A Phase 3 interventional study of dolutegravir in Infection, Human Immunodeficiency Virus, sponsored by ViiV Healthcare. Completed at 89 sites in 7 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2016-01-07.
Sponsored by ViiV Healthcare · Phase 3, Interventional, and Treatment
The purpose of this trial is to assess the antiviral activity and safety of a dolutegravir (DTG) containing regimen in HIV-1 infected, antiretroviral therapy (ART)-experienced adults with current or historical failure on an integrase inhibitor (INI) containing regimen. The study will assess DTG 50mg twice daily administered initially with the current failing ART regimen but then with an optimised background ART regimen (OBR) after Day 7. The first analyses will be conducted after the last subject enrolled has completed 24 weeks. Subjects may remain on study after Week 24.
ING112574 is a Phase 3, multicentre, open-label, single arm study to assess the antiviral activity and safety of DTG containing regimen in HIV-1 infected ART-experienced adults with historical or current evidence of resistance to RAL or ELV. Initially, a minimum of 100 subjects will be enrolled to receive DTG 50mg twice daily with the current failing regimen for 7 days but with OBR from Day 8. Subjects must also have documented genotypic and/or phenotypic resistance to at least one compound in two or more of the other approved classes of ART but must also be able to include at least one fully active drug in the OBR to be started Day 8. The first data cut will take place after the (approximate) 100th subject enrolled completes the Week 24 visit. Enrollment will continue until a further 50 to 100 subjects have been recruited. All subjects who successfully complete 24 weeks of treatment will continue to have access to DTG until it is locally available as long as they continue to derive clinical benefit.
ViiV Healthcare is the sponsor of this study.
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Exclusion Criteria:
dolutegravir plus background antiretroviral therapy optimised at Day 8
Drug: dolutegravir
50 mg twice daily
Mean Change From Baseline in Plasma HIV-1 RNA at Day 8
Mean change from Baseline in Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Day 8 was calculated as the Day 8 value minus the Baseline value. The last observation was carried forward if a participant had missed the Day 8 visit. The Baseline observation was carried forward if a participant had discontinued the treatment before Day 8. Blood samples for assessment of HIV-1 RNA levels were collected at Baseline and Day 8.
Time frame: Baseline and Day 8
Number of Participants With HIV-1 RNA Less Than 50 Copies/mL at Week 24
The number of participants who had viral load \<50 copies/mL at Week 24 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (VOI \[due to missing data/discontinuation of investigational product prior to the visit window\]) as nonresponders, as well as participants who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the VOI analysis window.
Time frame: Week 24
Number of Participants With HIV-1 RNA Less Than 50 Copies/mL at Week 48
The number of participants who had viral load \<50 copies/mL at Week 48 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (VOI \[due to missing data/discontinuation of investigational product prior to the visit window\]) as nonresponders, as well as participants who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the VOI analysis window.
Time frame: Week 48
Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE)
An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.
Time frame: From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
Number of Participants With Adverse Events of the Indicated Severity, Per the Division of Acquired Immune Deficiency Syndrome (DAIDS) Grading Scale
An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. AE/SAE severity was graded according to the DAIDS grading scale. The DAIDS displays events as Grades 1-4 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, potentially life threatening.
Time frame: From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
Number of Participants With the Maximum Post-Baseline-emergent Clinical Chemistry Toxicities of the Indicated Grade
The severity of clinical chemistry toxicities was graded according to the DAIDS toxicity scale. The DAIDS displays events as Grades 1-5 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, life threatening; G5, death related to toxicity.
Time frame: From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
Number of Participants With the Maximum Post-Baseline-emergent Hematology Toxicities of the Indicated Grade
The severity of hematology toxicities was graded according to the DAIDS. The DAIDS displays events as Grades 1-5 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, life threatening; G5, death related to toxicity.
