HIV Infections
Conditions
Brief summary
The purpose of this study was to evaluate the safety and antiviral activity to promote clearance of HIV-1 infected cells of VRC01 in infants with HIV beginning combination antiretroviral therapy (cART).
Detailed description
VRC01 is an experimental human immunoglobulin G1 (IgG1) monoclonal antibody. The purpose of this study was to evaluate the safety and antiviral activity to promote clearance of HIV-1 infected cells of VRC01 received within 12 weeks of birth in infants with HIV initiating cART. All infants were required to have initiated cART within 14 days before or at study entry. Infants were randomly assigned to either receive VRC01 (VRC01, Arm 1) or not receive VRC01 (No-VRC01, Arm 2). Randomization was stratified by whether the initial cART regimen included an integrase inhibitor. Infants in the VRC01 arm received VRC01 injections at study entry (Week 0) and Weeks 2, 6, and 10. Infants in the No-VRC01 arm received no study product. Infants attended study visits at Weeks 1, 2, 3, 6, 7, 10, 11, 14, 16, 20, 24, 36, and 48. Visits included physical examinations, blood and urine collection. Infants' mothers could optionally be enrolled in the study for one-time specimen collection for exploratory evaluations. Maternal study participation was not required for infant study participation. The study was closed to enrollment prematurely on March 19, 2020 due to the outbreak of coronavirus disease 2019 (COVID-19) and after enrolling 61 of the targeted 68 infants.
Interventions
BIOLOGICALVRC01
40 mg/kg of VRC01 administered by subcutaneous injection.
All infants received non-study provided cART selected by their primary care provider and supplied through non-study sources (i.e., cART not provided through the study).
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
0 Weeks to 12 Weeks
Healthy volunteers
No
Inclusion criteria
Infant Inclusion Criteria: * Weigh at least 2500 grams * Confirmed HIV-1 infection * The following laboratory values at screening: * Cluster of differentiation 4 (CD4) lymphocyte percentage greater than 15 * Severity grade 1 or lower hemoglobin, platelet count, and absolute neutrophil count * Severity grade 1 or lower alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase * First dose of initial combination antiretroviral therapy (cART) regimen taken on the day of randomization or within 14 days prior to the day of randomization * Expected to be available for 48 weeks of follow-up at study entry * Parent or legal guardian willing and able to provide written informed consent for infant participation in the study * Parent or legal guardian willing and able to complete reactogenicity memory aids for study purposes, based on parent/guardian report. Infant
Exclusion criteria
* Infant or infant's mother received exclusionary active or passive HIV-specific immunotherapy * Initiated a combination of three or more antiretrovirals, all at or above recommended treatment doses, within 48 hours of birth * Received within 30 days prior to study entry, or was identified as requiring, any of the following: * Chronic (more than 14 days) systemic steroid treatment * Immunoglobulin treatment * Immunomodulators (interleukins, interferons, cyclosporin) * Cytotoxic chemotherapy * Treatment for active tuberculosis (TB) disease * Any investigational agent * Note: Treatment for latent TB infection was permitted * Any documented or suspected clinically significant medical illness, clinically significant congenital anomaly, or immediately life-threatening condition that, in the opinion of the site investigator or designee, would interfere with the infant's ability to comply with study requirements * Any other condition that, in the opinion of the site investigator or