Trial Outcomes & Findings for Vicriviroc (SCH 417690) in Combination Treatment With Optimized ART Regimen in Experienced Participants (VICTOR-E1) (MK-7690-020/P03672) (NCT NCT00243230)

Last Updated: 2021-06-08

Results Overview

HIV RNA was measured by AMPLICOR HIV-1 MONITOR Standard assay. For participants who had HIV RNA below the lower quantification of the Standard assay (LOQ of 400 copies/mL), the AMPLICOR HIV-1.5 UltraSensitive assay was performed. If the HIV RNA measurement was below the lower quantification of the UltraSensitive assay (LOQ of 50 copies/mL), a value of 49 was imputed. If a continuing participant has a missing HIV RNA value at the time point of interest, the geometric mean of immediately preceding and following values was used. If the participants had no subsequent following value or discontinued study treatment before the time point of interest, then the change from baseline was set to zero. Analysis was performed with a variance (ANOVA) model that adjusted for the treatment and stratification factors (intended enfuvirtide (T20) use in current newly-optimized background regimen (OBT) (Y/N) and HIV RNA at Screening (\> or ≤100,000 copies/mL)).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

116 participants

Primary outcome timeframe

Baseline and Week 48 of the Double-blind Period

Results posted on

2021-06-08

Participant Flow

After completing 48 weeks of blinded treatment, participants were offered open-label VCV 30 mg QD in addition to optimized background therapy (OBT). Participants who discontinued before Week 48 of the double-blind segment of the trial for reasons other than adverse events were offered rescreening for the open label extension.

Participant milestones

Participant milestones
Measure	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Placebo Plus an ART Regimen Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Open-Label Period - Vicriviroc 30 mg Plus an ART Regimen Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized ART regimen containing a ritonavir-boosted protease inhibitor (PI/r) for up to 45 months.
Double-Blind Period STARTED	39	40	37	0
Double-Blind Period Treated	39	40	35	0
Double-Blind Period COMPLETED	33	35	18	0
Double-Blind Period NOT COMPLETED	6	5	19	0
Open Label Period STARTED	0	0	0	85
Open Label Period COMPLETED	0	0	0	0
Open Label Period NOT COMPLETED	0	0	0	85

Reasons for withdrawal

Reasons for withdrawal
Measure	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Placebo Plus an ART Regimen Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Open-Label Period - Vicriviroc 30 mg Plus an ART Regimen Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized ART regimen containing a ritonavir-boosted protease inhibitor (PI/r) for up to 45 months.
Double-Blind Period Adverse Event	0	2	2	0
Double-Blind Period Withdrawal by Subject	1	0	0	0
Double-Blind Period Protocol Violation	0	0	1	0
Double-Blind Period Randomized but Not Treated	0	0	2	0
Double-Blind Period Treatment Failure - Virologic Failure defined by investigator	5	3	14	0
Open Label Period Adverse Event	0	0	0	2
Open Label Period Treatment Failure - Virologic Failure	0	0	0	13
Open Label Period Progressive Disease (AIDS-Event)	0	0	0	1
Open Label Period Lost to Follow-up	0	0	0	2
Open Label Period Withdrawal by Subject	0	0	0	2
Open Label Period Protocol Violation	0	0	0	2
Open Label Period Administrative Reason	0	0	0	63

Baseline Characteristics

Vicriviroc (SCH 417690) in Combination Treatment With Optimized ART Regimen in Experienced Participants (VICTOR-E1) (MK-7690-020/P03672)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Placebo Plus an ART Regimen n=37 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Total n=116 Participants Total of all reporting groups
Age, Continuous	44.9 Years STANDARD_DEVIATION 7.3 • n=5 Participants	44.0 Years STANDARD_DEVIATION 8.0 • n=7 Participants	45.5 Years STANDARD_DEVIATION 8.8 • n=5 Participants	44.8 Years STANDARD_DEVIATION 8.0 • n=4 Participants
Sex: Female, Male Female	6 Participants n=5 Participants	9 Participants n=7 Participants	11 Participants n=5 Participants	26 Participants n=4 Participants
Sex: Female, Male Male	33 Participants n=5 Participants	31 Participants n=7 Participants	26 Participants n=5 Participants	90 Participants n=4 Participants
Race/Ethnicity, Customized White	26 Participants n=5 Participants	32 Participants n=7 Participants	21 Participants n=5 Participants	79 Participants n=4 Participants
Race/Ethnicity, Customized Black	9 Participants n=5 Participants	3 Participants n=7 Participants	8 Participants n=5 Participants	20 Participants n=4 Participants
Race/Ethnicity, Customized Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Other	4 Participants n=5 Participants	4 Participants n=7 Participants	8 Participants n=5 Participants	16 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline and Week 48 of the Double-blind Period

