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Background: Patients who start combination antiretroviral therapy (cART) during primary human immunodeficiency virus type 1 (HIV-1) infection show a smaller HIV-1 latent reservoir, less immune activation, and less viral diversity compared to patients who start cART during chronic infection. We conducted a pilot study to determine whether these properties would allow sustained virological suppression after simplification of cART to dolutegravir monotherapy., Methods: EARLY-SIMPLIFIED is a randomized, open-label, noninferiority trial. Patients who started cART <180 days after a documented primary HIV-1 infection and had an HIV-1 RNA <50 copies/mL plasma for at least 48 weeks were randomized (2:1) to monotherapy with dolutegravir 50 mg once daily or to continuation of cART. The primary efficacy endpoint was the proportion of patients with <50 HIV-1 RNA copies/mL on or before week 48; noninferiority margin 10%., Results: Of the 101 patients randomized, 68 were assigned to simplification to dolutegravir monotherapy and 33 to continuation of cART. At week 48 in the per-protocol population, 67/67 (100%) had virological response in the dolutegravir monotherapy group vs 32/32 (100%) in the cART group (difference, 0.00%; 95% confidence interval, -100%, 4.76%). This showed noninferiority of the dolutegravir monotherapy at the prespecified level., Conclusion: In this pilot study consisting of patients who initiated cART during primary HIV-1 infection and had <50 HIV-1 RNA copies/mL for at least 48 weeks, monotherapy with once-daily dolutegravir was noninferior to cART. Our results suggest that future simplification studies should use a stratification according to time of HIV infection and start of first cART., Clinical Trials Registration: NCT02551523., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Cerebrospinal fluid (CSF) viral escape occurs in 4%-20% of human immunodeficiency virus (HIV)-infected adults, yet the impact of antiretroviral therapy (ART) on CSF escape is unclear., Methods: A prospective study of 1063 participants with baseline plasma viral load (VL) ≤400 copies/mL between 2005 and 2016. The odds ratio (OR) for ART regimens (protease inhibitor with nucleoside reverse transcriptase inhibitor [PI + NRTI] vs other ART) and CSF escape was estimated using mixed-effects models., Results: Baseline mean age was 46 years, median plasma VL, and CD4 count were 50 copies/mL, and 424 cells/μL, respectively. During median follow-up of 4.4 years, CSF escape occurred in 77 participants (7.2%). PI + NRTI use was an independent predictor of CSF escape (OR, 3.1; 95% confidence interval, 1.8-5.0) in adjusted analyses and models restricted to plasma VL ≤50 copies/mL (P < .001). Regimens that contained atazanavir (ATV) were a stronger predictor of CSF viral escape than non-ATV PI + NRTI regimens. Plasma and CSF M184V/I combined with thymidine-analog mutations were more frequent in CSF escape vs no escape (23% vs 2.3%). Genotypic susceptibility score-adjusted central nervous system (CNS) penetration-effectiveness (CPE) values were calculated for CSF escape with M184V/I mutations (n = 34). Adjusted CPE values were low (<5) for CSF in 27 (79%), indicating suboptimal CNS drug availability., Conclusions: PI + NRTI regimens are independent predictors of CSF escape in HIV-infected adults. Reduced CNS ART bioavailability may predispose to CSF escape in patients with M184V/I mutations.

New tools are needed to understand human immunodeficiency virus central nervous system involvement. Testing 15 cerebrospinal fluid (CSF) samples for p24 antigen, using a high-sensitivity assay, we found a strong correlation trend between CSF p24 concentration and worse neuropsychological performance.

