HIV Infection
Conditions
Keywords
HIV Seronegativity
Brief summary
The purpose of this study is to determine whether immunizations with an integrated combination of ALVAC-HIV (vCP1521) boosted by AIDSVAX gp120 B/E prevent HIV infection in healthy Thai volunteers.
Detailed description
A vaccine for the prevention of HIV infection remains an urgent need as part of the efforts to control the HIV pandemic. In this phase III efficacy trial, a 'prime-boost' vaccine strategy is evaluated for prevention of infection and amelioration of disease course. ALVAC-HIV (vCP1521) from sanofi pasteur is given as the 'prime' vaccine at months 0, 1, 3 and 6; AIDSVAX gp120 B/E from VaxGen is given as the 'boost' at months 3 and 6. This regimen will be given to 8,000 adult Thai subjects, while another 8,000 will be given placebos in a double-blinded, randomized manner. Following the completion of each subjects immunization phase, he/she will be followed for 3 years with clinic visits every 6 months with HIV testing, pre- and post-test counseling. Subjects who become HIV infected will be counseled, referred to HIV treatment facilities for management according to national guidelines, and offered enrollment in a protocol for extended follow-up.
Interventions
BIOLOGICALALVAC-HIV vCP1521 + AIDSVAX
Combined dose of 600 μg (300 μg of each antigen), co-formulated and administered in alumi-um hydroxide gel at a dose of 600 μg/mL
OTHERALVAC Placebo + AIDSVAX Placebo
ALVAC carrier, supplied as a lyophilized product, without virus and Aluminum hydroxide adjuvant, 1.2 mL per vial, given as a 1 mL injection
Sponsors
United States Army Medical Materiel Development Activity
Armed Forces Research Institute of Medical Sciences, Thailand
Walter Reed Army Institute of Research (WRAIR)
MCM Vaccines B.V.
VaxGen
The Emmes Company, LLC
Ministry of Health, Thailand
Mahidol University
Royal Thai Army Medical Department
Tripler Army Medical Center
Henry M. Jackson Foundation for the Advancement of Military Medicine
U.S. Army Medical Research and Development Command
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 30 Years
Healthy volunteers
Yes
Inclusion criteria
* Possession of the 13-digit Thai National ID card * 18-30 years of age (inclusive), male or female * For women, a negative urine pregnancy test on the day of enrollment, as well as assurance that adequate birth control measures would be applied during the course of the injections and the 3 months after the last injection. * Absence of systemic disease or immunodeficiency as determined by medical history and directed physical examination. * Negative serology for HIV-1 infection within 45 days prior to enrollment. * Availability and commitment for 3.5 years of participation. * Able to understand the study (shown by receiving a passing score on the Test of Understanding administered under the screening protocol) and gave written informed consent. * Enrollment in and referral from screening protocol, RV148
Exclusion criteria
* Previous participation in any HIV vaccine trial (unless the volunteer could provide documentation that he/she received placebo). * Active tuberculosis, other systemic disease process, or immunodeficiency as detected by medical history and directed physical examination that would, in the opinion of the investigator, impede compliance with study requirements or complicate the interpretation of adverse events. * Any significant finding that in the opinion of the investigator would increase the risk of having an adverse outcome from participating in this study or might interfere with the volunteer's ability to successfully complete the study. * Occupational or other responsibilities that would prevent completion of 3.5 years of participation in the study. * History of anaphylaxis or other serious adverse reactions to vaccines, or allergies or reactions likely to be exacerbated by any component of the vaccine or placebo, including egg products and neomycin. * Women breast-feeding or pregnant (positive pregnancy test) or planning to become pregnant during the 9-month window between study enrollment and 3-months after the last vaccination visit. * Study site employees who were involved in the protocol and may have had direct access to trial-related data. * Chronic use of therapies which may modify immune response, such as IV immune globulin and systemic corticosteroids (in doses of \> 20 mg prednisone equivalent for periods exceeding 10 days), and use of experimental drugs or vaccines. * Receipt of a non-HIV vaccine or immune globulins within 14 days.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Kaplan-Meier Estimate of HIV-1 Infection Rate in Intent to Treat Population | 42 Months | HIV-1 infection rate. Detection of HIV-1 infection was defined according to the HIV diagnostic algorithm utilizing serologic and nucleic acid technologies. Incidence of HIV infection was compared in the vaccine and placebo-recipient groups. |
