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

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)).

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.

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.

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.

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.

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.

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.

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.

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.

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. After completion of the Double-Blind Period, eligible participants could enroll in the Open Label Period and continue treatment.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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%.

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%. Participants with emergence of CXCR4 tropism who had a concomitant decline in CD4 count by ≥50% below baseline was also computed.