Time frame: From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
Number of Participants With Plasma HIV-1 RNA Less Than 400 and 50 Copies/mL at Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48
The number of participants with plasma HIV-1 RNA less than 400 and 50 copies (c)/mL at Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40 and 48 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (VOI \[due to missing data/discontinuation of investigational product prior to the visit window\]) as nonresponders, as well as participants who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the par. was on treatment within the VOI analysis window
Time frame: Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48
Number of Participants With Plasma HIV-1 RNA Less Than 400 and 50 Copies/mL From Week 48 Every 12 Weeks up to Study Completion
The number of participants with plasma HIV-1 RNA less than 400 and 50 copies (c)/mL was assessed at Weeks 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 and 180 using data of observed cases. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).
Time frame: From Week 48 every 12 weeks up to study completion.
Mean Change From Baseline in Plasma HIV-1 RNA at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and From Week 48 Every 12 Weeks up to Study Completion
Mean change from Baseline in plasma HIV-1 RNA was assesseed at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, 48 , 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180 using data of the observed cases. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time frame: Baseline; Day 8; Weeks 4, 8, 12, 16, 24, 32, 40, and From Week 48 Every 12 Weeks up to Study completion (Up to Week 180)
Absolute Values for CD4+ Cell Counts at Baseline, Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and 48 and for CD8+ Cell Counts at Baseline and Weeks 4, 12, 24, and 48
Absolute values for CD4+ cell counts were assessed at Baseline, Day 8 and Weeks 4, 8, 12, 16, and 24, and absolute values for CD8+ cell counts were assessed at Baseline and Weeks 4, 12, 24, and 48.
Time frame: Baseline, Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and 48
Median Change From Baseline in CD4+ Cell Counts at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, and From Week 48 Every 12 Weeks Until Study Completion
Median change from Baseline in CD4+ cell counts was assessed at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time frame: Baseline; Day 8; Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 and 180. v
Ratio of CD4+/CD8+ Cell Count at Baseline and Weeks 4, 12, 24, and 48
The ratio of CD4+/CD8+ cell count (measured in cells/mm\^3) was assessed at Baseline and at Weeks 4, 12, 24, and 48. The ratio was calculated as the CD4+ cell count divided by CD8+ cell count.
Time frame: Baseline; Weeks 4, 12, 24, and 48
Number of Participants With HIV-1 Disease Progression (Acquired Immune Deficiency Syndrome [AIDS] or Death)
The number of participants with HIV-1 disease progression (AIDS or death) was assessed per the Centers for Disease Control and Prevention (CDC) 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. The CDC classifies HIV infection as Category A (participants with asymptomatic HIV infection, acute HIV infection with accompanying illness, or persistent generalized lymphadenopathy), Category B (participants with symptomatic non-AIDS condition, i.e., conditions that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection), and Category C (includes AIDS indicator conditions as defined by diagnostic or presumptive measures).
Time frame: From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
Cmax and Ctau of DTG
The maximum plasma concentration (Cmax) and the concentration at the end of a dosing interval (Ctau) of DTG were assessed by a population pharmacokinetic (PK) modeling approach using pooled DTG PK data from multiple studies. For this study, blood samples for pharmacokinetic assessments were collected pre-dose on Day 8 and at Weeks 4 and 24, at 1-3 hours post-dose on Day 8, and at 1-3 hours or 4-12 hours post-dose at Weeks 4 and 24.
Time frame: Day 8, Week 4, and Week 24
AUC(0-tau) and AUC(0-24) of DTG
The area under the time concentration curve over the dosing interval (AUC\[0-tau\]) and from 0 to 24 hours (AUC\[0-24\]) of DTG was assessed by a population PK modeling approach using pooled DTG PK data from multiple studies. For this study, blood samples for pharmacokinetic assessments were collected pre-dose on Day 8 and at Weeks 4 and 24, at 1-3 hours post-dose on Day 8, and at 1-3 hours or 4-12 hours post-dose at Weeks 4 and 24.
Time frame: Day 8, Week 4, and Week 24
C0 Assessment of DTG
The plasma DTG concentration immediately prior to dosing at steady state (C0) was assessed at Day 8, Week 4, and Week 24. Blood samples for pharmacokinetic assessments were collected pre-dose and 1-3 hours post-dose on Day 8 and at Week 4 and 4-12 hours post-dose at Week 24. Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the Pharmacokinetic Parameter Population.
