants · Participants

Genotypic Measures of Resistance to Reverse Transcriptase
Participants	All VF Participants
101i,V179I,M184V	1
A62V,K65R,S68G,K70R,V75I,F77L,K101Q,K103N,F116Y,Q151M,P225H	1
D67N,K219Q,N348I	1
E138A	1
E44D,E44DE,K103N,M184V	1
E44DE	1
K103KN,K103N,M184V	1
K103N	4
K103N,M184V	1
K103N,V179I	1
K103N,V179I,M184V	1
K103S,M184V,G190A,Y318F	1
K238R	2
K238R,M41LM,D67DN,T69NT,K70KR,L74IL,A98AG,M184MV,T215FIST,K219Q,M230IM	1
L74IL,L74V,K103N,E138G,M184V,M230L	1
M184V	3
M184V,H221Y	1
M184V,K238R	1
M41L,T215FL	1
M41LM,M184V,S68G,S68GS,Y181CY,M184MV	1
S68G,V106I,K238R	1
S68G,V90I,K103N,V179I,M184V	1
S68GS,K103KN,K238KR,K238R	1
T69NT,K103N,P225H	1
V106M,Y181C,P236LP	1
V179D,V179DV,G190A,G190AG	1
V179E,P225H	1
V179I	1
V179I,M184V	1
V179I,M184V,G190A,K219R	1
V179I,M184V,K238R	1
V179I,M184V,Y188L	1
V179S,M184V	1
V75M,K103N	1
V90I	1
missing	6
None	9

SecondaryPhenotypic Measures of Resistance

The participant viral culture is considered to be reduced susceptibility if more DTG is needed to inactivate 50% of the participant viral culture compared to the control viral specimen

Time frame:: Whenever virological failures took place from baseline to week 192
Reported as:: Count of participants · Participants

Phenotypic Measures of Resistance
Participants	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
Sensitive to DTG	8	4	0	2	0	5	4	9
Reduced susceptibility to DTG	2	0	1	0	1	1	0	0
missing	1	1	0	1	2	4	7	3

SecondaryWorst Case CDC HIV Classification Status

Disease progression as measured by change from baseline to the worst case CDC HIV classification status

Time frame:: From baseline through Week 192
Reported as:: Count of participants · Participants

Worst Case CDC HIV Classification Status
Participants	Not Symptomatic	Mildly Symptomatic	Moderately Symptomatic	Severely Symptomatic	Stage III	Stage I or II
Not symptomatic at entry	74	0	1	0	0	0
Mildly symptomatic at entry	0	37	0	0	0	0
Moderately symptomatic at entry	0	0	20	1	0	0
Severely symptomatic at entry	0	0	0	31	0	0
Stage III at entry	0	0	0	0	7	0
Stage I or II at entry	0	0	0	0	0	10

Adverse events

Collected over From study entry to completion of follow-up by Week 192 or longer, for participants on long-term follow-up. Five, 4, 3, 1 and 1 participants completed visit week 216, 228, 240, 278 and 284, respectively; all follow-up was included.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Cohort I	0/23 (0%)	8/23 (34.8%)	23/23 (100%)
Cohort IIA	1/23 (4.3%)	5/23 (21.7%)	23/23 (100%)
Cohort IIB	0/15 (0%)	1/15 (6.7%)	15/15 (100%)
Cohort III	0/17 (0%)	8/17 (47.1%)	17/17 (100%)
Cohort IV	0/7 (0%)	2/7 (28.6%)	7/7 (100%)
Cohort III-DT	1/36 (2.8%)	12/36 (33.3%)	36/36 (100%)
Cohort IV-DT	1/35 (2.9%)	8/35 (22.9%)	35/35 (100%)
Cohort V-DT	0/25 (0%)	2/25 (8%)	25/25 (100%)

Most frequent serious events

Showing 10 of 57

Most frequent serious events
Event	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
PyrexiaGeneral disorders	0/23	0/23	0/15	0/17	1/7	0/36	0/35	0/25
GastroenteritisInfections and infestations	0/23	0/23	0/15	0/17	1/7	0/36	2/35	1/25
PneumoniaInfections and infestations	0/23	1/23	0/15	0/17	1/7	1/36	1/35	1/25
Pneumonia viralInfections and infestations	0/23	0/23	0/15	0/17	1/7	1/36	0/35	0/25
Alanine aminotransferase increasedInvestigations	0/23	0/23	0/15	0/17	1/7	0/36	1/35	0/25
PregnancyPregnancy, puerperium and perinatal conditions	3/23	0/23	0/15	0/17	0/7	0/36	0/35	0/25
CellulitisInfections and infestations	0/23	0/23	0/15	2/17	0/7	0/36	0/35	0/25
Pneumonia bacterialInfections and infestations	0/23	0/23	0/15	2/17	0/7	1/36	0/35	0/25
Pelvic inflammatory diseaseInfections and infestations	2/23	0/23	0/15	0/17	0/7	0/36	0/35	0/25
Deep vein thrombosisVascular disorders	2/23	0/23	0/15	0/17	0/7	0/36	0/35	0/25

