HIV Infections
Conditions
Keywords
Treatment Experienced
Brief summary
Raltegravir (MK-0518) is an HIV-1 integrase inhibitor with potent in vitro activity against HIV-1 strains including those resistant to currently available antiretroviral drugs. The purpose of this study is to assess the effectiveness of raltegravir in further reducing viral load in HIV infected patients that have already achieved viral suppression below the level of detection of standard viral load assays when added to antiretroviral therapy (ART).
Detailed description
Although ART has reduced the morbidity and mortality from HIV-1 infection, most individuals who stop ART experience rapid viral rebound. Effective ART can suppress viral load to less than 50 copies/ml; however, current treatment regimens cannot completely eliminate the infection. The primary purpose of this study was to assess the ability of the HIV-1 integrase inhibitor, raltegravir, to reduce viral load when added to ART regimens of HIV-1 infected patients who have achieved viral suppression to less than 50 copies/ml. The study lasted 24 weeks. Participants were randomly assigned to one of two arms. Participants in Arm A were administered raltegravir in addition to their usual ART regimen from study entry until Week 12. At Week 12, subjects halted raltegravir use and received a placebo until Week 24. Participants in Arm B were administered the placebo in addition to their usual ART regimen from study entry until Week 12. At Week 12, subjects halted the placebo and received raltegravir until Week 24. A real-time polymerase chain reaction (PCR) single copy assay (SCA) capable of detecting 1 copy of HIV RNA was used to assay viral load. The cross-over design allowed assessment of the effect of intensification with raltegravir between the two arms at Weeks 10/12 and every participant enrolled in the study receiving raltegravir for 12 weeks. Primary analysis focused on weeks 10/12 measurement and with no washout period, typical analysis of cross-over design was not intended. All participants had scheduled visits at Weeks 0, 2, 4, 10, 12, 14, 16, 22, and 24. A targeted physical exam occurred at all visits. Blood and urine collection occurred at selected visits. A medical/medication assessment occurred at trial entry. Drug dispensing and an adherence questionnaire occurred at some visits. A pregnancy test occurred at select visits. Participants' background ART medications were not provided by the study.
Interventions
400 mg tablet taken orally twice daily
DRUGPlacebo
400 mg placebo tablet taken orally twice daily
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV-1 Infection * ART for at least 12 months prior to study entry that includes at least two NRTIs and either an NNRTI or a ritonavir-boosted PI * No change in ART regimen for at least 3 months prior to study entry * CD4 count of 200 or more at screening * Viral load below the limit of quantification of an ultrasensitive assay for at least 6 months prior to study entry * Viral load less than 50 copies/ml using Roche Amplicor HIV-1 RNA Ultrasensitive assay within 60 days of study entry * All viral load assays obtained within 6 months prior to study entry lower than limits of quantification on all tests * Pre-ART viral load level greater than 100,000 copies/ml * Detectable viral load of 1 copy or more on the screening SCA * Available pre-study entry plasma sample for SCA viral load determination * Absolute neutrophil count of 750/mm3 or more * Hemoglobin of 9 g/dL or more for female subjects and 10 g/dL or more for male subjects * Platelet count of 50,000/mm3 or more * Calculated creatinine clearance of 30 ml/min or more * AST, ALT, and alkaline phosphate less than or equal to 5 x ULN * Total bilirubin less than or equal to 2.5 x ULN. If subject is taking indinavir or atazanavir at screening, total bilirubin must be less than or equal to 5 x ULN. * Negative serum or urine pregnancy test within 48 hours prior to study entry for females with reproductive potential * Willing to use acceptable means of contraception
Exclusion criteria
* Previous documented virologic failure on an antiretroviral regimen * Unstable clinical condition that would preclude the subject from undergoing study procedures * Use of immunosuppressive medications within 60 days prior to study entry. Participants using inhaled or nasal steroids are not excluded. * Opportunistic infection within 60 days prior to study entry * Allergy or sensitivity to components of study drug * Active drug or alcohol abuse * Serious illness requiring systemic treatment within 60 days prior to study entry * Receipt of non-HIV vaccination within 30 days prior to study entry * Receipt of any HIV vaccines * Plan to change background ART within 24 weeks after study entry * Pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| HIV-1 RNA Level | At Weeks 10 and 12 | HIV-1 RNA level, as measured by single copy assay (units are copies/ml), averaged at weeks 10 and 12. The quantification limit of single copy assay was determined by the volume of plasma tested. When averaging the week 10 and 12 measurements, if one of both measurements were below the single copy assay lower limits, the lower limit of quantification was used to compute the average and the result was treated as below the averaged value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total CD4 Cell Count | At pre-entry, entry, and week 12 | CD4 cell counts were assessed by flow cytometry at pre-entry and entry (the baseline value was the average of the two measurements) and at week 12 |