Time frame: Day 8, Week 4, and Week 24
Number of Participants With the Indicated Treatment-emergent Integrase (IN) Mutations Detected at the Time of Protocol-defined Virologic Failure (PDVF) as a Measure of Genotypic Resistance
An analysis of changes at specific amino acids in the IN coding region associated with resistance to raltegravir, elvitegravir, or DTG was performed at Day 1 and at the time of PDVF. PDVF is a \<0.5 log10 copies(c)/mL decrease in plasma HIV-1 RNA at Day 8 unless the absolute value is \<400 c/mL. PDVF after Day 8 is defined as virological non-respones (decrease in plasma HIV-1 RNA of \<1 log10 c/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA \<400 c/mL and confirmed plasma HIV-1 RNA levels \>=400 c/mL on or after Week 24) and virological rebound (confirmed rebound in plasma HIV-1 RNA levels to \>=400 c/mL after prior confirmed suppression to \<400 c/mL and confirmed plasma HIV-1 RNA levels \>1 log10 c/mL above the nadir value \[nadir: \>=400 c/mL\]).
Time frame: From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
Number of Participants With the Indicated Fold Increase in DTG FC (Fold Change in IC50 Relative to Wild-type Virus) Between Baseline and the Time of PDVF, as a Measure of Post-Baseline Phenotypic Resistance
The FC in IC50 (50% inhibitory concentration) for DTG relative to wild-type virus was determined for virus isolated at Baseline and at the time of PDVF. The number of participants with the indicated change (ratio) in the two values at the time of PDVF is presented. PDVF is defined as a \<0.5 log10 copies/mL decrease in plasma HIV-1 RNA at Day 8 unless the absolute value is \<400 copies/mL. PDVF after Day 8 was defined for virological non-response (decrease in plasma HIV-1 RNA of less than 1 log10 copies/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA \<400 copies/mL and confirmed plasma HIV-1 RNA levels \>=400 copies/mL on or after Week 24) and virological rebound (confirmed rebound in plasma HIV-1 RNA levels to \>=400 copies/mL after prior confirmed suppression to \<400 copies/mL and confirmed plasma HIV-1 RNA levels \>1 log10 copies/mL above the nadir value, where nadir is \>=400 copies/mL).
Time frame: From the day of the first dose of study drug until end of treatment visit for each participant, up to Week 180 (median of 758 days)
Participants (par.) having documented Human immunodeficiency virus type 1 (HIV-1) infection with a plasma HIV-1 Ribonucleic acid(RNA) \>=500 copies per milliliter (c/mL) at Screening, Antiretroviral therapy (ART)-experienced and on stable ART for at least one month prior to Screening were enrolled
| Milestone | Dolutegravir 50 mg BID |
|---|---|
| Started | 183 |
| Completed | 126 |
| Not completed | 57 |
| Withdrew: Adverse event | 7 |
| Withdrew: Lack of efficacy | 27 |
| Withdrew: Protocol violation | 7 |
| Withdrew: Lost to follow-up | 7 |
| Withdrew: Physician decision | 2 |
| Withdrew: Withdrawal by subject | 7 |
Mean change from Baseline in Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) at Day 8 was calculated as the Day 8 value minus the Baseline value. The last observation was carried forward if a participant had missed the Day 8 visit. The Baseline observation was carried forward if a participant had discontinued the treatment before Day 8. Blood samples for assessment of HIV-1 RNA levels were collected at Baseline and Day 8.
| log10 copies/milliliter (mL) | Dolutegravir 50 mg BID |
|---|---|
| Mean Change From Baseline in Plasma HIV-1 RNA at Day 8 | -1.432 ± 0.6070 |
The number of participants who had viral load \<50 copies/mL at Week 24 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (VOI \[due to missing data/discontinuation of investigational product prior to the visit window\]) as nonresponders, as well as participants who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the VOI analysis window.
