Date of Award

January 2020

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Serena Spudich

Abstract

Introduction: Up to 30% of individuals treated with antiretroviral therapy (ART) during chronic HIV fail to recover CD4 counts to >500 cells/mm3 and up to 10% have quantifiable HIV RNA in cerebrospinal fluid (CSF), termed CSF escape, despite plasma viral suppression < 50 copies/mL. Previous studies have shown that ART initiation in the earliest stage of identifiable infection, acute HIV infection (prior to antibody seroconversion), may limit viral reservoir establishment and systemic immune activation and may improve clinical outcomes. We investigated the frequency, associations, and outcomes of suboptimal CD4 recovery (Project 1) and CSF escape (Project 2) after ART started during acute HIV infection (AHI).

Methods: Thai participants with laboratory-confirmed diagnosis of AHI (Fiebig stages I to V) were started immediately on ART and followed longitudinally with blood sampling, neuropsychological and neurobehavioral testing, and optional lumbar puncture. For Project 1, participants with ≥48 weeks of documented HIV RNA <50 copies/mL were stratified by CD4 count at latest study visit to suboptimal recovery (SR; CD4<350 cells/mm3), intermediate recovery (IR; 350≤CD4<500), and complete recovery (CR; CD4≥500). To assess determinants of CD4 recovery, clinical and laboratory parameters were evaluated at pre-ART baseline and latest study visit. Additional inflammatory and neurobehavioral endpoints were examined at baseline and 96 weeks. For Project 2, participants who underwent blood sampling and optional CSF sampling at weeks 24 and 96 were assessed for CSF escape. HIV RNA was quantified using Roche Amplicor and COBAS TaqMan assays with a lower limit of quantitation of 20-50 copies/mL in plasma and 80 copies/mL in CSF. Participants with quantifiable CSF HIV RNA greater than that in plasma during ART were identified as cases of CSF escape.

Results, Project 1: Of 304 participants (96% male, median 26 years old) evaluated after median 144 (range 60-420) weeks of ART initiated at median 19 days (range 1-62) post-exposure, 3.6% (n=11) had SR, 14.5% (n=44) had IR, and 81.9% (n=249) had CR. Degree of CD4 recovery occurred early following ART. Timing of ART initiation by Fiebig stage did not affect CD4 count during treatment. Pre-ART CD4 count in SR compared to CR participants was 265 vs 411 cells/mm3 (p=0.002). Following ART, the CD8+ T cell count (p=0.001) and CD4/CD8 ratio (p=0.047) were lower in SR compared to CR participants. Compared to the CR group at week 96, the combined SR and IR groups had higher sCD14 (p=0.008) and lower IL-6 (p=0.04) in plasma, without differences in neuropsychological or psychiatric indices. After adjusting for duration of ART, baseline HIV-RNA, and baseline CD4 count, odds of CD4 recovery < 500 cells/mm3 were higher in those with baseline CD4/CD8 ratio < 1 (odds ratio 3.2, p=0.01), on-ART CD4/CD8 ratio < 1 (odds ratio 2.4, p=0.007), and on-ART CD8 count < 500 cells/mm3 (odds ratio 3.1, p=0.0005).

Results, Project 2: 204 participants had paired blood and CSF sampling in at least one visit at baseline, week 24, or week 96. The participants were 98% male (199/204) with median age 26 years and baseline Fiebig stage 3 (96/204, 47%), CD4 count 386 cells/mm3, and plasma HIV RNA 5.87 log10 copies/mL. ART was started at a median of 19 days post estimated infection. At baseline, 126/165 participants (76%) had quantifiable CSF HIV RNA (median 3.13 log10 copies/mL). At week 24 (n=90), two participants (2%) had quantifiable CSF HIV RNA, with one case of CSF escape identified with plasma HIV RNA < 50 copies/mL and CSF HIV RNA 2.50 log10 copies/mL. At week 96 (n=55), one participant (2%) had quantifiable CSF HIV RNA, which did not meet criteria for CSF escape. The two other cases of quantifiable CSF HIV RNA were due to plasma HIV RNA > CSF HIV RNA. The participant with CSF escape was treated with efavirenz, tenofovir, and lamivudine and had a CD4 count of 840 cells/mm3 and CSF WBC and CSF protein of 4 cells/mm3 and 30 mg/dL. His MRI at week 24 showed a small nonspecific T2/FLAIR hyperintense focus in the right high frontal white matter. He did not have a lumbar puncture performed at baseline nor at subsequent visits.

Conclusions: Despite immediate and sustained treatment in AHI, suboptimal CD4 recovery is observed in rare individuals, associated with low pre-ART CD4 count as well as persistent low CD8 count and CD4/CD8 ratio during treatment. While levels of CSF HIV RNA in untreated AHI are high, initiating treatment during AHI results in a very low rate of CSF escape in the first two years of ART. The low rate of CSF escape may also be impacted by high levels of adherence to ART in this cohort or the short duration of ART. Longitudinal monitoring will be required to verify if CSF escape remains rare under long-term ART in early treated individuals.

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