Trial Outcomes & Findings for Modulating the Impact of Critical Events in Early HIV Infection: Effect of ART Initiation and Alcohol Use (NCT NCT02744040)

NCT ID: NCT02744040

Last Updated: 2022-03-29

Results Overview

Total HIV DNA reservoir at baseline (ART Initiation) Baseline total HIV DNA was measured in CD4+ T cells isolated from PBMC collected at the ART Initiation visit. Total DNA was quantitated using polymerase chain reaction (PCR) with primers within HIV (5'-LTR and gag).

Recruitment status

COMPLETED

Study phase

NA

Target enrollment

151 participants

Primary outcome timeframe

Baseline

Results posted on

2022-03-29

Participant Flow

Participant milestones

Participant milestones
Measure
EDDI-to-ART <= 30 Days
Participants who started ART within 30 days from the estimated date of infection
EDDI-to-ART 31-90 Days
Participants who started ART between 31 and 90 days from the estimated date of infection
EDDI-to-ART >90 Days
Participants who started ART more than 90 days from the estimated date of infection
Overall Study
STARTED
28
51
72
Overall Study
COMPLETED
22
40
50
Overall Study
NOT COMPLETED
6
11
22

Reasons for withdrawal

Reasons for withdrawal
Measure
EDDI-to-ART <= 30 Days
Participants who started ART within 30 days from the estimated date of infection
EDDI-to-ART 31-90 Days
Participants who started ART between 31 and 90 days from the estimated date of infection
EDDI-to-ART >90 Days
Participants who started ART more than 90 days from the estimated date of infection
Overall Study
Withdrawal by Subject
3
2
2
Overall Study
Physician Decision
0
8
13
Overall Study
Lost to Follow-up
3
1
7

Baseline Characteristics

Modulating the Impact of Critical Events in Early HIV Infection: Effect of ART Initiation and Alcohol Use

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure
EDDI-to-ART <= 30 Days
n=28 Participants
Participants who started ART within 30 days from the estimated date of infection
EDDI-to-ART 31-90 Days
n=51 Participants
Participants who started ART between 31 and 90 days from the estimated date of infection
EDDI-to-ART >90 Days
n=72 Participants
Participants who started ART more than 90 days from the estimated date of infection
Total
n=151 Participants
Total of all reporting groups
Age, Continuous
27 years
n=99 Participants
26 years
n=107 Participants
24 years
n=206 Participants
25 years
n=7 Participants
Sex: Female, Male
Female
0 Participants
n=99 Participants
0 Participants
n=107 Participants
0 Participants
n=206 Participants
0 Participants
n=7 Participants
Sex: Female, Male
Male
28 Participants
n=99 Participants
51 Participants
n=107 Participants
72 Participants
n=206 Participants
151 Participants
n=7 Participants
Ethnicity (NIH/OMB)
Hispanic or Latino
28 Participants
n=99 Participants
51 Participants
n=107 Participants
72 Participants
n=206 Participants
151 Participants
n=7 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
0 Participants
n=99 Participants
0 Participants
n=107 Participants
0 Participants
n=206 Participants
0 Participants
n=7 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
0 Participants
n=99 Participants
0 Participants
n=107 Participants
0 Participants
n=206 Participants
0 Participants
n=7 Participants
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants
n=99 Participants
0 Participants
n=107 Participants
0 Participants
n=206 Participants
0 Participants
n=7 Participants
Race (NIH/OMB)
Asian
0 Participants
n=99 Participants
0 Participants
n=107 Participants
0 Participants
n=206 Participants
0 Participants
n=7 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants
n=99 Participants
0 Participants
n=107 Participants
0 Participants
n=206 Participants
0 Participants
n=7 Participants
Race (NIH/OMB)
Black or African American
0 Participants
n=99 Participants
0 Participants
n=107 Participants
0 Participants
n=206 Participants
0 Participants
n=7 Participants
Race (NIH/OMB)
White
0 Participants
n=99 Participants
0 Participants
n=107 Participants
0 Participants
n=206 Participants
0 Participants
n=7 Participants
Race (NIH/OMB)
More than one race
28 Participants
n=99 Participants
51 Participants
n=107 Participants
72 Participants
n=206 Participants
151 Participants
n=7 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants
n=99 Participants
0 Participants
n=107 Participants
0 Participants
n=206 Participants
0 Participants
n=7 Participants
Region of Enrollment
Peru
28 participants
n=99 Participants
51 participants
n=107 Participants
72 participants
n=206 Participants
151 participants
n=7 Participants
HIV Viral Load
6.6 Log10(Copies/mL)
n=99 Participants
5.4 Log10(Copies/mL)
n=107 Participants
5.8 Log10(Copies/mL)
n=206 Participants
5.8 Log10(Copies/mL)
n=7 Participants
CD4 count
521 Cells/mm3
n=99 Participants
428 Cells/mm3
n=107 Participants
421 Cells/mm3
n=206 Participants
442 Cells/mm3
n=7 Participants