| participants | Dolutegravir 50 mg BID |
|---|---|
| Number of Participants With HIV-1 RNA Less Than 50 Copies/mL at Week 24 | 126 |
The number of participants who had viral load \<50 copies/mL at Week 48 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (VOI \[due to missing data/discontinuation of investigational product prior to the visit window\]) as nonresponders, as well as participants who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the participant was on treatment within the VOI analysis window.
| participants | Dolutegravir 50 mg BID |
|---|---|
| Number of Participants With HIV-1 RNA Less Than 50 Copies/mL at Week 48 | 116 |
An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.
| participants | Dolutegravir 50 mg BID |
|---|---|
| Any AE | 169 |
| Any SAE | 46 |
An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. AE/SAE severity was graded according to the DAIDS grading scale. The DAIDS displays events as Grades 1-4 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, potentially life threatening.
| participants | Dolutegravir 50 mg BID |
|---|---|
| Grade 1 | 45 |
| Grade 2 | 64 |
| Grade 3 | 44 |
| Grade 4 | 16 |
The severity of clinical chemistry toxicities was graded according to the DAIDS toxicity scale. The DAIDS displays events as Grades 1-5 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, life threatening; G5, death related to toxicity.
| participants | Dolutegravir 50 mg BID |
|---|---|
| Grade 1 | 49 |
| Grade 2 | 67 |
| Grade 3 | 43 |
| Grade 4 | 16 |
The severity of hematology toxicities was graded according to the DAIDS. The DAIDS displays events as Grades 1-5 based on this general guideline: Grade (G) 1, mild; G2, moderate; G3, severe; G4, life threatening; G5, death related to toxicity.
| Participants | Dolutegravir 50 mg BID |
|---|---|
| Grade 1 | 31 |
| Grade 2 | 15 |
| Grade 3 | 4 |
| Grade 4 | 2 |
The number of participants with plasma HIV-1 RNA less than 400 and 50 copies (c)/mL at Baseline; Day 8; and Weeks 4, 8, 12, 16, 24, 32, 40 and 48 based on the Food and Drug Administration's Snapshot algorithm was assessed. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (VOI \[due to missing data/discontinuation of investigational product prior to the visit window\]) as nonresponders, as well as participants who switched their concomitant antiretroviral (ART) prior to the VOI as follows: background ART substitutions not permitted per protocol; background ART substitutions permitted per protocol, however the decision to switch was not documented as being before or at the first on-treatment visit after switching to optimized background regimen (i.e., Week 4) where HIV-1 RNA was assessed. Otherwise, virologic success/failure was to be determined by the last available HIV-1 RNA assessment while the par. was on treatment within the VOI analysis window
| participants | Dolutegravir 50 mg BID |
|---|---|
| HIV-1 RNA <50 c/mL, Baseline | 1 |
| HIV-1 RNA <50 c/mL, Day 8 | 28 |
| HIV-1 RNA <50 c/mL, Week 4 | 98 |
| HIV-1 RNA <50 c/mL, Week 8 | 112 |
| HIV-1 RNA <50 c/mL, Week 12 | 116 |
| HIV-1 RNA <50 c/mL, Week 16 | 116 |
| HIV-1 RNA <50 c/mL, Week 24 | 126 |
| HIV-1 RNA <50 c/mL, Week 32 | 117 |
| HIV-1 RNA <50 c/mL, Week 40 | 108 |
| HIV-1 RNA <50 c/mL, Week 48 | 116 |
| HIV-1 RNA <400 c/mL, Baseline | 8 |
| HIV-1 RNA <400 c/mL, Day 8 | 82 |
| HIV-1 RNA <400 c/mL, Week 4 | 145 |
| HIV-1 RNA <400 c/mL, Week 8 | 146 |
| HIV-1 RNA <400 c/mL, Week 12 | 142 |
| HIV-1 RNA <400 c/mL, Week 16 | 139 |
| HIV-1 RNA <400 c/mL, Week 24 | 135 |
| HIV-1 RNA <400 c/mL, Week 32 | 127 |
| HIV-1 RNA <400 c/mL, Week 40 | 119 |
| HIV-1 RNA <400 c/mL, Week 48 | 125 |
The number of participants with plasma HIV-1 RNA less than 400 and 50 copies (c)/mL was assessed at Weeks 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 and 180 using data of observed cases. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).