designee, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives Maternal Inclusion Criteria (maternal study participation was not required for infant study participation): The mothers of enrolled infants were asked to consent to blood collection and storage for this study. The following criteria must have been met in order for mothers to undergo blood collection for this purpose: * Mother was willing and able to provide independent written informed consent for blood collection and storage for virology and immunology investigations * Mother had no documented or suspected condition that, in the opinion of the site investigator or designee, would make blood collection unsafe
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Infants Experiencing at Least One Grade 3 or Higher Adverse Event (AE) | From Week 0 to Week 14 | Includes reactogenicity outcomes, abnormal laboratory test results, signs, symptoms, and diagnoses. Adverse event severity grading was based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. Two-sided exact 95% Clopper-Pearson confidence intervals were calculated. |
| Change in HIV-1 DNA Concentration in Peripheral Blood Mononuclear Cells (PBMCs) From Week 0 to Week 14 | Week 0 and Week 14 | Mean changes (Week 14 - Week 0) were calculated on log10-transformed HIV-1 DNA concentration. Values below the assay detection limit were set to half the lower assay limit of 4.09 copies/million PBMCs. Values above the detection limit were set to the upper limit of 10,000 copies/million PBMCs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Pre-dose VRC01 Concentrations in the Plasma (VRC01 Arm Only) | Weeks 2, 6, 10, 14, and 16 | Median (mcg/ml) pre-dose VRC01 concentrations in the plasma (VRC01 Arm only) |
| Geometric Mean of Pre-dose VRC01 Concentrations in the Plasma (VRC01 Arm Only) | Weeks 2, 6, 10, 14, and 16 | Geometric mean (mcg/ml) of pre-dose VRC01 concentrations with 90% confidence intervals |
| Percentage of Infants With Pre-dose VRC01 Concentrations >= 20 mcg/ml in the Plasma (VRC01 Arm Only) | Weeks 2, 6, 10, 14, 16 | Percentage of infants with pre-dose VRC01 concentrations \>= 20 mcg/ml in the plasma (VRC01 Arm only) |
| Percentage of Infants With Pre-dose VRC01 Concentrations >= 50 mcg/ml in the Plasma (VRC01 Arm Only) | Weeks 2, 6, 10, 14, 16 | Percentage of infants with pre-dose VRC01 concentrations \>= 50 mcg/ml in the plasma (VRC01 Arm only) |
Countries
Botswana, Brazil, Malawi, Zimbabwe
Participant flow
Recruitment details
61 infants were enrolled at 7 sites in 4 countries (Botswana, Malawi, Zimbabwe and Brazil) between August 6, 2018 and March 11, 2020.
Pre-assignment details
Infants were randomized equally to the two study arms. Randomization was stratified by whether their initial combination antiretroviral (cART) regimen included an integrase inhibitor.
Participants by arm
| Arm | Count |
|---|---|
| VRC01 (Arm 1) Infants received VRC01 subcutaneous injections (40 mg/kg) at Weeks 0, 2, 6, and 10.
All infants on cART. | 30 |
| No-VRC01 (Arm 2) Infants did not receive VRC01.
All infants on cART. | 31 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 2 |
| Overall Study | Moved and unable to get to clinic | 1 | 0 |
| Overall Study | Unwilling to adhere to study requirements | 0 | 1 |
Baseline characteristics
| Characteristic | VRC01 (Arm 1) | No-VRC01 (Arm 2) | Total |
|---|---|---|---|
| Age, Continuous | 72 Days | 73 Days | 73 Days |
| Days on antiretrovirals prior to study entry 0 | 1 Participants | 5 Participants | 6 Participants |
| Days on antiretrovirals prior to study entry 1-7 | 11 Participants | 15 Participants | 26 Participants |
| Days on antiretrovirals prior to study entry >7 | 18 Participants | 11 Participants | 29 Participants |
| Days on antiretrovirals prior to study entry | 8 Days | 6 Days | 7 Days |
