Prevalence and Correlates of Persistent HIV-1 RNA in Cerebrospinal Fluid During Antiretroviral Therapy

Anderson, Albert M.; Muñoz-Moreno, José A.; McClernon, Daniel; Ellis, Ronald J.; Cookson, Debra; Clifford, David B.; Collier, Ann C.; Gelman, Benjamin B.; Marra, Christina M.; McArthur, Justin C.; McCutchan, J. Allen; Morgello, Susan; Sacktor, Ned; Simpson, David M.; Franklin, Donald; Heaton, Robert K.; Grant, Igor; Letendre, Scott

doi:10.1093/infdis/jiw505

Cited by 67 publications

(62 citation statements)

References 49 publications

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“…Though we did find associations between 2 CSF markers of myeloid immune activation (sCD14 and sCD163) and plasma viremia, in this cohort of continuously virally suppressed individuals, viral persistence does not appear to be a main driver of chronic immune activation within compartments, nor is the latter driving viral persistence. Other causes ticipants may be due to a number of factors (24). Given the fact that our cohort was enrolled and followed long-term within ACTG studies with documented viral suppression for numerous visits, it is likely that our cohort was more consistently well-suppressed than the participants in the CHARTER study who were identified by a single plasma HIV RNA less than or equal to 50 copies/mL.…”

Section: Discussionmentioning

confidence: 99%

Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance

Spudich

Robertson

Bosch

et al. 2019

Journal of Clinical Investigation

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BACKGROUND. Persistence of HIV in sanctuary sites despite antiretroviral therapy (ART) presents a barrier to HIV remission and may affect neurocognitive function. We assessed HIV persistence in cerebrospinal fluid (CSF) and associations with inflammation and neurocognitive performance during long-term ART. METHODS. Participants enrolled in the AIDS Clinical Trials Group (ACTG) HIV Reservoirs Cohort Study (A5321) underwent concurrent lumbar puncture, phlebotomy, and neurocognitive assessment. Cell-associated HIV DNA and HIV RNA (CA-DNA, CA-RNA) were measured by quantitative PCR (qPCR). in peripheral blood mononuclear cells (PBMCs) and in cell pellets from CSF. In CSF supernatant and blood plasma, cell-free HIV RNA was quantified by qPCR with single copy sensitivity, and inflammatory biomarkers were measured by enzyme immunoassay. RESULTS. Sixty-nine participants (97% male, median age 50 years, CD4 696 cells/mm 3 , plasma HIV RNA <100 copies/mL) were assessed after a median 8.6 years of ART. In CSF, cell-free RNA was detected in 4%, CA-RNA in 9%, and CA-DNA in 48% of participants (median level 2.1 copies/10 3 cells). Detection of cell-free CSF HIV RNA was associated with higher plasma HIV RNA (P = 0.007). CSF inflammatory biomarkers did not correlate with HIV persistence measures. Detection of CSF CA-DNA HIV was associated with worse neurocognitive outcomes including global deficit score (P = 0.005), even after adjusting for age and nadir CD4 count. CONCLUSION. HIV-infected cells persist in CSF in almost half of individuals on long-term ART, and their detection is associated with poorer neurocognitive performance.

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Section: Discussionmentioning

confidence: 99%

Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance

Spudich

Robertson

Bosch

et al. 2019

Journal of Clinical Investigation

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“…Currently, numerous recent trials have evaluated the use of two‐drug regimens to reduce toxicities, both in treatment‐naïve and in pretreated patients. The benefits of switching to an NRTI‐sparing regimen from E/C/F/TAF must be balanced against potential detriments: disruption of the single‐tablet regimen and increases in the number of pills and drug intake , changes in lipid parameters that may necessitate additional monitoring or treatment, persistence of viral replication in reservoir sites such as the central nervous system (CNS) , and absence of activity against hepatitis B virus (HBV). Only randomized clinical trials can definitively assess safety and efficacy differences between E/C/F/TAF and NRTI‐sparing regimens.…”

Section: Discussionmentioning

confidence: 99%

Comparison of 48‐week efficacies of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide and nucleoside/nucleotide reverse transcriptase inhibitor‐sparing regimens: a systematic review and network meta‐analysis

Gallien

Massetti²,

Flandre

et al. 2018

HIV Medicine

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The NMA results suggest that E/C/F/TAF represents a more effective option than NRTI-sparing regimens in terms of 48-week efficacy in treatment-naïve patients. Furthermore, TAF pharmacological properties, as well as tolerability results in clinical studies, suggest a safety profile similar to that of NRTI-sparing regimens. Thus, the E/C/F/TAF combination might represent a more appropriate option than NRTI-sparing regimens for initiation of antiretroviral therapy in treatment-naïve HIV-infected patients.

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“…In the current study, CSF sMAC was more likely to be detectable in HIV+ individuals compared to HIV negative individuals, even when only including HIV+ individuals on suppressive cART with negative hepatitis and syphilis tests. With recent research demonstrating that CSF HIV RNA is detectable by single copy assay in >40% of individuals on suppressive cART, it is possible that sMAC upregulation could be driven by very low levels of HIV that are not detectable with standard assays (Anderson et al, 2017). Alternatively, systemic sMAC elevation in the setting of HIV could be influenced by microbial gut translocation, which occurs in HIV-infected individuals and appears to be at least in part responsible for the immune activation that occurs despite cART (Brenchley et al, 2006).…”

Section: Discussion With Conclusionmentioning

confidence: 99%

Soluble membrane attack complex in the blood and cerebrospinal fluid of HIV-infected individuals, relationship to HIV RNA, and comparison with HIV negatives

Anderson

Schein

Kalapila

et al. 2017

Journal of Neuroimmunology

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The soluble membrane attack complex (sMAC) represents the terminal product of the complement cascade. We enrolled 47 HIV+ adults (12 of whom underwent a second visit at least 24 weeks after starting therapy) as well as 11 HIV negative controls. At baseline, cerebrospinal fluid (CSF) sMAC was detectable in 27.7% of HIV+ individuals. CSF sMAC correlated with CSF HIV RNA levels and was more likely to be detectable in HIV+ individuals on cART compared to HIV negative controls. In HIV+ participants, there were negative association trends between sMAC and neurocognitive performance but these did not reach statistical significance.

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Prevalence and Correlates of Persistent HIV-1 RNA in Cerebrospinal Fluid During Antiretroviral Therapy

Cited by 67 publications

References 49 publications

Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance

Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance

Comparison of 48‐week efficacies of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide and nucleoside/nucleotide reverse transcriptase inhibitor‐sparing regimens: a systematic review and network meta‐analysis

Soluble membrane attack complex in the blood and cerebrospinal fluid of HIV-infected individuals, relationship to HIV RNA, and comparison with HIV negatives

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