| Participants | Dolutegravir 50 mg BID |
|---|---|
| HIV-1 RNA <50 c/mL, Week 48, n =146 | 121 (40.0 to 330.0) |
| HIV-1 RNA <50 c/mL, Week 60, n=142 | 110 (60.0 to 350.0) |
| HIV-1 RNA <50 c/mL, Week 72, n=138 | 116 (80.0 to 350.0) |
| HIV-1 RNA <50 c/mL, Week 84, n=138 | 108 (100.0 to 350.0) |
| HIV-1 RNA <50 c/mL, Week 96, n=120 | 101 (110.0 to 360.0) |
| HIV-1 RNA <50 c/mL, Week 108, n=98 | 81 (130.0 to 400.0) |
| HIV-1 RNA <50 c/mL, Week 120, n=82 | 72 (130.0 to 420.0) |
| HIV-1 RNA <50 c/mL, Week 132, n=61 | 49 (170.0 to 440.0) |
| HIV-1 RNA <50 c/mL, Week 144, n=45 | 37 (200.0 to 440.0) |
| HIV-1 RNA <50 c/mL, Week 156, n=32 | 28 (200.0 to 450.0) |
| HIV-1 RNA <50 c/mL, Week 168, n=24 | 20 (540.0 to 1220.0) |
| HIV-1 RNA <50 c/mL, Week 180, n=6 | 4 (655.0 to 1405.0) |
| HIV-1 RNA <400 c/mL, Week 48, n=146 | 134 (730.0 to 1460.0) |
| HIV-1 RNA <400 c/mL, Week 60, n=142 | 131 (690.0 to 1460.0) |
| HIV-1 RNA <400 c/mL, Week 72, n=138 | 130 (720.0 to 1380.0) |
| HIV-1 RNA <400 c/mL, Week 84, n=138 | 127 |
| HIV-1 RNA <400 c/mL, Week 96, n=120 | 111 |
| HIV-1 RNA <400 c/mL, Week 108, n=98 | 92 |
| HIV-1 RNA <400 c/mL, Week 120, n=82 | 80 |
| HIV-1 RNA <400 c/mL, Week 132, n=61 | 59 |
| HIV-1 RNA <400 c/mL, Week 144, n=45 | 44 |
| HIV-1 RNA <400 c/mL, Week 156, n=32 | 31 |
| HIV-1 RNA <400 c/mL, Week 168, n=24 | 23 |
| HIV-1 RNA <400 c/mL, Week 180, n=6 | 5 |
Mean change from Baseline in plasma HIV-1 RNA was assesseed at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, 48 , 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180 using data of the observed cases. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
| Log10 copies/mL | Dolutegravir 50 mg BID |
|---|---|
| Day 8, n=182 | -1.432 ± 0.607 |
| Week 4, n=180 | -2.088 ± 0.885 |
| Week 8, n=179 | -2.101 ± 0.987 |
| Week 12, n=174 | -2.113 ± 1.069 |
| Week 16, n=165 | -2.216 ± 1.005 |
| Week 24, n=164 | -2.211 ± 1.023 |
| Week 32, n=146 | -2.373 ± 0.926 |
| Week 40, n=144 | -2.301 ± 0.955 |
| Week 48, n=146 | -2.321 ± 0.981 |
| Week 60, n=142 | -2.356 ± 0.928 |
| Week 72, n=138 | -2.390 ± 0.941 |
| Week 84, n=138 | -2.311 ± 0.996 |
| Week 96, n=120 | -2.346 ± 1.008 |
| Week 108, n=98 | -2.394 ± 0.966 |
| Week 120, n=82 | -2.515 ± 0.904 |
| Week 132, n=61 | -2.456 ± 0.988 |
| Week 144, n=45 | -2.585 ± 0.983 |
| Week 156, n=32 | -2.595 ± 1.009 |
| Week 168, n=24 | -2.719 ± 0.898 |
| Week 180, n=6 | -2.425 ± 1.557 |
Absolute values for CD4+ cell counts were assessed at Baseline, Day 8 and Weeks 4, 8, 12, 16, and 24, and absolute values for CD8+ cell counts were assessed at Baseline and Weeks 4, 12, 24, and 48.