PRIMARY outcome

Timeframe: Baseline

Population: The number of participants in the analysis of individual outcomes at some timepoints differs from the total number of participants shown in the participant flow due to lack of specimen availability and missed visits for some participants. In addition, some analyses were only conducted in selected participants (for example, restriction to participants with baseline specimens).

Total HIV DNA reservoir at baseline (ART Initiation) Baseline total HIV DNA was measured in CD4+ T cells isolated from PBMC collected at the ART Initiation visit. Total DNA was quantitated using polymerase chain reaction (PCR) with primers within HIV (5'-LTR and gag).

Outcome measures

Outcome measures
Measure
EDDI-to-ART <= 30 Days
n=9 Participants
Participants who started ART within 30 days from the estimated date of infection
EDDI-to-ART 31-90 Days
n=14 Participants
Participants who started ART between 31 and 90 days from the estimated date of infection
EDDI-to-ART >90 Days
n=19 Participants
Participants who started ART more than 90 days from the estimated date of infection
Baseline HIV DNA Reservoir: Total HIV DNA
3.83 Log10 HIV DNA copies/10^6 CD4 T cells
Interval 3.45 to 3.99
3.67 Log10 HIV DNA copies/10^6 CD4 T cells
Interval 3.24 to 4.13
3.40 Log10 HIV DNA copies/10^6 CD4 T cells
Interval 2.81 to 3.72

PRIMARY outcome

Timeframe: 4 years from ART initiation

Population: The number of participants in the analysis of individual outcomes at some timepoints differs from the total number of participants shown in the participant flow due to lack of specimen availability and missed visits for some participants. In addition, some analyses were only conducted in selected participants (for example, restriction to participants with baseline specimens or participants with continuous viral load suppression after ART initiation).

Decay of total HIV DNA was assessed in CD4+ T cells isolated from PBMC collected at 1, 2, 4, 8, 16, 24, 96 and 192 weeks (as available) from ART initiation (which occurred prior to enrollment into MERLIN). Total DNA was quantitated using polymerase chain reaction (PCR) with primers within HIV (5'-LTR and gag). The longitudinal decay in total HIV DNA was analyzed by use of a mixed-effects model from the time of ART initiation up to 192 weeks.

Outcome measures

Outcome measures
Measure
EDDI-to-ART <= 30 Days
n=9 Participants
Participants who started ART within 30 days from the estimated date of infection
EDDI-to-ART 31-90 Days
n=14 Participants
Participants who started ART between 31 and 90 days from the estimated date of infection
EDDI-to-ART >90 Days
n=19 Participants
Participants who started ART more than 90 days from the estimated date of infection
Two Phase Decay of HIV DNA Reservoir: Total HIV DNA
Slope 1
-0.145 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval -0.164 to -0.126
-0.058 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval -0.067 to -0.05
-0.018 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval -0.021 to -0.015
Two Phase Decay of HIV DNA Reservoir: Total HIV DNA
Slope 2
-0.006 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval -0.007 to -0.005
-0.004 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval -0.005 to -0.003
-0.001 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval -0.002 to 0.001

PRIMARY outcome

Timeframe: Baseline

Population: The number of participants in the analysis of individual outcomes at some timepoints differs from the total number of participants shown in the participant flow due to lack of specimen availability and missed visits for some participants. In addition, some analyses were only conducted in selected participants (for example, restriction to participants with baseline specimens).