| HIV-1 DNA (log10 copies/million PBMCs) | 3.12 log10 copies/million PBMCs | 3.16 log10 copies/million PBMCs | 3.15 log10 copies/million PBMCs |
| HIV-1 RNA (copies/ml) >= 100,000 copies/ml | 7 Participants | 10 Participants | 17 Participants |
| HIV-1 RNA (copies/ml) 10,000 - < 100,000 copies/ml | 11 Participants | 10 Participants | 21 Participants |
| HIV-1 RNA (copies/ml) 1000 - < 10,000 copies/ml | 10 Participants | 8 Participants | 18 Participants |
| HIV-1 RNA (copies/ml) <1000 copies/ml | 2 Participants | 3 Participants | 5 Participants |
| HIV-1 RNA (copies/ml) | 12,552 copies/ml | 22,625 copies/ml | 16,566 copies/ml |
| Race/Ethnicity, Customized Race/ethnicity Black Non-Hispanic | 25 Participants | 26 Participants | 51 Participants |
| Race/Ethnicity, Customized Race/ethnicity Hispanic (Regardless of Race) | 5 Participants | 5 Participants | 10 Participants |
| Region of enrollment Botswana | 0 Participants | 7 Participants | 7 Participants |
| Region of enrollment Brazil | 3 Participants | 3 Participants | 6 Participants |
| Region of enrollment Malawi | 25 Participants | 17 Participants | 42 Participants |
| Region of enrollment Zimbabwe | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Female | 14 Participants | 21 Participants | 35 Participants |
| Sex: Female, Male Male | 16 Participants | 10 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 30 | 2 / 30 |
| other Total, other adverse events | 30 / 30 | 30 / 30 |
| serious Total, serious adverse events | 7 / 30 | 11 / 30 |
Outcome results
Primary
Change in HIV-1 DNA Concentration in Peripheral Blood Mononuclear Cells (PBMCs) From Week 0 to Week 14
Mean changes (Week 14 - Week 0) were calculated on log10-transformed HIV-1 DNA concentration. Values below the assay detection limit were set to half the lower assay limit of 4.09 copies/million PBMCs. Values above the detection limit were set to the upper limit of 10,000 copies/million PBMCs.
Time frame: Week 0 and Week 14
Population: One infant in No-VRC01 arm did not return to clinic after week 0 and is not included in analysis population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| VRC01 (Arm 1) | Change in HIV-1 DNA Concentration in Peripheral Blood Mononuclear Cells (PBMCs) From Week 0 to Week 14 | -0.41 log10 copies/million PBMCs |
| No-VRC01 (Arm 2) | Change in HIV-1 DNA Concentration in Peripheral Blood Mononuclear Cells (PBMCs) From Week 0 to Week 14 | -0.53 log10 copies/million PBMCs |
p-value: 0.42Wilcoxon (Mann-Whitney)
Primary
Percentage of Infants Experiencing at Least One Grade 3 or Higher Adverse Event (AE)
Includes reactogenicity outcomes, abnormal laboratory test results, signs, symptoms, and diagnoses. Adverse event severity grading was based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. Two-sided exact 95% Clopper-Pearson confidence intervals were calculated.
Time frame: From Week 0 to Week 14
Population: One infant in the No-VRC01 arm did not return to clinic after Week 0 and is not included in the analysis population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| VRC01 (Arm 1) | Percentage of Infants Experiencing at Least One Grade 3 or Higher Adverse Event (AE) | 40.0 Percentage of participants |
| No-VRC01 (Arm 2) | Percentage of Infants Experiencing at Least One Grade 3 or Higher Adverse Event (AE) | 46.7 Percentage of participants |
p-value: 0.79Fisher Exact
Secondary
Geometric Mean of Pre-dose VRC01 Concentrations in the Plasma (VRC01 Arm Only)
Geometric mean (mcg/ml) of pre-dose VRC01 concentrations with 90% confidence intervals
Time frame: Weeks 2, 6, 10, 14, and 16
Population: One infant had no PK measurements run as sample sent to incorrect location for testing.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| VRC01 (Arm 1) | Geometric Mean of Pre-dose VRC01 Concentrations in the Plasma (VRC01 Arm Only) | Week 2 | 104.2 mcg/ml |