| Cells per millimeters cubed (cells/mm^3) | Dolutegravir 50 mg BID |
|---|---|
| CD4+, Baseline, n=183 | 140.0 ± 0.607 |
| CD4+, Day 8, n=181 | 170.0 ± 0.885 |
| CD4+, Week 4, n=178 | 185.0 ± 0.987 |
| CD4+, Week 8, n=178 | 210.0 ± 1.069 |
| CD4+, Week 12, n=171 | 210.0 ± 1.005 |
| CD4+, Week 16, n=165 | 210.0 ± 1.023 |
| CD4+, Week 24, n=163 | 250.0 ± 0.926 |
| CD4+, Week 32, n=147 | 270.0 ± 0.955 |
| CD4+, Week 40, n=143 | 290.0 ± 0.981 |
| CD4+, Week 48, n=145 | 310.0 ± 0.928 |
| CD8+, Week 4, n=181 | 860.0 ± 0.941 |
| CD8+, Week 4, n=176 | 970.0 ± 0.996 |
| CD8+, Week 12, n=170 | 1015.0 ± 1.008 |
| CD8+, Week 24, n=154 | 1020.0 ± 0.966 |
| CD8+, Week 48, n=140 | 1000.0 ± 0.904 |
Median change from Baseline in CD4+ cell counts was assessed at Day 8 and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, and 180. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
| Cells per millimeters cubed (cells/mm^3) | Dolutegravir 50 mg BID |
|---|---|
| CD4+, Day 8, n=181 | 20.0 (0.0 to 60.0) |
| CD4+, Week 4, n=178 | 30.0 (0.0 to 71.0) |
| CD4+, Week 8, n=178 | 40.0 (0.0 to 81.0) |
| CD4+, Week 12, n=171 | 50.0 (0.0 to 100.0) |
| CD4+, Week 16, n=165 | 60.0 (20.0 to 130.0) |
| CD4+, Week 24, n=163 | 61.0 (20.0 to 130.0) |
| CD4+, Week 32, n=147 | 100.0 (20.0 to 160.0) |
| CD4+, Week 40, n=143 | 90.0 (30.0 to 180.0) |
| CD4+, Week 48, n=145 | 110.0 (40.0 to 190.0) |
| CD4+, Week 60, n=142 | 120.0 (50.0 to 210.0) |
| CD4+, Week 72, n=138 | 140.0 (60.0 to 231.0) |
| CD4+, Week 84, n=137 | 150.0 (80.0 to 240.0) |
| CD4+, Week 96, n=117 | 160.0 (80.0 to 270.0) |
| CD4+, Week 108, n=98 | 180.5 (80.0 to 280.0) |
| CD4+, Week 120, n=82 | 180.0 (100.0 to 280.0) |
| CD4+, Week 132, n=61 | 221.0 (100.0 to 320.0) |
| CD4+, Week 144, n=46 | 205.0 (130.0 to 350.0) |
| CD4+, Week 156, n=32 | 225.0 (155. to 345.0) |
| CD4+, Week168, n=24 | 265.0 (155.0 to 380.0) |
| CD4+, Week180, n=6 | 170.5 (140.0 to 230.0) |
The ratio of CD4+/CD8+ cell count (measured in cells/mm\^3) was assessed at Baseline and at Weeks 4, 12, 24, and 48. The ratio was calculated as the CD4+ cell count divided by CD8+ cell count.