| Vaccine Efficacy as Determined by Acquisition of Infection in the Per-protocol Population | 42 Months | Cumulative Number of HIV Infections. Detection of HIV-1 infection was defined according to the HIV diagnostic algorithm utilizing serologic and nucleic acid technologies. Incidence of HIV infection was compared in the vaccine and placebo-recipient groups. |
| Changes in HIV-1 Viral Load in Volunteers Developing HIV Infection During the Trial for the MITT Population | 42 months | Log10 HIV-1 viral loads for diagnostic specimens for subjects with post-HIV infection. The trial quantitated HIV plasma viral load at the time of diagnosis and through the remainder of the follow-up period. Peri infection results were compared in vaccine and placebo recipients who became HIV-infected during the trial. |
| Changes in HIV-1 Viral Load in Volunteers Developing HIV Infection During the Trial for the Per Protocol Population | 42 months | Log10 HIV-1 viral loads for diagnostic specimens for subjects with post-HIV infection. The trial quantitated HIV plasma viral load at the time of diagnosis and through the remainder of the follow-up period. Peri infection results were compared in vaccine and placebo recipients who became HIV-infected during the trial. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety Assessment (SAE's and AEs) | Dose Interval 1: week 0, Dose Interval 2: Week 4, Dose Interval 3: Week 12, and Dose Interval 4: Week 24; every 6 months during 3 year f/u period | The intent-to-treat population is used for analysis of AEs and treatment emergent events are reported. Participant AE rates for all AEs, SAEs and treatment-related AEs are summarized |
| Change in HIV Risk Behaviors Associated With Participation in the Vaccine Trial (MITT) | Week 182 | Self Report of Risk Behavior Status by Treatment and Time. Specifically, this is the responses to the question Do you think that your everyday behavior puts you at risk for HIV infection? Modified intent to treat population (MITT) |
| Changes in CD4 T Cell Count in Volunteers Who Developed HIV Infection During the Trial for MITT Population | 42 weeks | Two CD4 cell counts were obtained (at the verification blood draw and the notification blood draw) and through the remainder of the follow-up period. Results were compared in vaccine and placebo recipients who became HIV-infected during the trial. |
Countries
Thailand
Participant flow
Recruitment details
16,402 subjects were randomized, 16,395 were infection free and assigned treatment groups
Pre-assignment details
16,402 individuals were randomly assigned to the 2 treatment arms. 7 individuals were identified as having human immunodeficiency virus (HIV) infection that was present pre-vaccination detected by polymerase chain reaction (PCR) amplification. These individuals were removed from the modified intent to treat (MITT) population.
Participants by arm
| Arm | Count |
|---|---|
| Vaccine ALVAC-HIV vCP1521 + AIDSVAX will both be administered by the intramuscular route (preferably in the deltoid region) on weeks 0, 4, 12, and 24.
ALVAC-HIV vCP1521 + AIDSVAX: Combined dose of 600 μg (300 μg of each antigen), co-formulated and administered in alumi-um hydroxide gel at a dose of 600 μg/mL | 8,197 |
| Placebo ALVAC Placebo + AIDSVAX Placebo will be administered at week 12 and 24. ALVAC Placebo only was additionally administered at week 0 and 4.
ALVAC Placebo + AIDSVAX Placebo: ALVAC carrier, supplied as a lyophilized product, without virus and Aluminum hydroxide adjuvant, 1.2 mL per vial, given as a 1 mL injection | 8,198 |
| Total | 16,395 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 85 | 74 |
| Overall Study | Lost to Follow-up | 259 | 284 |
| Overall Study | Moved from study area | 37 | 47 |
| Overall Study | Non-compliant | 7 | 7 |
| Overall Study | Other | 14 | 11 |
| Overall Study | Reason not provided | 141 | 140 |
| Overall Study | Required contraindicated med | 0 | 1 |