Most frequent other events

Showing 10 of 268

Most frequent other events
Event	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT
Blood sodium decreasedInvestigations	6/23	8/23	9/15	8/17	7/7	24/36	27/35	14/25
Blood bicarbonate decreasedInvestigations	11/23	10/23	6/15	13/17	6/7	33/36	34/35	23/25
CoughRespiratory, thoracic and mediastinal disorders	14/23	15/23	8/15	15/17	6/7	29/36	21/35	15/25
PyrexiaGeneral disorders	8/23	7/23	5/15	9/17	6/7	18/36	13/35	7/25
Haemoglobin decreasedInvestigations	1/23	6/23	0/15	5/17	3/7	14/36	24/35	20/25
Neutrophil count decreasedInvestigations	4/23	6/23	7/15	6/17	3/7	19/36	20/35	19/25
Decreased appetiteMetabolism and nutrition disorders	7/23	3/23	3/15	5/17	5/7	4/36	10/35	4/25
RhinorrhoeaRespiratory, thoracic and mediastinal disorders	7/23	8/23	8/15	10/17	5/7	15/36	11/35	6/25
DiarrhoeaGastrointestinal disorders	8/23	6/23	2/15	9/17	4/7	10/36	19/35	6/25
Nasal congestionRespiratory, thoracic and mediastinal disorders	10/23	10/23	5/15	6/17	4/7	8/36	5/35	5/25

Baseline characteristics

Participants who received at least one dose of DTG.

Age, Continuous
Age, Continuous(years)	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT	Total
Mean	14.26 ± 1.79	8.96 ± 1.99	7.73 ± 1.79	3.59 ± 1.00	1.14 ± 0.41	3.25 ± 1.18	1.13 ± 0.44	0.03 ± 0.01	4.84 ± 4.78

Sex: Female, Male
Sex: Female, Male(Participants)	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT	Total
Female	18	7	3	8	5	13	20	12	86
Male	5	16	12	9	2	23	15	13	95

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT	Total
Hispanic or Latino	6	6	4	8	1	6	4	2	37
Not Hispanic or Latino	16	13	6	6	6	28	31	23	129
Unknown or Not Reported	1	4	5	3	0	2	0	0	15

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT	Total
American Indian or Alaska Native	0	0	0	0	0	0	0	0	0
Asian	3	3	3	2	3	7	1	3	25
Native Hawaiian or Other Pacific Islander	0	1	0	0	0	0	0	0	1
Black or African American	12	12	10	11	3	25	30	20	123
White	7	3	0	2	0	1	2	0	15
More than one race	0	1	0	1	0	3	2	2	9
Unknown or Not Reported	1	3	2	1	1	0	0	0	8

Region of Enrollment
Region of Enrollment(Participants)	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT	Total
United States	20	16	5	5	0	3	2	0	51
Botswana	0	0	0	0	1	1	1	2	5
Tanzania	0	0	0	1	0	3	3	3	10
Brazil	0	0	2	5	1	6	2	3	19
South Africa	0	4	6	4	2	6	4	2	28
Uganda	0	0	0	0	0	0	2	1	3
Zimbabwe	0	0	0	0	0	3	15	10	28
Kenya	0	0	0	0	0	8	5	1	14
Thailand	3	3	2	2	3	6	1	3	23

Weight
Weight(kg)	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT	Total
Mean	55.1 ± 15.6	30.1 ± 10.4	23.0 ± 4.6	14.4 ± 2.9	8.4 ± 2.0	13.7 ± 2.6	8.5 ± 1.8	5.7 ± 1.1	19.6 ± 17.0

Height
Height(cm)	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT	Total
Mean	155.4 ± 8.9	131.1 ± 14.0	121.2 ± 9.6	95.9 ± 8.7	71.0 ± 6.0	93.4 ± 8.9	71.9 ± 5.7	59.2 ± 3.7	98.9 ± 32.4

CD4 Cell Count
CD4 Cell Count(cells/mm^3)	Cohort I	Cohort IIA	Cohort IIB	Cohort III	Cohort IV	Cohort III-DT	Cohort IV-DT	Cohort V-DT	Total
Median	466.0 (297 to 771)	645.0 (466 to 732)	749.0 (306 to 1041)	900.0 (565 to 1399)	1482.5 (1190 to 1827)	1049.5 (559.5 to 1883)	2121.0 (1422 to 2384)	1916.0 (1357 to 2680)	1053.0 (618 to 1914.5)

6 further baseline measures are reported on the registry.