Baseline integrated HIV DNA was measured in CD4+ T cells isolated from PBMC collected at the ART Initiation visit. Integrated DNA was quantitated using polymerase chain reaction (PCR) with primers within HIV (3'-LTR) and host DNA (alu).

Outcome measures

Outcome measures
Measure
EDDI-to-ART <= 30 Days
n=9 Participants
Participants who started ART within 30 days from the estimated date of infection
EDDI-to-ART 31-90 Days
n=14 Participants
Participants who started ART between 31 and 90 days from the estimated date of infection
EDDI-to-ART >90 Days
n=19 Participants
Participants who started ART more than 90 days from the estimated date of infection
Baseline HIV DNA Reservoir: Integrated HIV DNA
2.87 Log10 HIV DNA copies/10^6 CD4 T cells
Interval 2.8 to 3.26
2.76 Log10 HIV DNA copies/10^6 CD4 T cells
Interval 2.24 to 3.2
2.55 Log10 HIV DNA copies/10^6 CD4 T cells
Interval 2.23 to 2.97

PRIMARY outcome

Timeframe: 4 years from ART initiation

Population: The number of participants in the analysis of individual outcomes at some timepoints differs from the total number of participants shown in the participant flow due to lack of specimen availability and missed visits for some participants. In addition, some analyses were only conducted in selected participants (for example, restriction to participants with baseline specimens or participants with continuous viral load suppression after ART initiation).

Decay of integrated HIV DNA was assessed in CD4+ T cells isolated from PBMC collected at 1, 2, 4, 8, 16, 24, 96 and 192 weeks (as available) from ART initiation (which occurred prior to enrollment into MERLIN).. Integrated DNA was quantitated using polymerase chain reaction (PCR) with primers within HIV (3'-LTR) and host DNA (alu). The longitudinal decay in integrated HIV DNA was analyzed by use of a mixed-effects model from the time of ART initiation up to 192 weeks.

Outcome measures

Outcome measures
Measure
EDDI-to-ART <= 30 Days
n=9 Participants
Participants who started ART within 30 days from the estimated date of infection
EDDI-to-ART 31-90 Days
n=14 Participants
Participants who started ART between 31 and 90 days from the estimated date of infection
EDDI-to-ART >90 Days
n=19 Participants
Participants who started ART more than 90 days from the estimated date of infection
Two Phase Decay of HIV DNA Reservoir: Integrated HIV DNA
Slope 1
-0.149 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval -0.174 to -0.124
-0.049 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval -0.06 to -0.038
-0.014 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval -0.019 to -0.01
Two Phase Decay of HIV DNA Reservoir: Integrated HIV DNA
Slope 2
-0.002 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval -0.003 to -0.001
-0.001 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval -0.002 to 0.0
-0.001 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval -0.002 to 0.0

PRIMARY outcome

Timeframe: Baseline

Population: The number of participants in the analysis of individual outcomes at some timepoints differs from the total number of participants shown in the participant flow due to lack of specimen availability and missed visits for some participants. In addition, some analyses were only conducted in selected participants (for example, restriction to participants with baseline specimens).

Baseline HIV DNA by TILDA stimulation was measured in CD4+ T cells isolated from PBMC collected at the ART Initiation visit. The inducible HIV reservoir (TILDA stimulation) was quantitated using a tat/rev induced limiting dilution assay (TILDA). Cells with inducible HIV proviruses were assessed by quantifying the frequency of CD4+ cells producing multiply-spliced HIV RNA after in-vitro stimulation.

