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

NCT02744040 | Completed Results

• 3 other identifiers: R01DA040532-018544RG1001540
• Study Type: interventional
• Target: 151
• Locations: 1 country
• Sites: 1

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.

Conditions

HIV Infection

Keywords

HIV reservoir; alcohol; ART

Outcome Measures

Primary Outcomes (13)

• 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).

  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.

  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).

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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).

  4 years from ART initiation

• CD4 Count

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

  4 years from ART initiation

• Time to Undetectable HIV Viral Load

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

  4 years from ART initiation

Study Arms (2)

Early ART initiation

OTHER

Immediate ART initiation at the time of HIV diagnosis; daily dose of combination ART (one pill/day)

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)

Drug: ART at 24 weeks

Interventions

ART initiation at time of HIV diagnosis DRUG

Immediate ART initiation

Also known as: Early ART initiation

Early ART initiation

ART at 24 weeks DRUG

ART initiation 24 weeks after enrollment

Also known as: Deferred ART initiation

Deferred ART initiation

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• counter-indication for use of study antiretroviral drugs

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• University of California, San Francisco: collaborator
• University of Washington: collaborator
• Asociación Civil Impacta Salud y Educación, Peru: collaborator
• Université de Montréal: collaborator
• Seattle Children's Hospital: collaborator
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (1)

Asociación Civil Impacta Salud y Educación

Lima, Peru

Location

Related Publications (1)

• 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.

  PMID: 34841369 RESULT

MeSH Terms

Conditions

HIV Infections

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Results Point of Contact

• Title: Ann C Duerr, MD, PhD, MPH, Member
• Organization: Fred Hutchinson Cancer Research Center

aduerr@fredhutch.org

206-667-7938

Study Officials

• Ann Duerr

  Fred Hutchinson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Member

Study Record Dates

• First Submitted: April 8, 2016
• First Posted: April 20, 2016
• Study Start: August 28, 2017
• Primary Completion: November 30, 2020
• Study Completion: November 30, 2020
• Last Updated: March 29, 2022
• Results First Posted: March 29, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

PE (1)