CSF HIV Research Articles

Asymptomatic Cerebrospinal Fluid HIV-1 Escape: Incidence and Consequences.

The incidence and clinical relevance of asymptomatic cerebrospinal fluid escape (CSF-E) during antiretroviral therapy (ART) is uncertain. We examined the impact and incidence of asymptomatic CSF-E in a Swedish HIV cohort. Neuroasymptomatic people living with HIV (PLWH) who have been on ART for at least six months with suppressed plasma viral load were followed longitudinally. CSF-E was defined as either increased CSF HIV-1 RNA with concurrent plasma suppression or as CSF HIV-1 RNA exceeding that in plasma when both were quantifiable. Paired CSF and plasma were analyzed for HIV-1 RNA, neopterin, neurofilament light protein (NfL), white blood cell (WBC) count, and albumin ratio. Asymptomatic CSF-E (cut-off 50 copies/mL) was found in 4/173 PLWH (2%) and 5/449 samples (1%). The corresponding proportions were 8% of PLWH and 4% for samples using a 20 copies/mL cut-off for CSF HIV-1 RNA. CSF-E samples (cut-off 20 copies/mL) had a 25% higher geometric mean of CSF neopterin (P = .01) and 8% higher albumin ratio (P = .04) compared to samples without CSF-E. No differences were observed in CSF NfL levels (P = .8). The odds ratio for increased CSF WBC (≥ 3 cells/μL) in samples with CSF-E was 3.9 (P = .004), compared to samples without elevated CSF viral load. Asymptomatic CSF-E was identified in only four (2%) PLWH, with no cases of continuous CSF-E observed. Increased CSF HIV-1 RNA was associated with biomarkers of CNS immune activation and blood-brain-barrier impairment, but not with biomarkers of neuronal injury.

Relapse of neurosymptomatic cerebrospinal fluid HIV RNA escape.

Our objectives were to investigate the characteristics of people living with HIV who presented with new or recurrent symptoms in the context of re-emergence of cerebrospinal fluid HIV RNA escape after antiretroviral therapy (ART) modification (termed relapse of CSF HIV RNA escape). People living with HIV-1 with known CSF HIV RNA escape were identified, with clinical and laboratory data obtained from records in a tertiary centre. CSF HIV RNA escape was defined as quantifiable CSF HIV RNA in the presence of unquantifiable plasma HIV-RNA or CSF HIV RNA greater than plasma HIV RNA in cases where plasma HIV-RNA was quantifiable. Relapse was defined as a re-emergence of CSF HIV RNA escape with new symptoms after ART therapy intensification post-initial CSF HIV RNA escape. Among 40 people living with HIV who presented with neurosymptomatic CSF HIV RNA, eight (20%) presented with a relapse of CSF HIV RNA escape. Symptoms on relapse included confusion (n = 2), cognitive decline (n = 2), cerebellar dysfunction (n = 2) and worsening of pre-existing seizures (n = 1). Prior to their relapse, three people underwent drug therapy modification, with two people stopping raltegravir intensification, and one person switched from tenofovir alafenamide, emtricitabine and raltegravir for a new regimen. People with a relapse of CSF HIV RNA escape within this cohort presented with varied symptoms similar to their initial CSF HIV RNA escape. Clinicians should be vigilant of relapse of symptoms, particularly when simplifying ART regimens in people with CSF HIV RNA escape.

Genetic characterization of varicella-zoster and HIV-1 viruses from the cerebrospinal fluid of a co-infected encephalitic patient, Ghana

BackgroundEncephalitis is a serious disease of the brain characterized by prodromal and specific neurological symptoms. HIV infections offer opportunistic viruses, such as Varicella-zoster virus (VZV), the chance to cause encephalitis in patients. There is a lack of information on the genetic diversity of VZV in Ghana and other parts of Africa which requires sequencing and characterization studies to address. The active evolution of HIV-1 in West Africa also requires continuous surveillance for the emergence of new genetic forms.Case presentationVZV was detected in the CSF sample of an 11-year-old patient presenting with symptoms of encephalitis by real-time PCR diagnostics. To identify possible unknown aetiological pathogens, next-generation sequencing was performed, and revealed an HIV-1 co-infection.Alignments of concatenated HIV-1 genome fragments in the gag, pol, vif, env and nef regions and a near-complete VZV genome were analyzed by Bayesian inference, and phylogenetic trees were generated. The VZV sequence belongs to clade 5 and the HIV-1 sequence is a member of the CRF02_AG predominant circulating recombinant form in Ghana.ConclusionsDiagnostic tests for CSF HIV would be useful where possible in patients presenting with encephalitis due to VZV and other opportunistic viruses in Kumasi to shed light on the role of HIV in encephalitis cases in Ghana. This report reaffirms the role of the CRF02_AG circulating recombinant form in HIV infections in Ghana and also gives a preliminary genetic characterization of VZV in Kumasi, Ghana.