| Change in Total CD8 Cell Count | At pre-entry, entry, and week 12 | CD8 cell counts were assessed by flow cytometry at pre-entry and entry (the baseline value was the average of the two measurements) and at week 12 |
| Change in CD4+/CD38+/HLA-DR+ Percent | At pre-entry, entry, and week 12 | Level of CD4+ T-cell activation was determined by measuring the percentage of cells that expressed both the activation marker CD38 and Human leukocyte antigen (HLA)-DR. Levels measured at pre-entry and entry were averaged. Change from baseline to week 12 was defined as CD4+/CD38+/HLA-DR+% at week 12 minus CD4+/CD38+/HLA-DR+% at baseline. |
| Change in HIV-1 RNA Level | At pre-entry, entry, weeks 10 and 12 | Change in HIV-1 RNA level, as measured by single copy assay (units are copies/ml), from baseline to weeks 10/12 . When averaging the measurements at pre-entry and entry, and at weeks 10 and 12, measurements below the lower limit of quantification (LLQ) were imputed a value of the LLQ divided by 2. |
| Number of Participants Who Experienced Study Related Grade 2 or Higher Signs/Symptoms, Grade 3 or Higher Laboratory Abnormalities and Clinical Events From First Day of Treatment to Week 12 | From first day of treatment to week 12 | Participant who experienced at least one study related grade 2 or higher signs/symptoms, grade 3 or higher laboratory abnormalities and clinical events that are possibly, probably or definitely related to study treatment. DAIDS Toxicity Grading Table (2004) was used for grading. |
| Number of Participants Who Experienced Study Related Grade 2 or Higher Signs/Symptoms, Grade 3 or Higher Laboratory Abnormalities and Clinical Events From Week 12 to Week 24 | From week 12 to week 24 | Participant who experienced at least one study related grade 2 or higher signs/symptoms, grade 3 or higher laboratory abnormalities and clinical events that are 'possibly', probably', or definitely' related to study treatment. DAIDS Toxicity Grading Table (2004) was used for grading. |
| Number of Participants Who Discontinued Study Drug | From first day of treatment to week 12 | Participants who discontinued randomized study treatment for any reason |
| Change in CD8+/CD38+/HLA-DR+ Percent | At pre-entry, entry, and week 12 | Level of CD8+ T-cell activation was determined by measuring the percentage of cells that expressed both the activation marker CD38 and Human leukocyte antigen (HLA)-DR. Levels measured at pre-entry and entry were averaged. Change from baseline to week 12 was defined as CD8+/CD38+/HLA-DR+% at week 12 minus CD8+/CD38+/HLA-DR+% at baseline. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Raltegravir Then Placebo (Arm A) 400 mg raltegravir (MK-0518) administered twice daily in addition to optimized background regimen (OBR) from entry to Week 12; halt raltegravir at Week 12 and add placebo twice daily for 12 weeks | 27 |
| Placebo Then Raltegravir (Arm B) Placebo administered twice daily in addition to OBR from entry until Week 12; halt placebo at Week 12 and add 400 mg raltegravir tablet twice daily for 12 weeks. | 26 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (12 Weeks) | Unwilling to adhere to study requirement | 1 | 1 |
| Second Intervention (12 Weeks) | Consent withdraw | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo Then Raltegravir (Arm B) | Raltegravir Then Placebo (Arm A) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants | 27 Participants | 51 Participants |
| Age, Continuous | 49 years STANDARD_DEVIATION 11 | 50 years STANDARD_DEVIATION 7 | 49 years STANDARD_DEVIATION 8 |
| Region of Enrollment United States | 26 participants | 27 participants | 53 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 24 Participants | 24 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 52 | 16 / 52 |
| serious Total, serious adverse events | 0 / 52 | 0 / 52 |
Outcome results
Primary
HIV-1 RNA Level
HIV-1 RNA level, as measured by single copy assay (units are copies/ml), averaged at weeks 10 and 12. The quantification limit of single copy assay was determined by the volume of plasma tested. When averaging the week 10 and 12 measurements, if one of both measurements were below the single copy assay lower limits, the lower limit of quantification was used to compute the average and the result was treated as below the averaged value.
Time frame: At Weeks 10 and 12
Population: 49 subjects who were on study treatment before week 10 and did not experience virologic failure by week 12
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Raltegravir (Arm A) | HIV-1 RNA Level | 1.2 copies/mL |
| Placebo (Arm B) | HIV-1 RNA Level | 1.7 copies/mL |
p-value: 0.546Wilcoxon (Mann-Whitney)
Secondary
Change in CD4+/CD38+/HLA-DR+ Percent
Level of CD4+ T-cell activation was determined by measuring the percentage of cells that expressed both the activation marker CD38 and Human leukocyte antigen (HLA)-DR. Levels measured at pre-entry and entry were averaged. Change from baseline to week 12 was defined as CD4+/CD38+/HLA-DR+% at week 12 minus CD4+/CD38+/HLA-DR+% at baseline.
