HIV InfectionMERLINNCT02744040
Modulating the Impact of Critical Events in Early HIV Infection: Effect of ART Initiation and Alcohol Use
A study testing ART initiation at time of HIV diagnosis and ART at 24 weeks in people with HIV Infection, run by Fred Hutchinson Cancer Center at 1 site in Peru.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older, men onlyHealthy volunteers can take part
- Conditions the study is for
- HIV Infection
- What is being tested?
- ART initiation at time of HIV diagnosis and ART at 24 weeks
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 151 participants
- Where
- 1 sitePeru
- Study dates
- 28 Aug 2017to 30 Nov 2020
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Men only
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- counter-indication for use of study antiretroviral drugs
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the 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.
- Conditions
- HIV Infection
- Being tested
- ART initiation at time of HIV diagnosis, ART at 24 weeks
- Keywords
- HIV reservoir, alcohol, ART
- Medical subject headings
- HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ART initiation at time of HIV diagnosisDrug
Also called Early ART initiation
Immediate ART initiation
ART at 24 weeksDrug
Also called Deferred ART initiation
ART initiation 24 weeks after enrollment
| Study group | Role | What they receive |
|---|---|---|
| Early ART initiation | Other | Immediate ART initiation at the time of HIV diagnosis; daily dose of combination ART (one pill/day) Receives: Drug: ART initiation at time of HIV diagnosis |
| Deferred ART initiation | Other | ART initiation at 24 weeks after HIV diagnosis; daily dose of combination ART (one pill/day) Receives: Drug: ART at 24 weeks |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Baseline
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.
Measured: 4 years from ART initiation
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).
Measured: Baseline
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.
Measured: 4 years from ART initiation
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.
Measured: Baseline
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.
Measured: 4 years from ART initiation
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.
Measured: 4 years from ART initiation
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.
Measured: 4 years from ART initiation
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.
Measured: 4 years from ART initiation
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.
Measured: 4 years from ART initiation
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).
Measured: 4 years from ART initiation
CD4 Count
CD4 counts were measured by flow cytometry at multiple timepoints in all participants.
Measured: 4 years from ART initiation
Time to Undetectable HIV Viral Load
Number of days between ART start and Undetectable Viral Load (<40 copies/mL)
Measured: 4 years from ART initiation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Apr 2016 (estimated)
- Study start28 Aug 2017
- Primary completion30 Nov 2020
- Study completion30 Nov 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionStudies of the same condition, open and under way.
- More trials run by Fred Hutchinson Cancer CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 151 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fred Hutchinson Cancer Center
- Sponsor type
- University, hospital or other
- Collaborators
- 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)
- Responsible party
- Principal investigator, Ann C Duerr, Fred Hutchinson Cancer Center
- Investigators
- Ann Duerr, Principal investigator, Fred Hutchinson Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02744040
- Sponsor's protocol ID
- R01DA040532-01
- Other IDs
- 8544, RG1001540, R01DA040532-01
- Acronym
- MERLIN
- Status last verified
- Mar 2022
- First submitted
- 8 Apr 2016
- Last updated
- 29 Mar 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Massanella M, Ignacio RAB, Lama JR, Pagliuzza A, Dasgupta S, Alfaro R, Rios J, Ganoza C, Pinto-Santini D, Gilada T, Duerr A, Chomont N. Long-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical study. Lancet Microbe. 2021 May;2(5):e198-e209. doi: 10.1016/s2666-5247(21)00010-0. Epub 2021 Mar 23.
PubMed 34841369
Study at a glance
From the registry record, last updated by the sponsor on 29 Mar 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Modulating the Impact of Critical Events in Early HIV Infection: Effect of ART Initiation and Alcohol Use
- ClinicalTrials.gov ID
- NCT02744040
- Acronym / sponsor ID
- MERLIN / R01DA040532-01
- Conditions
- HIV Infection
- Keywords
- HIV reservoir, alcohol, ART
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 151 participants (actual)
- Lead sponsor
- Fred Hutchinson Cancer CenterUniversity, hospital or other
- Collaborators
- 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)
- Study start
- 28 Aug 2017 (actual)
- Primary completion
- 30 Nov 2020 (actual)
- Study completion
- 30 Nov 2020 (actual)
- First posted
- 20 Apr 2016 (estimated)
- Results
- Posted 29 Mar 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Early ART initiation | Other | Drug: ART initiation at time of HIV diagnosisImmediate ART initiation at the time of HIV diagnosis; daily dose of combination ART (one pill/day) |
| Deferred ART initiation | Other | Drug: ART at 24 weeksART initiation at 24 weeks after HIV diagnosis; daily dose of combination ART (one pill/day) |
Who may qualify
- Ages
- 18 years and older
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- 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
Key exclusion criteria (1 listed)
- counter-indication for use of study antiretroviral drugs
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ART initiation at time of HIV diagnosisAlso: Early ART initiationImmediate ART initiation | Drug | Early ART initiation |
| ART at 24 weeksAlso: Deferred ART initiationART initiation 24 weeks after enrollment | Drug | Deferred ART initiation |
Primary outcome
Baseline HIV DNA Reservoir: Total HIV DNA
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 4 years from ART initiation
CD4 counts were measured by flow cytometry at multiple timepoints in all participants.
Time to Undetectable HIV Viral Load
Time frame: 4 years from ART initiation
Number of days between ART start and Undetectable Viral Load (<40 copies/mL)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Mar 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 34841369Massanella M, Ignacio RAB, Lama JR, Pagliuzza A, Dasgupta S, Alfaro R, Rios J, Ganoza C, Pinto-Santini D, Gilada T, Duerr A, Chomont N. Long-term effects of early antiretroviral initiation on HIV reservoir markers: a longitudinal analysis of the MERLIN clinical study. Lancet Microbe. 2021 May;2(5):e198-e209. doi: 10.1016/s2666-5247(21)00010-0. Epub 2021 Mar 23.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ann Duerr principal investigator
Fred Hutchinson Cancer Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing ART initiation at time of HIV diagnosis and ART at 24 weeks in people with HIV Infection, run by Fred Hutchinson Cancer Center at 1 site in Peru.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Mar 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Peru. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 29 Mar 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Baseline HIV DNA Reservoir: Total HIV DNA (time frame: Baseline). The study lists 13 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02744040, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Mar 2022.