Background: Individuals infected with human immunodeficiency virus (HIV) who have previously had syphilis may have cognitive impairment. We tested the hypothesis that neurosyphilis causes cognitive impairment in HIV by amplifying HIV-related central nervous system (CNS) inflammation., Methods: HIV-infected participants enrolled in a study of cerebrospinal fluid (CSF) abnormalities in syphilis underwent the mental alternation test (MAT), venipuncture, and lumbar puncture. CSF concentrations of chemokine (C-X-C motif) ligand 10 (CXCL10), chemokine (C-C motif) ligand 2 (CCL2), and neurofilament light (NFL) were determined by commercial assays. The proportion of peripheral blood mononuclear cells (PBMCs) and of CSF white blood cells (WBCs) that were activated monocytes (CD14+CD16+) was determined by flow cytometry. Neurosyphilis was defined as detection of Treponema pallidum 16S RNA in CSF or CSF white blood cells (WBCs) >20/uL or a reactive CSF-Venereal Disease Research Laboratory (VDRL) test; uncomplicated syphilis was defined as undetectable CSF T. pallidum, CSF WBCs ≤5/uL and nonreactive CSF-VDRL. MAT <18 was considered low., Results: Median proportion of PBMCs that were activated monocytes (16.6 vs. 5.3), and median CSF CXCL10 (10658 vs. 2530 units), CCL2 (519 vs. 337 units) and HIV RNA (727 vs. 50 c/mL) were higher in neurosyphilis than in uncomplicated syphilis (P ≤ .001 for all comparisons). Neurosyphilis was not related to low MAT scores. Participants with low MAT scores had higher median CSF CXCL10 (10299 vs. 3650 units, P = .008) and CCL2 (519 vs. 365 units, P = .04) concentrations than those with high MAT scores., Conclusions: Neurosyphilis may augment HIV-associated CNS inflammation, but it does not explain cognitive impairment in HIV-infected individuals with syphilis., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The immunopathogenesis of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) remains incompletely understood, and we know of only 1 disease site-specific study of the underlying immunology; we recently showed that Mycobacterium tuberculosis culture positivity and increased neutrophils in the cerebrospinal fluid (CSF) of patients with tuberculous meningitis (TBM) are associated with TBM-IRIS. In this study we investigated inflammatory mediators at the disease site in patients with TBM-IRIS., Methods: We performed lumbar puncture at 3-5 time points in human immunodeficiency virus (HIV)-infected patients with TBM (n = 34), including at TBM diagnosis, at initiation of antiretroviral therapy (ART) (day 14), 14 days after ART initiation, at presentation of TBM-IRIS, and 14 days thereafter. We determined the concentrations of 40 mediators in CSF (33 paired with blood) with Luminex or enzyme-linked immunosorbent assays. Findings were compared between patients who developed TBM-IRIS (n = 16) and those who did not (TBM-non-IRIS; n = 18)., Results: At TBM diagnosis and 2 weeks after ART initiation, TBM-IRIS was associated with severe, compartmentalized inflammation in the CSF, with elevated concentrations of cytokines, chemokines, neutrophil-associated mediators, and matrix metalloproteinases, compared with TBM-non-IRIS. Patients with TBM-non-IRIS whose CSF cultures were positive for M. tuberculosis at TBM diagnosis (n = 6) showed inflammatory responses similar to those seen in patients with TBM-IRIS at both time points. However, at 2 weeks after ART initiation, S100A8/A9 was significantly increased in patients with TBM-IRIS, compared with patients with TBM-non-IRIS whose cultures were positive at baseline., Conclusions: A high baseline M. tuberculosis antigen load drives an inflammatory response that manifests clinically as TBM-IRIS in most, but not all, patients with TBM. Neutrophils and their mediators, especially S100A8/A9, are closely associated with the central nervous system inflammation that characterizes TBM-IRIS., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Background: Cerebrospinal fluid (CSF) concentrations of multiple drugs in a large human immunodeficiency virus (HIV)-infected patient population, the virtual phenotype profiles for HIV in the plasma and CSF compartments, and the correlation of these profiles with exposure to antiretroviral therapy need to be further investigated., Methods: Drug concentrations in CSF and plasma were concomitantly determined for a large group of HIV-infected individuals receiving highly active antiretroviral therapy (HAART). Samples were analyzed using a validated method consisting of liquid chromatography with mass spectrometry. For patients with detectable levels of virus, genotypic analysis was performed, followed by a virtual phenotype study., Results: Sixty-three HIV-infected patients were included in the study, 78% of whom were affected by neurological disease. Drug concentrations in CSF specimens were undetectable for didanosine, efavirenz, nelfinavir, and concomitantly administered ritonavir and saquinavir. CSF concentrations were higher for nevirapine, with a median CSF-to-plasma concentration ratio of 0.63, followed by lamivudine (0.23), stavudine (0.20), and indinavir (0.11). In 18 of the 40 patients with virtual phenotype data available for virus recovered from CSF samples and from plasma samples, differences in fold-change of resistance between the CSF virus and the plasma virus were noted for at least 1 drug. Factors associated with having differences in fold-change of resistance were number of drugs to which the patient had been exposed (P=.02) and presence of neurological disease (P=.05). A significant association was found between duration of therapy and fold-change of resistance in CSF and plasma isolates., Conclusions: Antiretrovirals have different levels of penetration in the CSF, with several drugs achieving only low CSF concentrations. CSF isolates have different resistance profiles than do plasma isolates. Effective treatment decisions for CSF manifestations of disease may require better knowledge of drug penetration and the drug susceptibility of HIV in the CSF.