Time frame: At pre-entry, entry, and week 12
Population: All participants who were on study treatment and had not experienced virologic failure
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Raltegravir (Arm A) | Change in CD4+/CD38+/HLA-DR+ Percent | -1 % CD4 cells co-express CD38+ and HLA-DR+ |
| Placebo (Arm B) | Change in CD4+/CD38+/HLA-DR+ Percent | 0 % CD4 cells co-express CD38+ and HLA-DR+ |
Secondary
Change in CD8+/CD38+/HLA-DR+ Percent
Level of CD8+ T-cell activation was determined by measuring the percentage of cells that expressed both the activation marker CD38 and Human leukocyte antigen (HLA)-DR. Levels measured at pre-entry and entry were averaged. Change from baseline to week 12 was defined as CD8+/CD38+/HLA-DR+% at week 12 minus CD8+/CD38+/HLA-DR+% at baseline.
Time frame: At pre-entry, entry, and week 12
Population: All participants who stayed on study treatment and had not experienced virologic failures.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Raltegravir (Arm A) | Change in CD8+/CD38+/HLA-DR+ Percent | -1 % CD8 cells co-express CD38+ and HLA-DR+ |
| Placebo (Arm B) | Change in CD8+/CD38+/HLA-DR+ Percent | 0 % CD8 cells co-express CD38+ and HLA-DR+ |
Secondary
Change in HIV-1 RNA Level
Change in HIV-1 RNA level, as measured by single copy assay (units are copies/ml), from baseline to weeks 10/12 . When averaging the measurements at pre-entry and entry, and at weeks 10 and 12, measurements below the lower limit of quantification (LLQ) were imputed a value of the LLQ divided by 2.
Time frame: At pre-entry, entry, weeks 10 and 12
Population: All participants who were on study treatment and had not experienced virologic failure
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Raltegravir (Arm A) | Change in HIV-1 RNA Level | -0.2 copies/mL |
| Placebo (Arm B) | Change in HIV-1 RNA Level | -0.1 copies/mL |
Secondary
Change in Total CD4 Cell Count
CD4 cell counts were assessed by flow cytometry at pre-entry and entry (the baseline value was the average of the two measurements) and at week 12
Time frame: At pre-entry, entry, and week 12
Population: All participants who were on study treatment and had not experienced virologic failure
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Raltegravir (Arm A) | Change in Total CD4 Cell Count | 42 cells/mm^3 |
| Placebo (Arm B) | Change in Total CD4 Cell Count | -44 cells/mm^3 |
Secondary
Change in Total CD8 Cell Count
CD8 cell counts were assessed by flow cytometry at pre-entry and entry (the baseline value was the average of the two measurements) and at week 12
Time frame: At pre-entry, entry, and week 12
Population: All participants who were on study treatment and had not experienced virologic failure
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Raltegravir (Arm A) | Change in Total CD8 Cell Count | 55 cells/mm^3 |
| Placebo (Arm B) | Change in Total CD8 Cell Count | -39 cells/mm^3 |
Secondary
Number of Participants Who Discontinued Study Drug
Participants who discontinued randomized study treatment for any reason
Time frame: From first day of treatment to week 12
Population: All 53 participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Raltegravir (Arm A) | Number of Participants Who Discontinued Study Drug | 4 participants |
| Placebo (Arm B) | Number of Participants Who Discontinued Study Drug | 1 participants |
Secondary
Number of Participants Who Experienced Study Related Grade 2 or Higher Signs/Symptoms, Grade 3 or Higher Laboratory Abnormalities and Clinical Events From First Day of Treatment to Week 12
Participant who experienced at least one study related grade 2 or higher signs/symptoms, grade 3 or higher laboratory abnormalities and clinical events that are possibly, probably or definitely related to study treatment. DAIDS Toxicity Grading Table (2004) was used for grading.
Time frame: From first day of treatment to week 12
Population: All participants on study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Raltegravir (Arm A) | Number of Participants Who Experienced Study Related Grade 2 or Higher Signs/Symptoms, Grade 3 or Higher Laboratory Abnormalities and Clinical Events From First Day of Treatment to Week 12 | 2 participants |
| Placebo (Arm B) | Number of Participants Who Experienced Study Related Grade 2 or Higher Signs/Symptoms, Grade 3 or Higher Laboratory Abnormalities and Clinical Events From First Day of Treatment to Week 12 | 0 participants |
Secondary
Number of Participants Who Experienced Study Related Grade 2 or Higher Signs/Symptoms, Grade 3 or Higher Laboratory Abnormalities and Clinical Events From Week 12 to Week 24
Participant who experienced at least one study related grade 2 or higher signs/symptoms, grade 3 or higher laboratory abnormalities and clinical events that are 'possibly', probably', or definitely' related to study treatment. DAIDS Toxicity Grading Table (2004) was used for grading.
Time frame: From week 12 to week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Raltegravir (Arm A) | Number of Participants Who Experienced Study Related Grade 2 or Higher Signs/Symptoms, Grade 3 or Higher Laboratory Abnormalities and Clinical Events From Week 12 to Week 24 | 0 participants |
| Placebo (Arm B) | Number of Participants Who Experienced Study Related Grade 2 or Higher Signs/Symptoms, Grade 3 or Higher Laboratory Abnormalities and Clinical Events From Week 12 to Week 24 | 0 participants |