| ratio | Dolutegravir 50 mg BID |
|---|---|
| Baseline, n=180 | 0.15 (0.05 to 0.34) |
| Week 4, n=176 | 0.19 (0.09 to 0.37) |
| Week 12, n=170 | 0.21 (0.10 to 0.46) |
| Week 24, n=154 | 0.26 (0.14 to 0.46) |
| Week 48, n=140 | 0.32 (0.19 to 0.52) |
The number of participants with HIV-1 disease progression (AIDS or death) was assessed per the Centers for Disease Control and Prevention (CDC) 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. The CDC classifies HIV infection as Category A (participants with asymptomatic HIV infection, acute HIV infection with accompanying illness, or persistent generalized lymphadenopathy), Category B (participants with symptomatic non-AIDS condition, i.e., conditions that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection), and Category C (includes AIDS indicator conditions as defined by diagnostic or presumptive measures).
| Participants | Dolutegravir 50 mg BID |
|---|---|
| Progression from CDC Class A to Class C Event | 1 (4.18 to 5.36) |
| Progression from CDC Class B to Class C Event | 2 (2.15 to 3.15) |
| Progression from CDC Class C to New Class C Event | 6 |
| Progression from Classes A, B, or C to Death | 2 |
The maximum plasma concentration (Cmax) and the concentration at the end of a dosing interval (Ctau) of DTG were assessed by a population pharmacokinetic (PK) modeling approach using pooled DTG PK data from multiple studies. For this study, blood samples for pharmacokinetic assessments were collected pre-dose on Day 8 and at Weeks 4 and 24, at 1-3 hours post-dose on Day 8, and at 1-3 hours or 4-12 hours post-dose at Weeks 4 and 24.
| Micrograms per milliliter (µg/mL) | Dolutegravir 50 mg BID |
|---|---|
| Cmax | 4.74 (4.18 to 5.36) |
| Ctau | 2.60 (2.15 to 3.15) |
The area under the time concentration curve over the dosing interval (AUC\[0-tau\]) and from 0 to 24 hours (AUC\[0-24\]) of DTG was assessed by a population PK modeling approach using pooled DTG PK data from multiple studies. For this study, blood samples for pharmacokinetic assessments were collected pre-dose on Day 8 and at Weeks 4 and 24, at 1-3 hours post-dose on Day 8, and at 1-3 hours or 4-12 hours post-dose at Weeks 4 and 24.
| µg*hour/mL | Dolutegravir 50 mg BID |
|---|---|
| AUC(0-tau) | 36.7 ± 91 |
| AUC(0-24) | 73.5 ± 113 |
The plasma DTG concentration immediately prior to dosing at steady state (C0) was assessed at Day 8, Week 4, and Week 24. Blood samples for pharmacokinetic assessments were collected pre-dose and 1-3 hours post-dose on Day 8 and at Week 4 and 4-12 hours post-dose at Week 24. Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the Pharmacokinetic Parameter Population.
| µg/mL | Dolutegravir 50 mg BID |
|---|---|
| Day 8, n=148 | 2.36 ± 91 |
| Week 4, n=161 | 1.90 ± 113 |
| Week 24, n=135 | 2.14 ± 93 |
An analysis of changes at specific amino acids in the IN coding region associated with resistance to raltegravir, elvitegravir, or DTG was performed at Day 1 and at the time of PDVF. PDVF is a \<0.5 log10 copies(c)/mL decrease in plasma HIV-1 RNA at Day 8 unless the absolute value is \<400 c/mL. PDVF after Day 8 is defined as virological non-respones (decrease in plasma HIV-1 RNA of \<1 log10 c/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA \<400 c/mL and confirmed plasma HIV-1 RNA levels \>=400 c/mL on or after Week 24) and virological rebound (confirmed rebound in plasma HIV-1 RNA levels to \>=400 c/mL after prior confirmed suppression to \<400 c/mL and confirmed plasma HIV-1 RNA levels \>1 log10 c/mL above the nadir value \[nadir: \>=400 c/mL\]).