To identify factors that affect normalization of laboratory measures after treatment for neurosyphilis, 59 subjects with neurosyphilis underwent repeated lumbar punctures and venipunctures after completion of therapy. The median duration of follow-up was 6.9 months. Stepwise Cox regression models were used to determine the influence of clinical and laboratory features on normalization of cerebrospinal fluid (CSF), white blood cells (WBCs), CSF protein concentration, CSF Venereal Disease Research Laboratory (VDRL) reactivity, and serum rapid plasma reagin (RPR) titer. Human immunodeficiency virus (HIV)-infected subjects were 2.5 times less likely to normalize CSF-VDRL reactivity than were HIV-uninfected subjects. HIV-infected subjects with peripheral blood CD4+ T cell counts of < or =200 cells/ mu L were 3.7 times less likely to normalize CSF-VDRL reactivity than were those with CD4+ T cell counts of >200 cells/ mu L. CSF WBC count and serum RPR reactivity were more likely to normalize but CSF-VDRL reactivity was less likely to normalize with higher baseline values. Future studies should address whether more intensive therapy for neurosyphilis is warranted in HIV-infected individuals.

In 6 patients with primary human immunodeficiency virus type 1 (HIV-1) infection, concentrations of HIV-1 RNA and beta(2)-microglobulin were monitored in cerebrospinal fluid (CSF) and in plasma during antiretroviral therapy. Four patients had neurological symptoms. At baseline, the CSF of 5 patients had detectable levels of HIV-1 RNA (median, 3.68 log(10) copies/mL; range, <2.60-5.67 log(10) copies/mL), and the CSF of 3 patients had elevated levels of beta(2)-microglobulin. After 8 weeks of treatment, the median concentrations of HIV-1 RNA in CSF had decreased to <2.60 log(10) copies/mL (range, <1.60-3.00 log(10) copies/mL; P=.04) and in plasma to 3.07 log(10) copies/mL (range, 2.57-3.79 log(10) copies/mL; P=.03). Median concentration of beta(2)-microglobulin in CSF had decreased to 1.2 mg/L (range, 0.9-1.7 mg/L; P=.06) and, in plasma, to 1.7 mg/L (range, 1.1-2.2 mg/L; P=.03). After 48 weeks, HIV-1 RNA concentrations in 1 patient were still 1.97 log(10) copies/mL in CSF and 1.51 log(10) copies/mL in plasma, although beta(2)-microglobulin concentrations in CSF and plasma had normalized after 8 weeks.

A duplex polymerase chain reaction (PCR) assay for DNA from herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) was applied to cerebrospinal fluid (CSF) from 918 human immunodeficiency virus (HIV)-infected patients with neurological symptoms. HSV-1 or HSV-2 (HSV-1/2) DNA was found in 19 patients (2%). For the 258 patients for whom a diagnosis was confirmed at autopsy, the sensitivity and specificity of PCR analysis for the diagnosis of HSV-1/2 encephalitis were 100% and 99.6%, respectively. Three patients with CD4+ cell counts of > or = 170/microL had HSV-1 central nervous system (CNS) infections (two) or HSV-2 meningitis (one). Sixteen patients with CD4+ cell counts of < 40/microL had HSV-1 CNS infections (two) or mixed HSV-1/2 and cytomegalovirus encephalitis (14). The response to antiviral treatment, which was assessed clinically and by CSF PCR analysis, was variable in the patients with the highest CD4+ cell counts and poor in those with more severe immunosuppression. CSF PCR analysis is of value for the diagnosis and follow-up of treatment of HSV-1/2 CNS infections in HIV-infected patients.