| Overall Study | Withdrawal by Subject | 253 | 232 |
Baseline characteristics
| Characteristic | Vaccine | Placebo | Total |
|---|---|---|---|
| Age, Customized 18 - 20 | 2297 Participants | 2246 Participants | 4543 Participants |
| Age, Customized 21 - 25 | 3633 Participants | 3708 Participants | 7341 Participants |
| Age, Customized 26 - 30 | 2267 Participants | 2244 Participants | 4511 Participants |
| Marital status Divorced | 602 participants | 541 participants | 1143 participants |
| Marital status Married | 4110 participants | 4169 participants | 8279 participants |
| Marital status Separated | 82 participants | 86 participants | 168 participants |
| Marital status Single | 3353 participants | 3338 participants | 6691 participants |
| Marital status Widowed | 50 participants | 64 participants | 114 participants |
| Number of sex partners 0 | 1864 participants | 1801 participants | 3665 participants |
| Number of sex partners 1 | 5428 participants | 5495 participants | 10923 participants |
| Number of sex partners > 1 | 619 participants | 620 participants | 1239 participants |
| Number of sex partners Did not answer | 280 participants | 273 participants | 553 participants |
| Number of sex partners Missing data | 6 participants | 9 participants | 15 participants |
| Province Chon Buri | 4107 participants | 4107 participants | 8214 participants |
| Province Rayong | 4090 participants | 4091 participants | 8181 participants |
| Risk group High | 1963 participants | 1982 participants | 3945 participants |
| Risk group Low | 3865 participants | 3924 participants | 7789 participants |
| Risk group Medium | 2369 participants | 2292 participants | 4661 participants |
| Sex: Female, Male Female | 3164 Participants | 3167 Participants | 6331 Participants |
| Sex: Female, Male Male | 5033 Participants | 5031 Participants | 10064 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 85 / 8,197 | 75 / 8,198 |
| other Total, other adverse events | 7,442 / 8,197 | 6,141 / 8,198 |
| serious Total, serious adverse events | 1,175 / 8,197 | 1,219 / 8,198 |
Outcome results
Primary
Changes in HIV-1 Viral Load in Volunteers Developing HIV Infection During the Trial for the MITT Population
Log10 HIV-1 viral loads for diagnostic specimens for subjects with post-HIV infection. The trial quantitated HIV plasma viral load at the time of diagnosis and through the remainder of the follow-up period. Peri infection results were compared in vaccine and placebo recipients who became HIV-infected during the trial.
Time frame: 42 months
Population: Modified Intent-to-Treat (MITT) Population: those participants who were infection free at entry into the study
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vaccine | Changes in HIV-1 Viral Load in Volunteers Developing HIV Infection During the Trial for the MITT Population | 3-weeks post identificaiton | 4.229 log [HIV-1 viral load (unitless)] | Standard Error 0.13 |
| Vaccine | Changes in HIV-1 Viral Load in Volunteers Developing HIV Infection During the Trial for the MITT Population | ~6-weeks post identification | 4.274 log [HIV-1 viral load (unitless)] | Standard Error 0.125 |
| Vaccine | Changes in HIV-1 Viral Load in Volunteers Developing HIV Infection During the Trial for the MITT Population | First positive serology | 4.379 log [HIV-1 viral load (unitless)] | Standard Error 0.127 |
| Placebo | Changes in HIV-1 Viral Load in Volunteers Developing HIV Infection During the Trial for the MITT Population | 3-weeks post identificaiton | 4.235 log [HIV-1 viral load (unitless)] | Standard Error 0.095 |
| Placebo | Changes in HIV-1 Viral Load in Volunteers Developing HIV Infection During the Trial for the MITT Population | ~6-weeks post identification | 4.167 log [HIV-1 viral load (unitless)] | Standard Error 0.104 |
| Placebo | Changes in HIV-1 Viral Load in Volunteers Developing HIV Infection During the Trial for the MITT Population | First positive serology | 4.187 log [HIV-1 viral load (unitless)] | Standard Error 0.101 |
Primary
Changes in HIV-1 Viral Load in Volunteers Developing HIV Infection During the Trial for the Per Protocol Population
Log10 HIV-1 viral loads for diagnostic specimens for subjects with post-HIV infection. The trial quantitated HIV plasma viral load at the time of diagnosis and through the remainder of the follow-up period. Peri infection results were compared in vaccine and placebo recipients who became HIV-infected during the trial.