Study locations

33 sites

University of California, UC San Diego CRS- Mother-Child-Adolescent HIV Program (Site ID: 4601)
La Jolla, California 92093-0672, United States
Miller Children's Hosp. Long Beach CA NICHD CRS (Site ID: 5093)
Long Beach, California 90806, United States
David Geffen School of Medicine at UCLA NICHD CRS (Site ID: 5112)
Los Angeles, California 90095-1752, United States
Univ. of California San Francisco NICHD CRS (Site ID: 5091)
San Francisco, California 94143, United States
Univ. of Colorado Denver NICHD CRS (Site ID: 5052)
Aurora, Colorado 80045, United States
Howard Univ. Washington DC NICHD CRS (Site ID: 5044)
Washington D.C., District of Columbia 20060, United States
South Florida CDTC Ft Lauderdale NICHD CRS (Site ID: 5055)
Fort Lauderdale, Florida 33316, United States
USF - Tampa NICHD CRS (Site ID: 5018)
Tampa, Florida 33606, United States
Rush Univ. Cook County Hosp. Chicago NICHD CRS (Site ID: 5083)
Chicago, Illinois 60612, United States
Lurie Children's Hospital of Chicago (LCH) CRS (Site ID: 4001)
Chicago, Illinois 60614-3393, United States
Children's Hosp. of Boston NICHD CRS (Site ID: 5009)
Boston, Massachusetts 02115, United States
Boston Medical Center Ped. HIV Program NICHD CRS (Site ID: 5011)
Boston, Massachusetts 02118, United States
Metropolitan Hosp. NICHD CRS (Site ID: 5003)
New York, New York 10029, United States
Bronx-Lebanon Hospital Center NICHD CRS (Site ID: 5114)
The Bronx, New York 10457, United States
Jacobi Med. Ctr. Bronx NICHD CRS (Site ID: 5013)
The Bronx, New York 10461, United States
DUMC Ped. CRS (Site ID: 4701)
Durham, North Carolina 27710, United States
Seattle Children's Research Institute CRS (Site ID: 5017)
Seattle, Washington 98101, United States
Gaborone CRS (Site ID: 12701)
Gaborone, South-East District, Botswana
Molepolole CRS (Site ID: 12702)
Gaborone, Botswana
SOM Federal University Minas Gerais Brazil NICHD CRS (Site ID: 5073)
Belo Horizonte, Minas Gerais 30.130-100, Brazil
Hospital Federal dos Servidores do Estado NICHD CRS (Site ID: 5072)
Rio de Janeiro, 20221-903, Brazil
Instituto de Puericultura e Pediatria Martagao Gesteira - UFRJ NICHD CRS (Site ID: 5071)
Rio de Janeiro, 21941-612, Brazil
Hosp. Geral De Nova Igaucu Brazil NICHD CRS (Site ID: 5097)
Rio de Janeiro, 26030, Brazil
Univ. of Sao Paulo Brazil NICHD CRS (Site ID: 5074)
São Paulo, 14049-900, Brazil
Kenya Medical Research Institute / Walter Reed Project Clinical Research Center, Kericho CRS (Site ID: 5121)
Kericho, 20200, Kenya
Wits RHI Shandukani Research Centre CRS (Site ID: 8051)
Johannesburg, Gauteng 2001, South Africa
Umlazi CRS (Site ID: 30300)
Durban, KwaZulu-Natal 4001, South Africa
FAMCRU CRS (Site ID: 8950)
Tygerberg, Western Cape 7505, South Africa
Kilimanjaro Christian Medical Centre (KCMC) (Site ID: 5118)
Moshi, Tanzania
Siriraj Hospital, Mahidol University NICHD CRS (Site ID: 5115)
Bangkok, Bangkoknoi 10700, Thailand
Chiangrai Prachanukroh Hospital NICHD CRS (Site ID: 5116)
Chiang Mai, 50100, Thailand
Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS (Site ID: 31784)
Chiang Mai, 50200, Thailand
Harare Family Care CRS (Site ID: 31890)
Harare, Zimbabwe

