HIV Infection
Conditions
Keywords
HIV reservoir, alcohol, ART
Brief summary
The overall objective is to determine the influence of timing of ART initiation and alcohol consumption on HIV disease course. ART initiation immediately after HIV infection largely results in smaller HIV reservoir and lower HIV-associated systemic inflammation, which has been linked to non-AIDS morbidity and mortality. Immediate ART also reduces HIV-associated bacterial translocation and may prevent intestinal microbiome dysbiosis, that has been linked to increased systemic inflammation. Immediate intervention is not, however, generally feasible and more information is required about the consequences of starting ART at later time-points, but still early after acquisition. The study will be conducted in Lima, Peru, in a cohort of 180 MSM and transgender women (TW) with acute (Ab-, HIV RNA+) or recent (≤ 3 months) HIV infection. Alcohol use disorder (AUDIT score ≥8) is present in \ 50% of HIV + participants in our cohort, four times higher than that seen among males in the general Peruvian population. Although the role of alcohol use in HIV pathogenesis and disease course remains unclear, some studies show a correlation with accelerated disease progression. The effects of alcohol resemble early post-infection changes in bacterial translocation and pro-inflammatory cytokines induced by HIV and their impact on HIV disease course before and after ART initiation remain unexplored. Specific Aim 1: To determine the relative long-term benefits of immediate vs. early vs. delayed ART initiation at 24 weeks after diagnosis. The investigators will study outcomes after 2 and 4 years in MSM and TW diagnosed with acute or recent HIV infection. Specific Aim 2: To determine the impact of alcohol use on the relative long-term benefits of immediate vs. early vs. delayed initiation of ART.
Detailed description
Specific Aims: Recent studies suggest that very early initiation of ART (prior to seroconversion) does not prevent the establishment of HIV reservoirs, which eventually expand when ART is discontinued. Early ART initiation is, however, associated with preservation of CD4+ T cells and lower levels of total HIV DNA and cell-associated RNA as well as preservation of gut Th17 cells, thereby averting a major driver of HIV-related immune activation and limiting the size of the HIV reservoir. When, by contrast, ART is initiated in Fiebig III (FIII) or later, many HIV-associated changes have already occurred, including seeding of HIV reservoirs, damage to GI mucosa, and initiation of inflammatory cascades. Since ART initiation within weeks of HIV acquisition is not a viable public health strategy, it is important to more completely understand the relative long-term benefits of initiating ART at very early times after infection (FI-II) as opposed to after a short (during FIII-V) or longer delay (at 24 weeks). Since the possibility that high-level alcohol use can mitigate the benefits of early ART is emerging as a potentially important public health issue, the investigators will evaluate the impact of time of ART initiation as well as alcohol use on HIV pathogenesis in Peruvian men who have sex with men (MSM) and TW, in whom high-level alcohol use is common. They will study outcomes after 2 and 4 years in MSM and TW diagnosed with acute (Ab-, HIV RNA+) or recent (≤3 months) HIV infection. Three groups based on time since estimated date of detectible HIV infection (EDDI) to ART initiation will be studied: a) EDDI-to-ART: ≤ 30 days b) EDDI-to-ART: 31-90 days and c) EDDI-to-ART: \>90 days The overarching hypotheses are: 1. Initiation of ART soon after HIV infection will dampen perturbations of GI microbiota, reduce HIV-induced inflammatory changes, and decrease seeding of the reservoir. Initiation of ART within 30 days will have the greatest benefit. 