Population: The analysis population included all randomized participants who received at least 1 dose of study medication during the Double-blind Period. Participants enrolled in the Open Label Period were not included in this analysis population.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Change From Baseline in Log10 Human Immunodeficiency Virus (HIV) Ribonucleic Acid (RNA) at Week 48 of the Double-blind Period Log10 HIV RNA at Baseline.	4.62 Log10 copies/mL Standard Deviation 0.79	4.52 Log10 copies/mL Standard Deviation 0.88	4.50 Log10 copies/mL Standard Deviation 0.89
Change From Baseline in Log10 Human Immunodeficiency Virus (HIV) Ribonucleic Acid (RNA) at Week 48 of the Double-blind Period Change from Baseline in Log10 HIV RNA at Week 48.	-0.80 Log10 copies/mL Standard Deviation 1.31	-1.78 Log10 copies/mL Standard Deviation 1.31	-1.73 Log10 copies/mL Standard Deviation 1.31

SECONDARY outcome

Timeframe: Baseline and 48 Weeks of the Double-blind Period

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Participants With ≥1.0 log10 Change From Baseline HIV RNA at Week 48 of the Double-blind Period	12 Participants	26 Participants	25 Participants

SECONDARY outcome

Timeframe: Week 48 of the Double-blind Period

HIV RNA was measured by AMPLICOR HIV-1 MONITOR Standard assay. For participants who had HIV RNA below the lower quantification of the Standard assay (LOQ of 400 copies/mL), the AMPLICOR HIV-1.5 UltraSensitive assay was performed. If a continuing participant has a missing HIV RNA value at the time point of interest, the geometric mean of immediately preceding and following values was used. If the participants had no subsequent following value or discontinued study treatment before the time point of interest, then the change from baseline was set to zero.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Participants With HIV RNA <400 Copies/mL at Week 48 of the Double-blind Period	9 Participants	25 Participants	24 Participants

SECONDARY outcome

Timeframe: Up to 48 weeks of the Double-blind Period

TLOVR defined as the time from randomization to either: 1. Failure to experience HIV RNA decline of ≥0.5 log10 from Baseline at Week 4, in which case time was set to 0; or 2. Rebound of HIV RNA to within 0.5 log10 of baseline value at any time after maximum suppression. HIV RNA was measured by AMPLICOR HIV-1 MONITOR Standard assay. For participants who had HIV RNA below the lower quantification of the Standard assay (LOQ of 400 c/mL), the AMPLICOR HIV-1.5 UltraSensitive assay was performed. If the HIV RNA measurement was below the lower quantification of the UltraSensitive assay (LOQ of 50 c/mL), a value of 49 was imputed. If a continuing participant has a missing HIV RNA value at the time point of interest, the geometric mean of immediately preceding and following values was used. If the participants had no subsequent following value or discontinued study treatment before the time point of interest, then the change from baseline was set to zero.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Participants With a Time to Loss of Virologic Response (TLOVR) Based on 0.5 Log10 Reduction by 48 Weeks of the Double-blind Period Participants with Sustained ≥0.5 Log10 Reduction by Week 4	15 Participants	31 Participants	32 Participants
Participants With a Time to Loss of Virologic Response (TLOVR) Based on 0.5 Log10 Reduction by 48 Weeks of the Double-blind Period Participants with Rebound by Week 12	1 Participants	1 Participants	1 Participants
Participants With a Time to Loss of Virologic Response (TLOVR) Based on 0.5 Log10 Reduction by 48 Weeks of the Double-blind Period Participants with Rebound by Week 24	1 Participants	2 Participants	1 Participants
Participants With a Time to Loss of Virologic Response (TLOVR) Based on 0.5 Log10 Reduction by 48 Weeks of the Double-blind Period Participants with Rebound after Week 24	1 Participants	1 Participants	1 Participants
Participants With a Time to Loss of Virologic Response (TLOVR) Based on 0.5 Log10 Reduction by 48 Weeks of the Double-blind Period Participants Suppressed through Week 48	12 Participants	27 Participants	29 Participants
Participants With a Time to Loss of Virologic Response (TLOVR) Based on 0.5 Log10 Reduction by 48 Weeks of the Double-blind Period Participants with No ≥0.5 Log10 Reduction by Week 4	3 Participants	1 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline and Week 12 of the Double-blind Period