IgG intrathecal synthesis in HIV-associated neurocognitive disorder (HAND) according to the HIV-1 subtypes and pattern of HIV RNA in CNS and plasma compartments

We hypothesized that humoral immunity stimulation in the CNS in HIV-1C patients would be lower than that in HIV-1B due to a defective Tat chemokine dimotif (C30C31) that might influence cellular trafficking and CNS inflammation. Sixty-eight paired CSF and blood samples from people with HIV (PWH), free of CNS opportunistic infections, were included, HIV-1B (n = 27), HIV-1C (n = 26), and HIV negative (n = 25). IgG intrathecal synthesis was assayed using quantitative and qualitative methods. IgG oligoclonal bands (OCB) in CSF were observed in 51% of PWH, comparable between HIV-1B and HIV-1C, as well as the medians of IgG intrathecal synthesis formulas. The group with HIV infection aviremic in CSF and blood showed 75% of OCB. There was a poor positive correlation between the IgG quotient and GDS. The impact of HIV-1 on IgG intrathecal production was not subtype dependent. Low-grade CNS intrathecal IgG production persists in HIV CNS infection even in PWH with CSF and blood HIV RNA controlled.

Cerebrospinal fluid CXCL10 is associated with the presence of low level CSF HIV during suppressive antiretroviral therapy

Surrogate markers of HIV central nervous system (CNS) persistence are needed because direct HIV measurements from the CNS require specialized protocols and are not always detectable or quantifiable. We analyzed paired plasma and CSF samples from people with HIV (PWH) on suppressive therapy (ART) with a validated HIV single copy RNA assay. Two potential markers of CNS persistence were measured (CXCL10 and sCD30). We then examined associations with CSF HIV RNA positivity in univariable and multivariable analyses. Among 66 individuals, 18.2% had detectable CSF HIV. Individuals who had detectable HIV in CSF had higher CSF CXCL10 concentrations (median 514 pg/ml versus median 317 pg/ml, p = 0.019), but did not have significantly different CSF sCD30 concentrations (median 7.5 ng/ml versus median 7.6 ng/ml, p = 0.78). In the multiple logistic analysis, both higher CSF CXCL10 (p = 0.038) and plasma HIV detectability (p = 0.035) were significantly associated with detectable CSF HIV. Both sCD30 and CXCL10 correlated positively with NfL and NSE, two neuronal markers. This study demonstrates that CSF CXCL10 concentrations reflect low level HIV CNS persistence despite virologic suppression on ART. Given that it is readily detectable and quantifiable, this chemokine may be a promising biomarker to evaluate HIV eradication therapies that target the CNS.

Minimal detection of cerebrospinal fluid escape after initiation of antiretroviral therapy in acute HIV-1 infection.

Despite suppression of HIV-1 replication in the periphery by antiretroviral therapy (ART), up to 10% of treated individuals have quantifiable HIV-1 in the CSF, termed CSF escape. CSF escape may be asymptomatic but has also been linked to progressive neurological disease, and may indicate persistence of HIV in the central nervous system (CNS). CSF escape has not yet been assessed after initiation of ART during acute HIV-1 infection (AHI). Prospective cohort study. Major voluntary counseling and testing site in Bangkok, Thailand. Participants identified and initiated on ART during AHI who received an optional study lumbar puncture at pre-ART baseline or after 24 or 96 weeks of ART. Paired levels of CSF and plasma HIV-1 RNA, with CSF greater than plasma HIV-1 RNA defined as CSF escape. Two hundred and four participants had paired blood and CSF sampling in at least one visit at baseline, week 24, or week 96. Twenty-nine participants had CSF sampling at all three visits. CSF escape was detected in 1/90 at week 24 (CSF HIV-1 RNA 2.50 log10 copies/ml, plasma HIV-1 RNA <50 copies/ml), and 0/55 at week 96. Although levels of CSF HIV-1 RNA in untreated AHI are high, initiating treatment during AHI results in a very low rate of CSF escape in the first 2 years of treatment. Early treatment may improve control of HIV-1 within the CNS compared with treatment during chronic infection, which may have implications for long-term neurological outcomes and CNS HIV-1 persistence.