2. Irrespective of the time of ART initiation, alcohol use will compound the negative effects of HIV. SPECIFIC AIM 1) To determine the relative long-term benefits of immediate vs. early vs. delayed initiation of ART. Initiation of ART within 30 days of infection, while theoretically appealing, is infeasible in clinical practice because antibody-based tests, used almost world-wide, are unable to diagnose very early infection. Six months of ART initiated shortly after seroconversion can improve many immune parameters, although not to the near normal level seen when ART is initiated earlier.. Longer-term follow-up of seropositive participants who started ART \ 2-8 months after HIV acquisition compared to those initiating ART within 30 days is needed to see whether markers of inflammation and residual viral load might continue to improve after 6 months, decreasing the difference between the groups. Methods: the investigators will evaluate the 3 groups using specimens from equivalent times after ART initiation for a total of 4 years of ART, comparing viral load, CD4 counts, time to reach undetectable VL, the GI microbiota, and inflammatory markers. Specimens from uninfected and chronically infected subjects are available as controls for some outcomes. They will model the size and persistence of the viral reservoir across all ART-compliant study subjects, measuring total HIV DNA, integrated HIV DNA and multi-spliced HIV RNA via TILDA (Tat/Rev Induced Limiting Dilution Assay) assay. In a subset of individuals from each group, the proviral integration sites will be defined at ART initiation and after 2 and 4 years to assess the maintenance of the reservoir by proliferating CD4 cells. SPECIFIC AIM 2) To determine the impact of high-level alcohol use on the relative long-term benefits of immediate vs. early vs. delayed ART initiation. High-level alcohol use results in changes in the GI microbiome, increasing dysbiosis and gut permeability, and these changes are associated with up-regulation of inflammatory pathways.. Dysbiosis is present in many HIV-infected patients. Methods: Investigators will compare outcomes between subjects by their reported alcohol use or by assessing alcohol use blood biomarkers (Phosphatidylethanol; PEth) at specified timepoints.. Finally, among ART-adherent subjects with persistent viral suppression, the investigators will assess inflammatory markers and HIV reservoirs in those with and without high-level alcohol use at 2 and 4 years after ART initiation.
Interventions
DRUGART initiation at time of HIV diagnosis
Immediate ART initiation
DRUGART at 24 weeks
ART initiation 24 weeks after enrollment
Sponsors
University of California, San Francisco
University of Washington
Asociación Civil Impacta Salud y Educación, Peru
Université de Montréal
Seattle Children's Hospital
National Institute on Drug Abuse (NIDA)
Fred Hutchinson Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Men who have sex with men or transgender women HIV-infected with prior participation in SABES study in Lima Peru OR Established HIV infection OR HIV uninfected
Exclusion criteria
* counter-indication for use of study antiretroviral drugs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline HIV DNA Reservoir: Total HIV DNA | Baseline | 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). |
| Two Phase Decay of HIV DNA Reservoir: Total HIV DNA | 4 years from 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. |
| Baseline HIV DNA Reservoir: Integrated HIV DNA | Baseline | 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). |
| Two Phase Decay of HIV DNA Reservoir: Integrated HIV DNA | 4 years from 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. |
| Baseline HIV DNA Reservoir: TILDA Stimulation | Baseline | 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. |
| Two Phase Decay of HIV DNA Reservoir: TILDA Stimulation | 4 years from 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. |
| HIV DNA Integration Sites | 4 years from ART initiation | 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. |
| GI Microbiome | 4 years from ART initiation | The GI microbiome will be assessed using 16S rRNA-based phylogenetic characterization of microbiome composition using stool specimens obtained before and after ART initiation. |
| Levels of Inflammatory Markers | 4 years from ART initiation | Levels of inflammatory biomarkers measured in plasma by Meso Scale Discovery (MSD) and ELISA assays prior to infection and after viral load suppression. |
| Impact of Alcohol Use | 4 years from ART initiation | 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. |
| HIV RNA Viral Load | 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). |