HIV RNA was measured by AMPLICOR HIV-1 MONITOR Standard assay. For participants who had HIV RNA below the lower quantification of the Standard assay (LOQ of 400 c/mL), the AMPLICOR HIV-1.5 UltraSensitive assay was performed. If the HIV RNA measurement was below the lower quantification of the UltraSensitive assay (LOQ of 50 c/mL), a value of 49 was imputed. If a continuing participant has a missing HIV RNA value at the time point of interest, the geometric mean of immediately preceding and following values was used. Missing values of change from baseline were imputed by the average of immediately preceding and following non-missing values, and in any other cases, missing values were imputed by zero.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Change From Baseline in Log10 HIV RNA at Week 12 of the Double-blind Period Log10 HIV RNA at Baseline.	4.62 Log10 copies/mL Standard Deviation 0.79	4.52 Log10 copies/mL Standard Deviation 0.88	4.50 Log10 copies/mL Standard Deviation 0.89
Change From Baseline in Log10 HIV RNA at Week 12 of the Double-blind Period Change from Baseline in Log10 HIV RNA at Week 12.	-1.11 Log10 copies/mL Standard Deviation 1.14	-2.11 Log10 copies/mL Standard Deviation 1.14	-1.94 Log10 copies/mL Standard Deviation 1.14

SECONDARY outcome

Timeframe: Baseline and Week 24 of the Double-blind Period

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Change From Baseline in Log10 HIV RNA at Week 24 of the Double-blind Period Log10 HIV RNA at Baseline.	4.62 Log10 copies/mL Standard Deviation 0.79	4.52 Log10 copies/mL Standard Deviation 0.88	4.50 Log10 copies/mL Standard Deviation 0.89
Change From Baseline in Log10 HIV RNA at Week 24 of the Double-blind Period Change from Baseline in Log10 HIV RNA at Week 24.	-0.96 Log10 copies/mL Standard Deviation 1.28	-2.07 Log10 copies/mL Standard Deviation 1.28	-2.04 Log10 copies/mL Standard Deviation 1.28

SECONDARY outcome

Timeframe: Baseline and Week 12 of the Double-blind Period

Population: The analysis population included all randomized participants who received at least 1 dose of study medication and had baseline and Week 12 endpoint measurements during the Double-blind Period. Participants enrolled in the Open Label Period were not included in this analysis population.

Blood was collected and CD4+ cell count assessment was done by flow cytometry. Mean change from baseline in CD4 cell counts was determined. Any missing value was replaced by carrying forward baseline except if the immediately preceding and following value are available, in which case the arithmetic average of the two was used. If more than 1 CD4 count was available during a visit window, the value that was the closest to the time point of interest was used. If more than 1 pre-treatment CD4 value was available at baseline, the arithmetic mean of the 2 CD4 counts was taken.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=39 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Change From Baseline CD4 Cells Count at Week 12 of the Double-blind Period CD4 Cells Count at Baseline	214.41 Cells/mm^3 Standard Deviation 185.62	202.23 Cells/mm^3 Standard Deviation 159.22	202.10 Cells/mm^3 Standard Deviation 144.47
Change From Baseline CD4 Cells Count at Week 12 of the Double-blind Period Change from Baseline CD4 Cells Count at Week 12	52.09 Cells/mm^3 Standard Deviation 110.21	109.85 Cells/mm^3 Standard Deviation 110.23	94.46 Cells/mm^3 Standard Deviation 110.31

SECONDARY outcome

Timeframe: Baseline and Week 24 of the Double-blind Period

Population: The analysis population included all randomized participants who received at least 1 dose of study medication and had baseline and Week 24 endpoint measurements during the Double-blind Period. Participants enrolled in the Open Label Period were not included in this analysis population.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=39 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Change From Baseline CD4 Count at Week 24 of the Double-blind Period CD4 Count at Baseline.	214.41 Cells/mm^3 Standard Deviation 185.62	202.23 Cells/mm^3 Standard Deviation 159.22	202.10 Cells/mm^3 Standard Deviation 144.47
Change From Baseline CD4 Count at Week 24 of the Double-blind Period Change from Baseline CD4 Count at Week 24.	59.46 Cells/mm^3 Standard Deviation 113.64	97.58 Cells/mm^3 Standard Deviation 113.66	103.58 Cells/mm^3 Standard Deviation 113.74