Time frame: 42 months
Population: Per-protocol population: The per-protocol analysis is restricted to the individuals who were infection-free at the completion of vaccination and who received a timely set of 4 vaccinations.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vaccine | Changes in HIV-1 Viral Load in Volunteers Developing HIV Infection During the Trial for the Per Protocol Population | First positive serology | 4.307 log [HIV-1 viral load (unitless)] | Standard Error 0.154 |
| Vaccine | Changes in HIV-1 Viral Load in Volunteers Developing HIV Infection During the Trial for the Per Protocol Population | 3-weeks post identificaiton | 4.128 log [HIV-1 viral load (unitless)] | Standard Error 0.161 |
| Vaccine | Changes in HIV-1 Viral Load in Volunteers Developing HIV Infection During the Trial for the Per Protocol Population | ~6-weeks post identification | 4.280 log [HIV-1 viral load (unitless)] | Standard Error 0.152 |
| Placebo | Changes in HIV-1 Viral Load in Volunteers Developing HIV Infection During the Trial for the Per Protocol Population | First positive serology | 4.153 log [HIV-1 viral load (unitless)] | Standard Error 0.136 |
| Placebo | Changes in HIV-1 Viral Load in Volunteers Developing HIV Infection During the Trial for the Per Protocol Population | 3-weeks post identificaiton | 4.276 log [HIV-1 viral load (unitless)] | Standard Error 0.118 |
| Placebo | Changes in HIV-1 Viral Load in Volunteers Developing HIV Infection During the Trial for the Per Protocol Population | ~6-weeks post identification | 4.143 log [HIV-1 viral load (unitless)] | Standard Error 0.143 |
Primary
Kaplan-Meier Estimate of HIV-1 Infection Rate in Intent to Treat Population
HIV-1 infection rate. Detection of HIV-1 infection was defined according to the HIV diagnostic algorithm utilizing serologic and nucleic acid technologies. Incidence of HIV infection was compared in the vaccine and placebo-recipient groups.
Time frame: 42 Months
Population: Modified Intent-to-Treat (MITT) Population: those participants who were infection free at entry into the study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vaccine | Kaplan-Meier Estimate of HIV-1 Infection Rate in Intent to Treat Population | 42 months | 0.68 Percetage of subjects |
| Vaccine | Kaplan-Meier Estimate of HIV-1 Infection Rate in Intent to Treat Population | 12 months | 0.15 Percetage of subjects |
| Vaccine | Kaplan-Meier Estimate of HIV-1 Infection Rate in Intent to Treat Population | 24 months | 0.41 Percetage of subjects |
| Vaccine | Kaplan-Meier Estimate of HIV-1 Infection Rate in Intent to Treat Population | 36 months | 0.58 Percetage of subjects |
| Placebo | Kaplan-Meier Estimate of HIV-1 Infection Rate in Intent to Treat Population | 36 months | 0.84 Percetage of subjects |
| Placebo | Kaplan-Meier Estimate of HIV-1 Infection Rate in Intent to Treat Population | 42 months | 0.96 Percetage of subjects |
| Placebo | Kaplan-Meier Estimate of HIV-1 Infection Rate in Intent to Treat Population | 24 months | 0.64 Percetage of subjects |
| Placebo | Kaplan-Meier Estimate of HIV-1 Infection Rate in Intent to Treat Population | 12 months | 0.38 Percetage of subjects |
Primary
Vaccine Efficacy as Determined by Acquisition of Infection in the Per-protocol Population
Cumulative Number of HIV Infections. Detection of HIV-1 infection was defined according to the HIV diagnostic algorithm utilizing serologic and nucleic acid technologies. Incidence of HIV infection was compared in the vaccine and placebo-recipient groups.
Time frame: 42 Months
Population: Per-protocol population: The per-protocol analysis is restricted to the individuals who were infection-free at the completion of vaccination and who received a timely set of 4 vaccinations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vaccine | Vaccine Efficacy as Determined by Acquisition of Infection in the Per-protocol Population | 12 months | 0.08 Percentage of subjects |
| Vaccine | Vaccine Efficacy as Determined by Acquisition of Infection in the Per-protocol Population | 24 months | 0.36 Percentage of subjects |
| Vaccine | Vaccine Efficacy as Determined by Acquisition of Infection in the Per-protocol Population | 42 months | 0.59 Percentage of subjects |
| Vaccine | Vaccine Efficacy as Determined by Acquisition of Infection in the Per-protocol Population | 36 months | 0.52 Percentage of subjects |
| Placebo | Vaccine Efficacy as Determined by Acquisition of Infection in the Per-protocol Population | 42 months | 0.80 Percentage of subjects |
| Placebo | Vaccine Efficacy as Determined by Acquisition of Infection in the Per-protocol Population | 12 months | 0.25 Percentage of subjects |
| Placebo | Vaccine Efficacy as Determined by Acquisition of Infection in the Per-protocol Population | 24 months | 0.49 Percentage of subjects |