| CD4 Count | 4 years from ART initiation | CD4 counts were measured by flow cytometry at multiple timepoints in all participants. |
| Time to Undetectable HIV Viral Load | 4 years from ART initiation | Number of days between ART start and Undetectable Viral Load (\<40 copies/mL) |
Countries
Peru
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| EDDI-to-ART <= 30 Days Participants who started ART within 30 days from the estimated date of infection | 28 |
| EDDI-to-ART 31-90 Days Participants who started ART between 31 and 90 days from the estimated date of infection | 51 |
| EDDI-to-ART >90 Days Participants who started ART more than 90 days from the estimated date of infection | 72 |
| Total | 151 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 1 | 7 |
| Overall Study | Physician Decision | 0 | 8 | 13 |
| Overall Study | Withdrawal by Subject | 3 | 2 | 2 |
Baseline characteristics
| Characteristic | EDDI-to-ART <= 30 Days | EDDI-to-ART 31-90 Days | EDDI-to-ART >90 Days | Total |
|---|---|---|---|---|
| Age, Continuous | 27 years | 26 years | 24 years | 25 years |
| CD4 count | 521 Cells/mm3 | 428 Cells/mm3 | 421 Cells/mm3 | 442 Cells/mm3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 28 Participants | 51 Participants | 72 Participants | 151 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| HIV Viral Load | 6.6 Log10(Copies/mL) | 5.4 Log10(Copies/mL) | 5.8 Log10(Copies/mL) | 5.8 Log10(Copies/mL) |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 28 Participants | 51 Participants | 72 Participants | 151 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Peru | 28 participants | 51 participants | 72 participants | 151 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 28 Participants | 51 Participants | 72 Participants | 151 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 51 | 0 / 72 |
| other Total, other adverse events | 14 / 28 | 26 / 51 | 46 / 72 |
| serious Total, serious adverse events | 0 / 28 | 0 / 51 | 1 / 72 |
Outcome results
Primary
Baseline HIV DNA Reservoir: Integrated HIV DNA
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).
Time frame: 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).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EDDI-to-ART <= 30 Days | Baseline HIV DNA Reservoir: Integrated HIV DNA | 2.87 Log10 HIV DNA copies/10^6 CD4 T cells |
| EDDI-to-ART 31-90 Days | Baseline HIV DNA Reservoir: Integrated HIV DNA | 2.76 Log10 HIV DNA copies/10^6 CD4 T cells |
| EDDI-to-ART >90 Days | Baseline HIV DNA Reservoir: Integrated HIV DNA | 2.55 Log10 HIV DNA copies/10^6 CD4 T cells |
Comparison: Integrated HIV DNA at the time of ART initiation in each of the three EDDI groupsp-value: >0.05Mixed Effects Models
Primary
Baseline HIV DNA Reservoir: TILDA Stimulation
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.
Time frame: 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).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EDDI-to-ART <= 30 Days | Baseline HIV DNA Reservoir: TILDA Stimulation | 2.94 Log10 HIV DNA copies/10^6 CD4 T cells |
| EDDI-to-ART 31-90 Days | Baseline HIV DNA Reservoir: TILDA Stimulation | 2.02 Log10 HIV DNA copies/10^6 CD4 T cells |
| EDDI-to-ART >90 Days | Baseline HIV DNA Reservoir: TILDA Stimulation | 1.66 Log10 HIV DNA copies/10^6 CD4 T cells |
Comparison: TILDA stimulation reservoir measure at the time of ART initiation in each of the three EDDI groupsp-value: 0.057Mixed Effects Models
Primary
Baseline HIV DNA Reservoir: Total HIV DNA
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).
Time frame: 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).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EDDI-to-ART <= 30 Days | Baseline HIV DNA Reservoir: Total HIV DNA | 3.83 Log10 HIV DNA copies/10^6 CD4 T cells |
| EDDI-to-ART 31-90 Days | Baseline HIV DNA Reservoir: Total HIV DNA | 3.67 Log10 HIV DNA copies/10^6 CD4 T cells |
| EDDI-to-ART >90 Days | Baseline HIV DNA Reservoir: Total HIV DNA | 3.40 Log10 HIV DNA copies/10^6 CD4 T cells |
Comparison: Total HIV DNA at the time of ART initiation in each of the three EDDI groupsp-value: 0.048Mixed Effects Models
Primary
CD4 Count
CD4 counts were measured by flow cytometry at multiple timepoints in all participants.