SECONDARY outcome

Timeframe: Baseline and Week 48 of the Double-blind Period

Population: The analysis population included all randomized participants who received at least 1 dose of study medication and had baseline and Week 48 endpoint measurements during the Double-blind Period. Participants enrolled in the Open Label Period were not included in this analysis population.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=39 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Change From Baseline CD4 Count at Week 48 of the Double-blind Period CD4 Count at Baseline.	214.41 Cells/mm^3 Standard Deviation 185.62	202.23 Cells/mm^3 Standard Deviation 159.22	202.10 Cells/mm^3 Standard Deviation 144.47
Change From Baseline CD4 Count at Week 48 of the Double-blind Period Change from Baseline CD4 Count at Week 48.	64.80 Cells/mm^3 Standard Deviation 141.65	102.12 Cells/mm^3 Standard Deviation 141.68	133.88 Cells/mm^3 Standard Deviation 141.79

SECONDARY outcome

Timeframe: Baseline and Month 42 of the Open Label Period

Population: The analysis population included all randomized participants who received at least 1 dose of study medication and had baseline and Month 42 endpoint measurements during the Open Label Period. Participants enrolled in the Double-blind Period were not included in this analysis population.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=85 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Change From Baseline CD4 Count at Month 42 of the Open Label Extension CD4 Count at Baseline (Open Label Extension).	—	366.16 Cells/mm^3 Standard Deviation 191.86	—
Change From Baseline CD4 Count at Month 42 of the Open Label Extension Change from Baseline CD4 Count at Month 42.	—	-78.67 Cells/mm^3 Standard Deviation 283.28	—

SECONDARY outcome

Timeframe: Week 12 of the Double-blind Period

HIV RNA was measured by AMPLICOR HIV-1 MONITOR Standard assay. For participants who had HIV RNA below the lower quantification of the Standard assay (LOQ of 400 copies/mL), the AMPLICOR HIV-1.5 UltraSensitive assay was performed. If a continuing participant has a missing HIV RNA value at the time point of interest, the geometric mean of immediately preceding and following values was used. If the participants had no subsequent following value or discontinued study treatment before the time point of interest, then the change from baseline was set to zero. HIV RNA \<400 copies/mL is a less stringent measure of viral suppression and indicates that a participant responded to treatment.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Participants With <400 Copies/mL HIV RNA at Week 12 of the Double-blind Period	14 Participants	28 Participants	25 Participants

SECONDARY outcome

Timeframe: Week 24 of the Double-blind Period

HIV RNA was measured by AMPLICOR HIV-1 MONITOR Standard assay. For participants who had HIV RNA below the lower quantification of the Standard assay (LOQ of 400 copies/mL), the AMPLICOR HIV-1.5 UltraSensitive assay was performed. If a continuing participant has a missing HIV RNA value at the time point of interest, the geometric mean of immediately preceding and following values was used. If the participants had no subsequent following value or discontinued study treatment before the time point of interest, then the change from baseline was set to zero. HIV RNA \<400 copies/mL is a less stringent measure of viral suppression and indicates that a participant responded to treatment.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Participants With <400 Copies/mL HIV RNA at Week 24 of the Double-blind Period	12 Participants	28 Participants	29 Participants

SECONDARY outcome

Timeframe: Up to 45 months of the Open Label Extension

Population: The analysis population included all randomized participants who received at least 1 dose of study medication during the Open Label Period. Participants enrolled in the Double-blind Period were not included in this analysis population.