Outcome measures

Outcome measures
Measure
EDDI-to-ART <= 30 Days
n=5 Participants
Participants who started ART within 30 days from the estimated date of infection
EDDI-to-ART 31-90 Days
n=10 Participants
Participants who started ART between 31 and 90 days from the estimated date of infection
EDDI-to-ART >90 Days
n=17 Participants
Participants who started ART more than 90 days from the estimated date of infection
Baseline HIV DNA Reservoir: TILDA Stimulation
2.94 Log10 HIV DNA copies/10^6 CD4 T cells
Interval 1.6 to 3.14
2.02 Log10 HIV DNA copies/10^6 CD4 T cells
Interval 1.8 to 2.56
1.66 Log10 HIV DNA copies/10^6 CD4 T cells
Interval 1.21 to 2.14

PRIMARY outcome

Timeframe: 4 years from ART initiation

Population: The number of participants in the analysis of individual outcomes at some timepoints differs from the total number of participants shown in the participant flow due to lack of specimen availability and missed visits for some participants. In addition, some analyses were only conducted in selected participants (for example, restriction to participants with baseline specimens or participants with continuous viral load suppression after ART initiation).

Decay of inducible HIV DNA proviruses (TILDA stimulation) was assessed in CD4+ T cells isolated from PBMC collected at 1, 2, 4, 8, 16, 24, 96 and 192 weeks (as available) from ART initiation (which occurred prior to enrollment into MERLIN). The inducible HIV reservoir (TILDS stimulation) was quantitated using a tat/rev induced limiting dilution assay (TILDA). Cells with inducible HIV proviruses were assessed by quantifying the frequency of CD4+ cells producing multiply-spliced HIV RNA after in-vitro stimulation. The longitudinal decay in the inducible HIV DNA reservoir was analyzed by use of a mixed-effects model from the time of ART initiation up to 192 weeks.

Outcome measures

Outcome measures
Measure
EDDI-to-ART <= 30 Days
n=5 Participants
Participants who started ART within 30 days from the estimated date of infection
EDDI-to-ART 31-90 Days
n=10 Participants
Participants who started ART between 31 and 90 days from the estimated date of infection
EDDI-to-ART >90 Days
n=17 Participants
Participants who started ART more than 90 days from the estimated date of infection
Two Phase Decay of HIV DNA Reservoir: TILDA Stimulation
Slope 1
-0.266 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval -0.311 to -0.221
-0.170 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval -0.204 to -0.136
-0.143 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval -0.17 to -0.115
Two Phase Decay of HIV DNA Reservoir: TILDA Stimulation
Slope 2
-0.002 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval -0.003 to 0.0
-0.001 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval -0.002 to 0.001
0.001 Log10 HIV DNA copies/10^6 CD4 T cells/WK
Interval 0.0 to 0.002

PRIMARY outcome

Timeframe: 4 years from ART initiation

Population: Specimen collection has been completed but the analysis could not be completed due to unforeseen circumstances.

HIV DNA integration sites were measured for up to 4 years after initiation of ART (which occurred prior to enrollment in MERLIN). HIV DNA integration was assessed using CD4+ T cells isolated from PBMC at enrollment, ART initiation and 24, 96 and 192 weeks after ART initiation. HIV integration into the STAT5 and BACH2 genes was measured by assessing hybrid transcript structure (HIV LTR to BACH2 or STAT5 exon); hybrid transcript structure was confirmed by sequencing.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 4 years from ART initiation

Population: Specimen collection has been completed but the analysis could not be completed due to unforeseen circumstances.

The GI microbiome will be assessed using 16S rRNA-based phylogenetic characterization of microbiome composition using stool specimens obtained before and after ART initiation.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 4 years from ART initiation

Population: Specimen collection has been completed but the analysis could not be completed due to unforeseen circumstances.