Time frame: 4 years from ART initiation
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| EDDI-to-ART <= 30 Days | CD4 Count | Four years on ART | 707 Cells/mm^3 |
| EDDI-to-ART <= 30 Days | CD4 Count | Three years on ART | 675 Cells/mm^3 |
| EDDI-to-ART <= 30 Days | CD4 Count | At ART Initiation | 656 Cells/mm^3 |
| EDDI-to-ART <= 30 Days | CD4 Count | Two years on ART | 653 Cells/mm^3 |
| EDDI-to-ART <= 30 Days | CD4 Count | One year on ART | 622 Cells/mm^3 |
| EDDI-to-ART 31-90 Days | CD4 Count | Two years on ART | 595 Cells/mm^3 |
| EDDI-to-ART 31-90 Days | CD4 Count | Three years on ART | 703 Cells/mm^3 |
| EDDI-to-ART 31-90 Days | CD4 Count | Four years on ART | 643 Cells/mm^3 |
| EDDI-to-ART 31-90 Days | CD4 Count | At ART Initiation | 609 Cells/mm^3 |
| EDDI-to-ART 31-90 Days | CD4 Count | One year on ART | 584 Cells/mm^3 |
| EDDI-to-ART >90 Days | CD4 Count | Three years on ART | 706 Cells/mm^3 |
| EDDI-to-ART >90 Days | CD4 Count | Four years on ART | 690 Cells/mm^3 |
| EDDI-to-ART >90 Days | CD4 Count | One year on ART | 635 Cells/mm^3 |
| EDDI-to-ART >90 Days | CD4 Count | Two years on ART | 696 Cells/mm^3 |
| EDDI-to-ART >90 Days | CD4 Count | At ART Initiation | 552 Cells/mm^3 |
Primary
GI Microbiome
The GI microbiome will be assessed using 16S rRNA-based phylogenetic characterization of microbiome composition using stool specimens obtained before and after ART initiation.
Time frame: 4 years from ART initiation
Population: Specimen collection has been completed but the analysis could not be completed due to unforeseen circumstances.
Primary
HIV DNA Integration Sites
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.
Time frame: 4 years from ART initiation
Population: Specimen collection has been completed but the analysis could not be completed due to unforeseen circumstances.
Primary
HIV RNA Viral Load
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).
Time frame: 4 years from ART initiation
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| EDDI-to-ART <= 30 Days | HIV RNA Viral Load | Three years on ART | 1.6 Log10 HIV RNA copies/mL |
| EDDI-to-ART <= 30 Days | HIV RNA Viral Load | Two years on ART | 1.6 Log10 HIV RNA copies/mL |
| EDDI-to-ART <= 30 Days | HIV RNA Viral Load | At ART Initiation | 6.63 Log10 HIV RNA copies/mL |
| EDDI-to-ART <= 30 Days | HIV RNA Viral Load | One year on ART | 1.6 Log10 HIV RNA copies/mL |
| EDDI-to-ART <= 30 Days | HIV RNA Viral Load | Four years on ART | 1.6 Log10 HIV RNA copies/mL |
| EDDI-to-ART 31-90 Days | HIV RNA Viral Load | Two years on ART | 1.6 Log10 HIV RNA copies/mL |
| EDDI-to-ART 31-90 Days | HIV RNA Viral Load | At ART Initiation | 5.42 Log10 HIV RNA copies/mL |
| EDDI-to-ART 31-90 Days | HIV RNA Viral Load | One year on ART | 1.6 Log10 HIV RNA copies/mL |
| EDDI-to-ART 31-90 Days | HIV RNA Viral Load | Three years on ART | 1.6 Log10 HIV RNA copies/mL |
| EDDI-to-ART 31-90 Days | HIV RNA Viral Load | Four years on ART | 1.6 Log10 HIV RNA copies/mL |
| EDDI-to-ART >90 Days | HIV RNA Viral Load | Four years on ART | 1.6 Log10 HIV RNA copies/mL |
| EDDI-to-ART >90 Days | HIV RNA Viral Load | Three years on ART | 1.6 Log10 HIV RNA copies/mL |
| EDDI-to-ART >90 Days | HIV RNA Viral Load | At ART Initiation | 4.96 Log10 HIV RNA copies/mL |
| EDDI-to-ART >90 Days | HIV RNA Viral Load | Two years on ART | 1.6 Log10 HIV RNA copies/mL |
| EDDI-to-ART >90 Days | HIV RNA Viral Load | One year on ART | 1.6 Log10 HIV RNA copies/mL |
Primary
Impact of Alcohol Use
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.