HIV RNA was measured by AMPLICOR HIV-1 MONITOR Standard assay (the lower quantification, \[LOQ of 400 copies/mL\]) and for HIV RNA below the LOQ, with the AMPLICOR HIV-1.5 UltraSensitive assay. HIV RNA \<400 copies/mL is a less stringent measure of viral suppression (participant responded to treatment). HIV RNA \< 50 copies/mL is a very stringent measure of viral suppression (participant achieved full virologic suppression). If a continuing participant has a missing HIV RNA value at the time point of interest, the geometric mean of immediately preceding and following values was used. Missing value for any reason will be imputed as non-responder except if the immediately preceding and following viral counts are both \<50 copies/mL. Results are shown for Group 1. for participants with baseline HIV RNA \<50 copies/mL, Group 2. baseline HIV RNA 50 to \<400 copies/mL, and Group 3. baseline HIV RNA\>400 copies/mL.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=85 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Number of Participants With <50, 50 to <400, and ≥400 Copies/mL HIV RNA of the Open Label Extension Group 1. Baseline for RNA <50 copies/mL	—	48 Participants	—
Number of Participants With <50, 50 to <400, and ≥400 Copies/mL HIV RNA of the Open Label Extension Group 1. Last RNA <50 copies/mL	—	42 Participants	—
Number of Participants With <50, 50 to <400, and ≥400 Copies/mL HIV RNA of the Open Label Extension Group 1. Last RNA 50 to <400 copies/mL	—	5 Participants	—
Number of Participants With <50, 50 to <400, and ≥400 Copies/mL HIV RNA of the Open Label Extension Group 1. Last RNA ≥400 copies/mL	—	1 Participants	—
Number of Participants With <50, 50 to <400, and ≥400 Copies/mL HIV RNA of the Open Label Extension Group 2. Baseline for RNA 50 to <400 copies/mL	—	10 Participants	—
Number of Participants With <50, 50 to <400, and ≥400 Copies/mL HIV RNA of the Open Label Extension Group 2. Last RNA <50 copies/mL	—	5 Participants	—
Number of Participants With <50, 50 to <400, and ≥400 Copies/mL HIV RNA of the Open Label Extension Group 2. Last RNA 50 to <400 copies/mL	—	2 Participants	—
Number of Participants With <50, 50 to <400, and ≥400 Copies/mL HIV RNA of the Open Label Extension Group 2. Last RNA ≥400 copies/mL	—	3 Participants	—
Number of Participants With <50, 50 to <400, and ≥400 Copies/mL HIV RNA of the Open Label Extension Group 3. Baseline for RNA ≥400 copies/mL	—	27 Participants	—
Number of Participants With <50, 50 to <400, and ≥400 Copies/mL HIV RNA of the Open Label Extension Group 3. Last RNA <50 copies/mL	—	10 Participants	—
Number of Participants With <50, 50 to <400, and ≥400 Copies/mL HIV RNA of the Open Label Extension Group 3. Last RNA 50 to <400 copies/mL	—	0 Participants	—
Number of Participants With <50, 50 to <400, and ≥400 Copies/mL HIV RNA of the Open Label Extension Group 3. Last RNA ≥400 copies/mL	—	15 Participants	—

SECONDARY outcome

Timeframe: Week 12 of the Double-blind Period

The lower limit of HIV RNA \<50 copies/mL was determined by the UltraSensitive assay. HIV RNA \<50 copies/mL is a very stringent measure of viral suppression and indicates that a participant achieved full virologic suppression. Missing value for any reason were imputed as non-responder except if the immediately preceding and following viral counts are both \<50 copies/mL.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Participants With <50 Copies/mL HIV RNA at Week 12 of the Double-blind Period	8 Participants	18 Participants	17 Participants

SECONDARY outcome

Timeframe: Week 24 of the Double-blind Period

The lower limit of HIV RNA \<50 copies/mL was determined by the UltraSensitive assay. HIV RNA \< 50 copies/mL is a very stringent measure of viral suppression and indicates that a participant achieved full virologic suppression. Missing value for any reason will be imputed as non-responder except if the immediately preceding and following viral counts are both \<50 copies/mL.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Participants With <50 Copies/mL HIV RNA at Week 24 of the Double-blind Period	9 Participants	25 Participants	23 Participants

SECONDARY outcome

Timeframe: Week 48 of the Double-blind Period

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Participants With <50 Copies/mL HIV RNA at Week 48 of the Double-blind Period	5 Participants	22 Participants	21 Participants

SECONDARY outcome

Timeframe: Up to 48 weeks of the Double-blind Period

All potential AIDS-defining events (ADEs) identified by investigators and the sponsor were submitted with supporting clinical data to an Adjudication Committee of HIV experts. These experts did not participant in the study and reviewed the data without knowledge of treatment assignment. To be analyzed as an ADE, the event required concurrence on the diagnosis by at least two of the three Adjudication Committee members. Their review consisted of available clinical and laboratory data, including relevant radiologic, endoscopic, and pathology assessments, when applicable as well as autopsy reports and/or hospital admission and discharge summaries. An independent radiologist was called upon when necessary. Guidelines for Diagnosis of AIDS-Defining Conditions (CDC's 1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS Among Adolescents and Adults) was used.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Participants With Acquired Immunodeficiency Syndrome (AIDS)-Defining Events of the Double-blind Period	1 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to 45 months of the Open Label Extension