| VRC01 (Arm 1) | Geometric Mean of Pre-dose VRC01 Concentrations in the Plasma (VRC01 Arm Only) | Week 6 | 64.7 mcg/ml |
| VRC01 (Arm 1) | Geometric Mean of Pre-dose VRC01 Concentrations in the Plasma (VRC01 Arm Only) | Week 10 | 57.5 mcg/ml |
| VRC01 (Arm 1) | Geometric Mean of Pre-dose VRC01 Concentrations in the Plasma (VRC01 Arm Only) | Week 14 | 47.6 mcg/ml |
| VRC01 (Arm 1) | Geometric Mean of Pre-dose VRC01 Concentrations in the Plasma (VRC01 Arm Only) | Week 16 | 26.7 mcg/ml |
Secondary
Median Pre-dose VRC01 Concentrations in the Plasma (VRC01 Arm Only)
Median (mcg/ml) pre-dose VRC01 concentrations in the plasma (VRC01 Arm only)
Time frame: Weeks 2, 6, 10, 14, and 16
Population: One infant had no PK measurements run as sample sent to incorrect location for testing.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| VRC01 (Arm 1) | Median Pre-dose VRC01 Concentrations in the Plasma (VRC01 Arm Only) | Week 2 | 109.4 mcg/ml |
| VRC01 (Arm 1) | Median Pre-dose VRC01 Concentrations in the Plasma (VRC01 Arm Only) | Week 6 | 79.5 mcg/ml |
| VRC01 (Arm 1) | Median Pre-dose VRC01 Concentrations in the Plasma (VRC01 Arm Only) | Week 10 | 96.5 mcg/ml |
| VRC01 (Arm 1) | Median Pre-dose VRC01 Concentrations in the Plasma (VRC01 Arm Only) | Week 14 | 82.3 mcg/ml |
| VRC01 (Arm 1) | Median Pre-dose VRC01 Concentrations in the Plasma (VRC01 Arm Only) | Week 16 | 53.2 mcg/ml |
Secondary
Percentage of Infants With Pre-dose VRC01 Concentrations >= 20 mcg/ml in the Plasma (VRC01 Arm Only)
Percentage of infants with pre-dose VRC01 concentrations \>= 20 mcg/ml in the plasma (VRC01 Arm only)
Time frame: Weeks 2, 6, 10, 14, 16
Population: One infant had no PK measurements run as sample sent to incorrect location for testing.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| VRC01 (Arm 1) | Percentage of Infants With Pre-dose VRC01 Concentrations >= 20 mcg/ml in the Plasma (VRC01 Arm Only) | Week 2 | 28 Participants |
| VRC01 (Arm 1) | Percentage of Infants With Pre-dose VRC01 Concentrations >= 20 mcg/ml in the Plasma (VRC01 Arm Only) | Week 6 | 25 Participants |
| VRC01 (Arm 1) | Percentage of Infants With Pre-dose VRC01 Concentrations >= 20 mcg/ml in the Plasma (VRC01 Arm Only) | Week 10 | 25 Participants |
| VRC01 (Arm 1) | Percentage of Infants With Pre-dose VRC01 Concentrations >= 20 mcg/ml in the Plasma (VRC01 Arm Only) | Week 14 | 24 Participants |
| VRC01 (Arm 1) | Percentage of Infants With Pre-dose VRC01 Concentrations >= 20 mcg/ml in the Plasma (VRC01 Arm Only) | Week 16 | 18 Participants |
Secondary
Percentage of Infants With Pre-dose VRC01 Concentrations >= 50 mcg/ml in the Plasma (VRC01 Arm Only)
Percentage of infants with pre-dose VRC01 concentrations \>= 50 mcg/ml in the plasma (VRC01 Arm only)
Time frame: Weeks 2, 6, 10, 14, 16
Population: One infant had no PK measurements run as sample sent to incorrect location for testing.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| VRC01 (Arm 1) | Percentage of Infants With Pre-dose VRC01 Concentrations >= 50 mcg/ml in the Plasma (VRC01 Arm Only) | Week 2 | 27 Participants |
| VRC01 (Arm 1) | Percentage of Infants With Pre-dose VRC01 Concentrations >= 50 mcg/ml in the Plasma (VRC01 Arm Only) | Week 6 | 21 Participants |
| VRC01 (Arm 1) | Percentage of Infants With Pre-dose VRC01 Concentrations >= 50 mcg/ml in the Plasma (VRC01 Arm Only) | Week 10 | 20 Participants |
| VRC01 (Arm 1) | Percentage of Infants With Pre-dose VRC01 Concentrations >= 50 mcg/ml in the Plasma (VRC01 Arm Only) | Week 14 | 18 Participants |
| VRC01 (Arm 1) | Percentage of Infants With Pre-dose VRC01 Concentrations >= 50 mcg/ml in the Plasma (VRC01 Arm Only) | Week 16 | 15 Participants |