Time frame: 4 years from ART initiation
Population: Specimen collection has been completed but the analysis could not be completed due to unforeseen circumstances.
Primary
Levels of Inflammatory Markers
Levels of inflammatory biomarkers measured in plasma by Meso Scale Discovery (MSD) and ELISA assays prior to infection and after viral load suppression.
Time frame: 4 years from ART initiation
Population: Specimen collection has been completed but the analysis could not be completed due to unforeseen circumstances.
Primary
Time to Undetectable HIV Viral Load
Number of days between ART start and Undetectable Viral Load (\<40 copies/mL)
Time frame: 4 years from ART initiation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EDDI-to-ART <= 30 Days | Time to Undetectable HIV Viral Load | 163.5 Days |
| EDDI-to-ART 31-90 Days | Time to Undetectable HIV Viral Load | 110 Days |
| EDDI-to-ART >90 Days | Time to Undetectable HIV Viral Load | 154 Days |
Primary
Two Phase Decay of HIV DNA Reservoir: Integrated HIV DNA
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.
Time frame: 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).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| EDDI-to-ART <= 30 Days | Two Phase Decay of HIV DNA Reservoir: Integrated HIV DNA | Slope 1 | -0.149 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
| EDDI-to-ART <= 30 Days | Two Phase Decay of HIV DNA Reservoir: Integrated HIV DNA | Slope 2 | -0.002 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
| EDDI-to-ART 31-90 Days | Two Phase Decay of HIV DNA Reservoir: Integrated HIV DNA | Slope 2 | -0.001 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
| EDDI-to-ART 31-90 Days | Two Phase Decay of HIV DNA Reservoir: Integrated HIV DNA | Slope 1 | -0.049 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
| EDDI-to-ART >90 Days | Two Phase Decay of HIV DNA Reservoir: Integrated HIV DNA | Slope 1 | -0.014 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
| EDDI-to-ART >90 Days | Two Phase Decay of HIV DNA Reservoir: Integrated HIV DNA | Slope 2 | -0.001 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
Comparison: The decay in integrated HIV DNA was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for integrated HIV DNA.p-value: <0.0001Tukey's Honest Significant Difference (H
Comparison: The decay in integrated HIV DNA was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for integrated HIV DNA.p-value: <0.0001Tukey's Honest Significant Difference (H
Comparison: The decay in integrated HIV DNA was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for integrated HIV DNA.p-value: <0.0001Tukey's Honest Significant Difference (H
Comparison: The decay in integrated HIV DNA was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for integrated HIV DNA.p-value: >0.05Tukey's Honest Significant Difference (H
Comparison: The decay in integrated HIV DNA was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for integrated HIV DNA.p-value: >0.05Tukey's Honest Significant Difference (H
Comparison: The decay in integrated HIV DNA was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for integrated HIV DNA.p-value: >0.05Tukey's Honest Significant Difference (H
Primary
Two Phase Decay of HIV DNA Reservoir: TILDA Stimulation
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.
