Study Of Chemokine Coreceptor 5 (CCR5) Antagonist GW873140 In R5-Tropic Treatment-Experienced HIV-Infected Subjects

Assessment for plasma HIV-1 RNA was done at Week 24 and also planned at Week 48 by PCR analysis. Data is reported for number of participants with plasma HIV-1 RNA <50 copies/mL at Week 24. Data was not collected for Week 48 due to early termination of the study.

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the 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, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition, hypersensitivity reaction to abacavir. AEs were classified as potentially drug-related, based on the investigator's judgment.

The participants with treatment emergent toxicities of laboratory abnormalities for chemistry data is reported . Participants with toxicities were categorized according to the division of AIDS (DAIDS) toxicity grading scale. Scale ranges from grade 1(mild)=symptoms causing no or minimal interference with usual social \& functional activities, grade 2 (moderate)=symptoms causing greater than minimal interference with usual social \& functional activities, grade 3 (severe)=symptoms causing inability to perform usual social \& functional activities and grade 4 (potentially life threatening)=symptoms causing inability to perform basic self-care functions or medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death. Scale ranges from 1-4, where higher grade reflects greater severity of symptoms. Baseline was defined as assessments done at Day 1. Only those parameters for which at least one value of toxicity grade was reported are summarized.

Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values.

Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values.

Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values.

Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values.

Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values.

Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values.

Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values.

Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values.

Assessment was performed at Day 1, Week 12 and Week 24. Baseline was defined as the assessments done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12 and 24) values.

12-lead ECG assessments were obtained at Day 1 (triplicate measurements), Week 4 and Week 24. The assessments were done using an ECG machine that automatically calculated the heart rate. Baseline was defined as the mean of the triplicate assessment done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 4 and 24) values.

12-lead ECG assessments were obtained at Day 1 (triplicate measurements), Week 4 and Week 24. The assessments were done using an ECG machine that automatically measured RR, PR, QRS, uncorrected QT, QTc (Bazette) and QTc (Fridericia) intervals. Baseline was defined as the mean of the triplicate assessment done at Day 1. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 4 and Week 24) values.

The CD4 cell count is an indication of the strength of the immune system. The assessment of CD4 cell count was done by flow cytometry. Baseline was defined as the mean of the Baseline (Day 1) and pre-treatment visit values. Change from Baseline was calculated by subtracting the Baseline value from the individual post-Baseline (Week 12, 24 and 40) values.

The time to CDC class C AIDS-defining event or death was planned to be assessed as per the 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).

Assessment for the development of antiretroviral resistance was performed at each visit up to Follow-up. The genotypic analysis of viral resistance associated mutations was done using protease and reverse transcriptase enzymes. The number of participants with treatment emergent changes in reverse transcriptase and protease genotypic mutations were reported.

The IC50 is a measure of the effectiveness of a substance in inhibiting a specific biological or biochemical function. IC50 was collected for abacavir (ABC), atazanavir (ATV), delavirdine (DLV), didanosine (DDI), efavirenz (EFV), emtricitabine, enfuvirtide , fosamprenavir (AMP), GW873140 (APL), indinavir (IDV), indinavir rooted with ritonavir (IDV/r), lamivudine, lopinavir rooted with ritonavir (LPV/r), nelfinavir (NFV), nevirapine (NVP), ritonavir (RTV), saquinavir (SQV), stavudine, tenofovir (TFV), tipranavir rooted with ritonavir (TPV/r), zidovudine (ZDV). Data is categorized for number of participants with each IC50 concentration of the individual drugs at Baseline (Day 1).

AUC (0- tau) GW873140 was defined as the area under the plasma concentration-time curve from time 0 to tau. Blood samples for evaluation of GW873140 plasma PK was planned to be collected from all participants at Week 4, 12, and 24. Intensive PK sampling was planned to be conducted with the enrolled participants. All participants who were not part of the intensive PK group was planned to be part of the limited PK sample group. Participants were supposed to complete a diary card with the date and time of investigational product administration of the last dose prior to clinic visits on Weeks 4, 12, and 24. It was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.

Cmax is defined as the first occurrence of the maximum observed plasma concentration determined directly from the raw concentration-time data. Blood samples for evaluation of GW873140 plasma PK was planned to be collected from all participants at Week 4, 12, and 24. Intensive PK sampling was planned to be conducted with the enrolled participants. All participants who were not part of the intensive PK group was planned to be part of the limited PK sample group. Participants were supposed to complete a diary card with the date and time of investigational product administration of the last dose prior to clinic visits on Weeks 4, 12, and 24.

Tmax is defined as the time at which Cmax is observed, determined directly from the raw concentration-time data. Blood samples for evaluation of GW873140 plasma PK was planned to be collected from all participants at Week 4, 12, and 24. Intensive PK sampling was planned to be conducted with the enrolled participants. All participants who were not part of the intensive PK group was planned to be part of the limited PK sample group. Participants were supposed to complete a diary card with the date and time of investigational product administration of the last dose prior to clinic visits on Weeks 4, 12, and 24.

Blood samples for evaluation of GW873140 plasma PK was planned to be collected from all participants at Week 4, 12, and 24. Intensive PK sampling was planned to be conducted with the enrolled participants. All participants who were not part of the intensive PK group was planned to be part of the limited PK sample group. Participants were supposed to complete a diary card with the date and time of investigational product administration of the last dose prior to clinic visits on Weeks 4, 12, and 24.

Adherence to investigational product was planned to be evaluated using pill counts of unused investigational product (blinded GW873140 or placebo, open-label GW873140 for open label phase). This assessment was planned to be conducted at each time the participant received a new (refill) supply of study medication.

The HIV Symptom Index Questionnaire was planned to be used to evaluate how bothersome certain symptoms were during the conduct of this clinical study. The participant self-report instrument had 20 items, each of which asked about a specific symptom or group of related symptoms that participants might have had during the past 4 weeks and the degree to which the participant is bothered by the symptom. The symptom index comprised 32 common and HIV-specific symptoms scored in terms of presence/absence (1, 0) and severity on a 4-point scale (0 = not at all to 3 =quite a bit). Higher score represented greater severity of symptoms.

The EuroQol is a standardized instrument for use as a measure of health related quality of life. It consists of two pages comprising the EuroQoL 5 Dimension 5 level (EQ-5D5) descriptive system and the EQ visual analogue scale (VAS). The EQ-5D5 comprises of five dimensions of health (mobility, self-care, usual activities, pain/discomfort, and depression/anxiety). Each dimension comprises five levels of response (no problems, mild problems, moderate problems, moderate to extreme problems, and extreme problems). The EQ VAS records the respondents self-rated health status on a vertical graduated (0 to 100) VAS. Higher score represented greater severity of diseases.