Levels of inflammatory biomarkers measured in plasma by Meso Scale Discovery (MSD) and ELISA assays prior to infection and after viral load suppression.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 4 years from ART initiation

Population: Specimen collection has been completed but the analysis could not be completed due to unforeseen circumstances.

High level alcohol use will be measured using self report (AUDIT Score and Quick Drinking Survey) and a blood biomarker (PEth). Alcohol use level will be included in multivariate analysis of GI Microbiome composition as well as a covariate in other analyses.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 4 years from ART initiation

HIV viral load was measured in plasma at multiple timepoints beginning with the first visit after HIV diagnosis (which occurred prior to enrollment in MERLIN), using standard commercial viral load kits with a cut-off of 40 HIV RNA copies/mL. The log10 of HIV RNA copies/mL is reported. A value of 1.6 or less represent an undetectable log10 viral load (log10 \<40 copies/mL).

Outcome measures

Outcome measures
Measure
EDDI-to-ART <= 30 Days
n=28 Participants
Participants who started ART within 30 days from the estimated date of infection
EDDI-to-ART 31-90 Days
n=51 Participants
Participants who started ART between 31 and 90 days from the estimated date of infection
EDDI-to-ART >90 Days
n=72 Participants
Participants who started ART more than 90 days from the estimated date of infection
HIV RNA Viral Load
At ART Initiation
6.63 Log10 HIV RNA copies/mL
Interval 6.06 to 7.0
5.42 Log10 HIV RNA copies/mL
Interval 4.82 to 6.385
4.96 Log10 HIV RNA copies/mL
Interval 4.6 to 5.53
HIV RNA Viral Load
One year on ART
1.6 Log10 HIV RNA copies/mL
Interval 0.0 to 1.6
1.6 Log10 HIV RNA copies/mL
Interval 0.0 to 1.6
1.6 Log10 HIV RNA copies/mL
Interval 0.0 to 1.6
HIV RNA Viral Load
Two years on ART
1.6 Log10 HIV RNA copies/mL
Interval 0.0 to 1.6
1.6 Log10 HIV RNA copies/mL
Interval 0.0 to 1.6
1.6 Log10 HIV RNA copies/mL
Interval 0.0 to 1.6
HIV RNA Viral Load
Three years on ART
1.6 Log10 HIV RNA copies/mL
Interval 0.0 to 1.6
1.6 Log10 HIV RNA copies/mL
Interval 0.0 to 1.6
1.6 Log10 HIV RNA copies/mL
Interval 0.0 to 1.6
HIV RNA Viral Load
Four years on ART
1.6 Log10 HIV RNA copies/mL
Interval 0.0 to 1.6
1.6 Log10 HIV RNA copies/mL
Interval 0.0 to 1.6
1.6 Log10 HIV RNA copies/mL
Interval 0.0 to 1.6

PRIMARY outcome

Timeframe: 4 years from ART initiation

CD4 counts were measured by flow cytometry at multiple timepoints in all participants.

Outcome measures

Outcome measures
Measure
EDDI-to-ART <= 30 Days
n=28 Participants
Participants who started ART within 30 days from the estimated date of infection
EDDI-to-ART 31-90 Days
n=51 Participants
Participants who started ART between 31 and 90 days from the estimated date of infection
EDDI-to-ART >90 Days
n=72 Participants
Participants who started ART more than 90 days from the estimated date of infection
CD4 Count
At ART Initiation
656 Cells/mm^3
Interval 564.0 to 724.0
609 Cells/mm^3
Interval 377.0 to 754.0
552 Cells/mm^3
Interval 452.0 to 700.0
CD4 Count
One year on ART
622 Cells/mm^3
Interval 525.0 to 770.0
584 Cells/mm^3
Interval 473.0 to 738.0
635 Cells/mm^3
Interval 502.0 to 795.0
CD4 Count
Two years on ART
653 Cells/mm^3
Interval 599.0 to 919.0
595 Cells/mm^3
Interval 396.0 to 781.0
696 Cells/mm^3
Interval 550.0 to 902.0
CD4 Count
Three years on ART
675 Cells/mm^3
Interval 592.0 to 846.0
703 Cells/mm^3
Interval 493.0 to 820.0
706 Cells/mm^3
Interval 586.0 to 874.0
CD4 Count
Four years on ART
707 Cells/mm^3
Interval 610.0 to 985.0
643 Cells/mm^3
Interval 516.0 to 790.0
690 Cells/mm^3
Interval 535.0 to 850.0