| participants | Dolutegravir 50 mg BID |
|---|---|
| Any IN mutation | 25 |
| T97A | 8 |
| T97T/A | 4 |
| E138A | 1 |
| E138E/A | 1 |
| E138E/K | 3 |
| E138K | 4 |
| E138T/A | 1 |
| N155H | 6 |
| N155N/H | 1 |
| Q148H | 3 |
| Q148Q/H | 2 |
| Q148R | 1 |
| Q148Q/R/K | 1 |
| G140G/S | 1 |
| G140S | 3 |
| L74L/M/V | 1 |
| L74L/M | 1 |
| L74I | 1 |
| E92E/Q | 2 |
| S147G | 2 |
| E157E/Q | 1 |
| V151V/M/I | 1 |
| Y143Y/H | 1 |
The FC in IC50 (50% inhibitory concentration) for DTG relative to wild-type virus was determined for virus isolated at Baseline and at the time of PDVF. The number of participants with the indicated change (ratio) in the two values at the time of PDVF is presented. PDVF is defined as a \<0.5 log10 copies/mL decrease in plasma HIV-1 RNA at Day 8 unless the absolute value is \<400 copies/mL. PDVF after Day 8 was defined for virological non-response (decrease in plasma HIV-1 RNA of less than 1 log10 copies/mL by Week 16, with subsequent confirmation, unless plasma HIV-1 RNA \<400 copies/mL and confirmed plasma HIV-1 RNA levels \>=400 copies/mL on or after Week 24) and virological rebound (confirmed rebound in plasma HIV-1 RNA levels to \>=400 copies/mL after prior confirmed suppression to \<400 copies/mL and confirmed plasma HIV-1 RNA levels \>1 log10 copies/mL above the nadir value, where nadir is \>=400 copies/mL).
| Participants | Dolutegravir 50 mg BID |
|---|---|
| <1 fold | 6 |
| 1-<2 fold | 16 |
| 2-<4 fold | 4 |
| 4-<8 fold | 4 |
| >=8 fold | 12 |
| Missing | 3 |
Collected over On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from start of study treament until the end of treatment visit for each participant (up to Week 180). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Dolutegravir 50 mg BID | — | 46/183 (25.1%) | 143/183 (78.1%) |
| Event | Dolutegravir 50 mg BID |
|---|---|
| PneumoniaInfections and infestations | 5/183 |
| PyrexiaGeneral disorders | 3/183 |
| DehydrationMetabolism and nutrition disorders | 3/183 |
| Progressive multifocal leukoencephalopathyInfections and infestations | 2/183 |
| CholelithiasisHepatobiliary disorders | 2/183 |
| Squamous cell carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 2/183 |
| Pleural effusionRespiratory, thoracic and mediastinal disorders | 2/183 |
| Cardiac failure congestiveCardiac disorders | 2/183 |
| DiarrhoeaGastrointestinal disorders | 2/183 |
| Lung disorderRespiratory, thoracic and mediastinal disorders | 2/183 |
| Event | Dolutegravir 50 mg BID |
|---|---|
| DiarrhoeaGastrointestinal disorders | 41/183 |
| CoughRespiratory, thoracic and mediastinal disorders | 29/183 |
| NauseaGastrointestinal disorders | 26/183 |
| BronchitisInfections and infestations | 25/183 |
| HeadacheNervous system disorders | 24/183 |
| Upper respiratory tract infectionInfections and infestations | 22/183 |
| PyrexiaGeneral disorders | 19/183 |
| Back painMusculoskeletal and connective tissue disorders | 18/183 |
| FatigueGeneral disorders | 17/183 |
| RashSkin and subcutaneous tissue disorders | 17/183 |
| Age, Continuous(Years) | Dolutegravir 50 mg BID |
|---|---|
| Median | 48 (19 to 67) |
| Sex: Female, Male(Participants) | Dolutegravir 50 mg BID |
|---|---|
| Female | 42 |
| Male | 141 |
| Race/Ethnicity, Customized(participants) | Dolutegravir 50 mg BID |
|---|---|
| African American/African Heritage | 49 |
| American Indian or Alaska Native and White | 1 |
| Asian-Central/South Asian Heritage | 1 |
| White | 130 |
| White and African American/African Heritage | 2 |
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