All potential AIDS-defining events (ADEs) identified by investigators and the sponsor were submitted with supporting clinical data to an Adjudication Committee of HIV experts, who did not participant in the study and reviewed the blinded data. Their review consisted of available clinical and laboratory data, including relevant radiologic, endoscopic, and pathology assessments, autopsy reports and/or hospital admission and discharge summaries. An independent radiologist was called upon when necessary. Guidelines for Diagnosis of AIDS-Defining Conditions (CDC's 1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS Among Adolescents and Adults) was used. To be analyzed as an ADE, the event required concurrence on the diagnosis by at least 2 of 3 Adjudication Committee members. After completion of the Double-blind Period, eligible participants could enroll in the Open Label Period and continue treatment.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=85 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Participants With AIDS-defining Events of the Open Label Extension	—	1 Participants	—

SECONDARY outcome

Timeframe: Up to 48 weeks of the Double-blind Period

Population: The analysis population included all randomized participants who received at least 1 dose of study medication and had an AIDS-defining Event during the Double-blind Period. Participants enrolled in the Open Label Period were not included in this analysis population.

All potential AIDS-defining events (ADEs) identified by investigators and the sponsor were submitted with supporting clinical data to an independent and blinded Adjudication Committee of HIV experts. To be analyzed as an ADE, the event required concurrence on the diagnosis by at least 2 of the 3 Adjudication Committee members. Their review included available clinical and laboratory data, including relevant radiologic, endoscopic, and pathology assessments, when applicable as well as autopsy reports and/or hospital admission and discharge summaries. An independent radiologist was called upon when necessary. Guidelines for Diagnosis of AIDS-Defining Conditions (CDC's 1993 Revised Classification System for HIV Infection and Expanded Surveillance Case Definition for AIDS Among Adolescents and Adults) was used.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=1 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Time to Occurrence of an AIDS-defining Event of the Double-blind Period	256 Days	—	—

SECONDARY outcome

Timeframe: Two blood samples 2 hours apart on Week 4, Week 12, and Week 24 of the Double-blind Period

Population: The analysis population included all randomized participants who received at least 1 dose of Vicriviroc during the Double-blind Period. Pharmacokinetics studies were not performed with participants receiving Placebo. Participants enrolled in the Open Label Period were not included in this analysis population.

Key pharmacokinetic (PK) parameters (maximum plasma concentration \[Cmax\], minimum plasma concentration \[Cmin\], area under the plasma concentration-time curve \[AUC\]) were estimated using a population PK modeling approach based on a two-compartment model with first-order absorption and elimination. Cmin is a measure of the minimum amount of drug in the plasma after the dose is given. Pharmacokinetics studies were not performed with participants receiving Placebo.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Observed Minimum Serum Concentration of Vicriviroc (Cmin) of the Double-blind Period	—	206.56 ng/mL Standard Deviation 76.82	156.95 ng/mL Standard Deviation 62.17

SECONDARY outcome

Timeframe: Two blood samples 2 hours apart on Week 4, Week 12, and Week 24 of the Double-blind Period

Key pharmacokinetic (PK) parameters (maximum plasma concentration \[Cmax\], minimum plasma concentration \[Cmin\], area under the plasma concentration-time curve \[AUC\]) were estimated using a population PK modeling approach based on a two-compartment model with first-order absorption and elimination. Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. Pharmacokinetics studies were not performed with participants receiving Placebo.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Observed Maximum (Peak) Plasma Concentration of Vicriviroc (Cmax) of the Double-blind Period	—	316.21 ng/mL Standard Deviation 84.41	229.33 ng/mL Standard Deviation 61.74

SECONDARY outcome

Timeframe: Two blood samples 2 hours apart on Week 4, Week 12, and Week 24 of the Double-blind Period