| Placebo | Vaccine Efficacy as Determined by Acquisition of Infection in the Per-protocol Population | 36 months | 0.70 Percentage of subjects |
Secondary
Change in HIV Risk Behaviors Associated With Participation in the Vaccine Trial (MITT)
Self Report of Risk Behavior Status by Treatment and Time. Specifically, this is the responses to the question Do you think that your everyday behavior puts you at risk for HIV infection? Modified intent to treat population (MITT)
Time frame: Week 182
Population: Prior to the analysis, the SAP identified the MITT as those participants who were infection free at entry into the study. Although individuals were screened for HIV antibody prior to entry, individuals identified by laboratory examination of PCR assessments of blinded pre-randomization specimens that were performed subsequent to entry were excluded
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vaccine | Change in HIV Risk Behaviors Associated With Participation in the Vaccine Trial (MITT) | Yes | 702 participants |
| Vaccine | Change in HIV Risk Behaviors Associated With Participation in the Vaccine Trial (MITT) | No | 6223 participants |
| Vaccine | Change in HIV Risk Behaviors Associated With Participation in the Vaccine Trial (MITT) | Don't know/Not sure | 473 participants |
| Vaccine | Change in HIV Risk Behaviors Associated With Participation in the Vaccine Trial (MITT) | Missing value | 1 participants |
| Placebo | Change in HIV Risk Behaviors Associated With Participation in the Vaccine Trial (MITT) | Missing value | 0 participants |
| Placebo | Change in HIV Risk Behaviors Associated With Participation in the Vaccine Trial (MITT) | Yes | 763 participants |
| Placebo | Change in HIV Risk Behaviors Associated With Participation in the Vaccine Trial (MITT) | Don't know/Not sure | 502 participants |
| Placebo | Change in HIV Risk Behaviors Associated With Participation in the Vaccine Trial (MITT) | No | 6130 participants |
Secondary
Changes in CD4 T Cell Count in Volunteers Who Developed HIV Infection During the Trial for MITT Population
Two CD4 cell counts were obtained (at the verification blood draw and the notification blood draw) and through the remainder of the follow-up period. Results were compared in vaccine and placebo recipients who became HIV-infected during the trial.
Time frame: 42 weeks
Population: Prior to the analysis, the SAP identified the MITT as those participants who were infection free at entry into the study. Although individuals were screened for HIV antibody prior to entry, individuals identified by laboratory examination of PCR assessments of blinded pre-randomization specimens that were performed subsequent to entry were excluded
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Vaccine | Changes in CD4 T Cell Count in Volunteers Who Developed HIV Infection During the Trial for MITT Population | 1st verification | 565.4 cells / µL | Standard Error 43.5 |
| Vaccine | Changes in CD4 T Cell Count in Volunteers Who Developed HIV Infection During the Trial for MITT Population | Notification | 539.6 cells / µL | Standard Error 37.1 |
| Placebo | Changes in CD4 T Cell Count in Volunteers Who Developed HIV Infection During the Trial for MITT Population | 1st verification | 566.7 cells / µL | Standard Error 26.5 |
| Placebo | Changes in CD4 T Cell Count in Volunteers Who Developed HIV Infection During the Trial for MITT Population | Notification | 570.6 cells / µL | Standard Error 29.2 |
Secondary
Safety Assessment (SAE's and AEs)
The intent-to-treat population is used for analysis of AEs and treatment emergent events are reported. Participant AE rates for all AEs, SAEs and treatment-related AEs are summarized
Time frame: Dose Interval 1: week 0, Dose Interval 2: Week 4, Dose Interval 3: Week 12, and Dose Interval 4: Week 24; every 6 months during 3 year f/u period
Population: intent-to-treat population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Vaccine | Safety Assessment (SAE's and AEs) | 30-day post dose interval 2 | 816 adverse events |
| Vaccine | Safety Assessment (SAE's and AEs) | 30-day post dose interval 4 | 599 adverse events |
| Vaccine | Safety Assessment (SAE's and AEs) | 30-day post dose interval 3 | 614 adverse events |
| Vaccine | Safety Assessment (SAE's and AEs) | All treatment emergent | 5627 adverse events |
| Vaccine | Safety Assessment (SAE's and AEs) | 30-day post dose interval 1 | 1277 adverse events |
| Placebo | Safety Assessment (SAE's and AEs) | All treatment emergent | 5685 adverse events |
| Placebo | Safety Assessment (SAE's and AEs) | 30-day post dose interval 1 | 1336 adverse events |
| Placebo | Safety Assessment (SAE's and AEs) | 30-day post dose interval 2 | 860 adverse events |
| Placebo | Safety Assessment (SAE's and AEs) | 30-day post dose interval 3 | 597 adverse events |
| Placebo | Safety Assessment (SAE's and AEs) | 30-day post dose interval 4 | 630 adverse events |