PRIMARY outcome

Timeframe: 4 years from ART initiation

Number of days between ART start and Undetectable Viral Load (\<40 copies/mL)

Outcome measures

Outcome measures
Measure
EDDI-to-ART <= 30 Days
n=26 Participants
Participants who started ART within 30 days from the estimated date of infection
EDDI-to-ART 31-90 Days
n=47 Participants
Participants who started ART between 31 and 90 days from the estimated date of infection
EDDI-to-ART >90 Days
n=63 Participants
Participants who started ART more than 90 days from the estimated date of infection
Time to Undetectable HIV Viral Load
163.5 Days
Interval 84.0 to 171.25
110 Days
Interval 84.0 to 169.0
154 Days
Interval 84.0 to 168.0

Adverse Events

EDDI-to-ART <= 30 Days

Serious events: 0 serious events
Other events: 14 other events
Deaths: 0 deaths

EDDI-to-ART 31-90 Days

Serious events: 0 serious events
Other events: 26 other events
Deaths: 0 deaths

EDDI-to-ART >90 Days

Serious events: 1 serious events
Other events: 46 other events
Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure
EDDI-to-ART <= 30 Days
n=28 participants at risk
Participants who started ART within 30 days from the estimated date of infection
EDDI-to-ART 31-90 Days
n=51 participants at risk
Participants who started ART between 31 and 90 days from the estimated date of infection
EDDI-to-ART >90 Days
n=72 participants at risk
Participants who started ART more than 90 days from the estimated date of infection
Gastrointestinal disorders
rectal bleeding
0.00%
0/28 • Up to 3 years and 3 months
0.00%
0/51 • Up to 3 years and 3 months
1.4%
1/72 • Number of events 1 • Up to 3 years and 3 months

Other adverse events

Other adverse events
Measure
EDDI-to-ART <= 30 Days
n=28 participants at risk
Participants who started ART within 30 days from the estimated date of infection
EDDI-to-ART 31-90 Days
n=51 participants at risk
Participants who started ART between 31 and 90 days from the estimated date of infection
EDDI-to-ART >90 Days
n=72 participants at risk
Participants who started ART more than 90 days from the estimated date of infection
Gastrointestinal disorders
Hemorrhoids
17.9%
5/28 • Up to 3 years and 3 months
9.8%
5/51 • Up to 3 years and 3 months
12.5%
9/72 • Up to 3 years and 3 months
Metabolism and nutrition disorders
Obesity
0.00%
0/28 • Up to 3 years and 3 months
3.9%
2/51 • Up to 3 years and 3 months
13.9%
10/72 • Up to 3 years and 3 months
Infections and infestations
Pharyngitis
7.1%
2/28 • Up to 3 years and 3 months
3.9%
2/51 • Up to 3 years and 3 months
6.9%
5/72 • Up to 3 years and 3 months
Infections and infestations
SARS-Cov-2 Infection (COVID-19 Disease)
3.6%
1/28 • Up to 3 years and 3 months
5.9%
3/51 • Up to 3 years and 3 months
2.8%
2/72 • Up to 3 years and 3 months
Infections and infestations
Syphilis
21.4%
6/28 • Up to 3 years and 3 months
27.5%
14/51 • Up to 3 years and 3 months
27.8%
20/72 • Up to 3 years and 3 months

Additional Information

Ann C Duerr, MD, PhD, MPH, Member

Fred Hutchinson Cancer Research Center

Phone: 206-667-7938

Results disclosure agreements

  • Principal investigator is a sponsor employee
  • Publication restrictions are in place