References and documents

Publications

Bennetto-Hood C, Tabolt G, Savina P, Acosta EP. A sensitive HPLC-MS/MS method for the determination of dolutegravir in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2014 Jan 15;945-946:225-32. doi: 10.1016/j.jchromb.2013.11.054. Epub 2013 Dec 3. PubMed 24361860 ↗
Viani RM, Alvero C, Fenton T, Acosta EP, Hazra R, Townley E, Steimers D, Min S, Wiznia A; P1093 Study Team. Safety, Pharmacokinetics and Efficacy of Dolutegravir in Treatment-experienced HIV-1 Infected Adolescents: Forty-eight-week Results from IMPAACT P1093. Pediatr Infect Dis J. 2015 Nov;34(11):1207-13. doi: 10.1097/INF.0000000000000848. PubMed 26244832 ↗
Viani RM, Ruel T, Alvero C, Fenton T, Acosta EP, Hazra R, Townley E, Palumbo P, Buchanan AM, Vavro C, Singh R, Graham B, Anthony P, George K, Wiznia A; P1093 Study Team. Long-Term Safety and Efficacy of Dolutegravir in Treatment-Experienced Adolescents With Human Immunodeficiency Virus Infection: Results of the IMPAACT P1093 Study. J Pediatric Infect Dis Soc. 2020 Apr 30;9(2):159-165. doi: 10.1093/jpids/piy139. PubMed 30951600 ↗
McKenna M, Lulic Z, Buchanan AM, Brothers C, Tan LK, Wang M, Brummel S, Ziemba L, Ruel T, Flynn PM, Rabie H, Wiznia A. Growth Outcomes After 48 Weeks of Dolutegravir in Children and Adolescents with HIV-1 in IMPAACT P1093 and IMPAACT 2019. J Pediatric Infect Dis Soc. 2026 Sep 12:piag088. doi: 10.1093/jpids/piag088. Online ahead of print. PubMed 42731017 ↗
Ruel TD, Acosta EP, Liu JP, Gray KP, George K, Montanez N, Popson S, Buchanan AM, Bartlett M, Dayton D, Anthony P, Brothers C, Vavro C, Singh R, Koech L, Vhembo T, Mmbaga BT, Pinto JA, Dobbels EFM, Archary M, Chokephaibulkit K, Ounchanum P, Deville JG, Hazra R, Townley E, Wiznia A; IMPAACT P1093 team. Pharmacokinetics, safety, tolerability, and antiviral activity of dolutegravir dispersible tablets in infants and children with HIV-1 (IMPAACT P1093): results of an open-label, phase 1-2 trial. Lancet HIV. 2022 May;9(5):e332-e340. doi: 10.1016/S2352-3018(22)00044-3. PubMed 35489377 ↗
Singh RP, Adkison KK, Baker M, Parasrampuria R, Wolstenholme A, Davies M, Sewell N, Brothers C, Buchanan AM. Development of Dolutegravir Single-entity and Fixed-dose Combination Formulations for Children. Pediatr Infect Dis J. 2022 Mar 1;41(3):230-237. doi: 10.1097/INF.0000000000003366. PubMed 34817414 ↗
Vavro C, Ruel T, Wiznia A, Montanez N, Nangle K, Horton J, Buchanan AM, Stewart EL, Palumbo P. Emergence of Resistance in HIV-1 Integrase with Dolutegravir Treatment in a Pediatric Population from the IMPAACT P1093 Study. Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0164521. doi: 10.1128/AAC.01645-21. Epub 2021 Oct 25. PubMed 34694878 ↗

Study documents

Study protocol · Jul 12, 2018
Study protocol · Jun 10, 2020
Statistical analysis plan · Apr 22, 2021
Statistical analysis plan · Apr 8, 2019
Informed consent form · Jul 12, 2018

Documents are hosted by the registry — open the source record to download them.

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Dec 12, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT01302847
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Responsible party: Sponsor
First posted: Feb 24, 2011
Start date: Apr 20, 2011
Primary completion: Jan 20, 2021
Completion: Oct 18, 2023
Results posted: Mar 22, 2022
Last update: Dec 12, 2024

Study contacts

Andrew Wiznia, M.D.

study chair · Jacobi Medical Center

Theodore Ruel, M.D.

study chair · University of California, San Francisco

Oversight

Data monitoring committee: Yes

View the source record on ClinicalTrials.gov ↗

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