Time frame: 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).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| EDDI-to-ART <= 30 Days | Two Phase Decay of HIV DNA Reservoir: TILDA Stimulation | Slope 1 | -0.266 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
| EDDI-to-ART <= 30 Days | Two Phase Decay of HIV DNA Reservoir: TILDA Stimulation | Slope 2 | -0.002 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
| EDDI-to-ART 31-90 Days | Two Phase Decay of HIV DNA Reservoir: TILDA Stimulation | Slope 1 | -0.170 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
| EDDI-to-ART 31-90 Days | Two Phase Decay of HIV DNA Reservoir: TILDA Stimulation | Slope 2 | -0.001 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
| EDDI-to-ART >90 Days | Two Phase Decay of HIV DNA Reservoir: TILDA Stimulation | Slope 1 | -0.143 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
| EDDI-to-ART >90 Days | Two Phase Decay of HIV DNA Reservoir: TILDA Stimulation | Slope 2 | 0.001 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
Comparison: The decay in TILDA stimulation was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for TILDA Stimulation.p-value: 0.01Tukey's Honest Significant Difference (H
Comparison: The decay in TILDA stimulation was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for TILDA Stimulation.p-value: <0.0001Tukey's Honest Significant Difference (H
Comparison: The decay in TILDA stimulation was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for TILDA Stimulation.p-value: >0.05Tukey's Honest Significant Difference (H
Comparison: The decay in TILDA stimulation was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for TILDA Stimulation.p-value: >0.05Tukey's Honest Significant Difference (H
Comparison: The decay in TILDA stimulation was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for TILDA Stimulation.p-value: 0.052Tukey's Honest Significant Difference (H
Comparison: The decay in TILDA stimulation was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for TILDA Stimulation.p-value: >0.05Tukey's Honest Significant Difference (H
Primary
Two Phase Decay of HIV DNA Reservoir: Total HIV DNA
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.
Time frame: 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).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| EDDI-to-ART <= 30 Days | Two Phase Decay of HIV DNA Reservoir: Total HIV DNA | Slope 1 | -0.145 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
| EDDI-to-ART <= 30 Days | Two Phase Decay of HIV DNA Reservoir: Total HIV DNA | Slope 2 | -0.006 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
| EDDI-to-ART 31-90 Days | Two Phase Decay of HIV DNA Reservoir: Total HIV DNA | Slope 1 | -0.058 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
| EDDI-to-ART 31-90 Days | Two Phase Decay of HIV DNA Reservoir: Total HIV DNA | Slope 2 | -0.004 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
| EDDI-to-ART >90 Days | Two Phase Decay of HIV DNA Reservoir: Total HIV DNA | Slope 1 | -0.018 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
| EDDI-to-ART >90 Days | Two Phase Decay of HIV DNA Reservoir: Total HIV DNA | Slope 2 | -0.001 Log10 HIV DNA copies/10^6 CD4 T cells/WK |
Comparison: The decay in total HIV DNA was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for Total HIV DNA.p-value: <0.0001Tukey's Honest Significant Difference (H
Comparison: The decay in total HIV DNA was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for Total HIV DNA.p-value: <0.0001Tukey's Honest Significant Difference (H
Comparison: The decay in total HIV DNA was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for Total HIV DNA.p-value: <0.0001Tukey's Honest Significant Difference (H
Comparison: The decay in total HIV DNA was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for Total HIV DNA.p-value: <0.0001Tukey's Honest Significant Difference (H
Comparison: The decay in total HIV DNA was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for Total HIV DNA.p-value: <0.0001Tukey's Honest Significant Difference (H
Comparison: The decay in total HIV DNA was modeled from the time of ART initiation in each of the three EDDI groups until the end of follow-up. The decay was analyzed on the log10 scale with a mixed-effects model to account for correlation between measurements from the same individual. We used a piecewise linear function to model the decay, where the number of linear segments was fixed at 2 (two-phase segmentation model) for Total HIV DNA.p-value: <0.0001Tukey's Honest Significant Difference (H