Key pharmacokinetic (PK) parameters (maximum plasma concentration \[Cmax\], minimum plasma concentration \[Cmin\], area under the plasma concentration-time curve \[AUC\]) were estimated using a population PK modeling approach based on a two-compartment model with first-order absorption and elimination. AUC is a measure of the mean concentration levels of drug in the plasma after the dose. Pharmacokinetics studies were not performed with participants receiving Placebo.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Area Under the Plasma Concentration Versus Time Curve of Vicriviroc (AUC) of the Double-blind Period	—	5795.62 hr*ng/mL Standard Deviation 1906.59	4314.88 hr*ng/mL Standard Deviation 1497.70

SECONDARY outcome

Timeframe: Up to 48 weeks of the Double-blind Period

Resistance testing was performed at Baseline and again at the time of virologic failure or study discontinuation using the Phenosense GT assay (Monogram Biosciences, South San Francisco, CA). This assay used a combination of genotypic and phenotypic resistance techniques to determine an overall sensitivity score (OSS). The OSS represents the total number of drugs in the optimized background regimen (OBT) to which the virus was fully susceptible. Partial sensitivity is not counted towards the OSS. VCV susceptibility testing was performed with a maximal percent inhibition (MPI) plateau value of \<85% as a cutoff for resistance.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Participants With Detectable Vicriviroc Resistance of the Double-blind Period	0 Participants	1 Participants	4 Participants

SECONDARY outcome

Timeframe: Up to 48 weeks of the Double-blind Period

Viral tropism was determined using the Monogram Trofile assay and antiviral drug susceptibility was measured by Monogram PhenoSense GT assay, based on both genotypic and phenotypic sensitivity of HIV isolates. The lower limit of sensitivity of the Trofile assay employed in this study for detection of minor X-4 using variants was 5-10%.

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Participants With Detectable C-X-C Chemokine Receptor Type 4 (CXCR4)-Tropic Virus of the Double-blind Period Participants With detectable CV (on study drug)	3 Participants	9 Participants	7 Participants
Participants With Detectable C-X-C Chemokine Receptor Type 4 (CXCR4)-Tropic Virus of the Double-blind Period Participants With detectable CV with other virologic failures	2 Participants	8 Participants	7 Participants
Participants With Detectable C-X-C Chemokine Receptor Type 4 (CXCR4)-Tropic Virus of the Double-blind Period Participants With detectable CV anytime who discontinued	2 Participants	4 Participants	3 Participants

SECONDARY outcome

Timeframe: Up to 48 weeks of the Double-blind Period

Outcome measures

Outcome measures
Measure	Double-Blind Period - Placebo Plus an ART Regimen n=35 Participants Placebo QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.	Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen n=39 Participants Vicriviroc 30 mg once daily (QD), orally (PO), plus an open-label optimized antiretroviral therapy (ART) regimen containing a ritonavir-boosted protease inhibitor (PI/r) for 48 weeks.	Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen n=40 Participants Vicriviroc 20 mg QD, PO, plus an open-label optimized ART regimen containing a PI/r for 48 weeks.
Participants With Detectable CXCR4-Tropic Virus and Immune Decline (≥50% Fall in CD4 Count From Baseline) of the Double-blind Period Participants with detectable CXCR4 virus pretreatment	2 Participants	3 Participants	1 Participants
Participants With Detectable CXCR4-Tropic Virus and Immune Decline (≥50% Fall in CD4 Count From Baseline) of the Double-blind Period Participants with ≥50% fall in CD4 count from baseline	0 Participants	3 Participants	1 Participants

Adverse Events

Double-Blind Period - Vicriviroc 30 mg Plus an ART Regimen

Serious events: 4 serious events

Other events: 34 other events

Deaths: 0 deaths

Double-Blind Period - Vicriviroc 20 mg Plus an ART Regimen

Serious events: 5 serious events

Other events: 31 other events

Deaths: 2 deaths

Double-Blind Period - Placebo Plus an ART Regimen

Serious events: 5 serious events

Other events: 29 other events

Deaths: 2 deaths

Open-Label Period - Vicriviroc 30 mg Plus an ART Regimen

Serious events: 13 serious events

Other events: 58 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The investigator agrees not to publish or publicly present any interim results of the study without the prior written consent of the sponsor. The investigator further agrees to provide to the sponsor 45 days prior to submission for publication or for presentation, review copies of the publication or presentation for review and comment on the data analysis and presentation including proprietary information, the accuracy of the information, and to ensure compliance with FDA regulations.
Publication restrictions are in place

Restriction type: OTHER