CD8 encephalitis with CSF EBV viraemia and HIV drug resistance, a case series

IntroductionCD8 encephalitis is a relatively recently described condition in the setting of HIV infection. It is becoming increasingly recognised in recent years though is still likely underdiagnosed. MethodsWe present three cases of encephalitis in HIV-positive black African females initially presenting with neurological pathology. Two cases concern recent presentations of patients attending HIV services at a large tertiary referral hospital and the third case involves a retrospective analysis of an archived case. Results and discussionMRI brain demonstrated periventricular white matter changes in 2 cases and a cerebellar lesion in the third case. CSF examination revealed lymphocytosis and elevated protein levels. CSF HIV viral load analysis showed viral escape along with new antiretroviral drug resistance mutations. CSF flow cytometry studies demonstrated a reversed CD4:CD8 ratio with a high CD8+ cells percentage. All patients had EBV DNA detected in their CSF. Brain biopsy in two patients confirmed CD8 encephalitis and also revealed isolated cells demonstrating EBV positivity by in-situ hybridization using EBER (Epstein–Barr virus-encoded small RNAs). Treatment with steroids and ART optimisation led to significant clinical and radiological improvements in all cases. DiscussionCD8 encephalitis should be considered as a cause of neurological symptoms and confusion in the HIV-positive patient, particularly if poor ART adherence or viral resistance are suspected. Brain biopsy should be considered in HIV-positive patients with encephalopathy of uncertain cause. Early treatment with high-dose corticosteroids when suspecting this diagnosis is essential for a favourable outcome. The prognosis is variable but can be favourable even following severe encephalopathy. The presence of new INSTI mutations in the CSF but absent peripherally in two INSTI-era patients is a novel finding for this case series in the context of CD8 encephalitis. The role played by EBV in this disease remains unclear and warrants further investigation.

Distinct cellular immune properties in cerebrospinal fluid are associated with cognition in HIV-infected individuals initiating antiretroviral therapy

We examined the relationship between CSF immune cells and neurocognition and neuronal damage in HIV+ individuals before and after initiating antiretroviral therapy. Multivariate analysis at baseline indicated that greater CD4+ T cell abundance was associated with better cognition (p = .017), while higher CSF HIV RNA was associated with increased neuronal damage (p = .014). Following 24 weeks of antiretroviral therapy, CD8+ T cells, HLA-DR expressing CD4+ and CD8+ T cells, B cells, NK cells, and non-classical monocyte percentage decreased in CSF. Female gender was negatively associated with cognitive performance over time, as was higher percentage of HLA-DR expressing CD8+ T cells at baseline.

Conserved CSF HIV Antibody Response in Central Nervous System Escape (1647)

Conserved CSF HIV Antibody Response in Central Nervous System Escape (1647)

Brain MRI Features of CSF Human Immunodeficiency Virus Escape.

HIV infection of the central nervous system (CNS) is a nearly universal feature of untreated systemic HIV infection. While combination antiretroviral therapy (ART) that suppresses systemic infection usually suppresses CNS (CNS) HIV infection, exceptions have been reported with discordance between CSF and blood HIV RNA concentrations such that CSF demonstrates higher HIV concentrations than blood, referred to as CSF HIV escape. Rarely, CSF HIV escape presents with neurological symptoms, called neurosymptomatic escape. In this report, we describe the MRI findings in 6 patients with neurosymptomatic escape who were identified at our institution. MR imaging suggests an encephalitis possibly evolving from a distinct HIV subpopulation within the CNS. A major difference between primary HIV infection and the current case series is that untreated HIV encephalitis usually occurs in the setting of late disease and a low CD4 whereas CSF Escape develops in setting of a higher CD4, as well as more robust immune and inflammatory responses. Our findings show a burden and distribution of white matter signal abnormalities atypical for patients adherent to ART and that differs from that seen in untreated HIV encephalitis and leukoencephalopathy. Moreover, these patients may also demonstrate perivascular enhancement, a finding not previously reported in the CSF HIV escape literature. Recognition of these imaging characteristics-patchy subcortical white matter intensities and a perivascular pattern of enhancement-may be helpful in recognition and, along with other clinical information and CSF findings, in diagnosis of neurosymptomatic escape.

Antiretroviral-treated HIV-1 patients can harbour resistant viruses in CSF despite an undetectable viral load in plasma.

HIV therapy reduces the CSF HIV RNA viral load (VL) and prevents disorders related to HIV encephalitis. However, these brain disorders may persist in some cases. A large population of antiretroviral-treated patients who had a VL > 1.7 log 10 copies/mL in CSF with detectable or undetectable VL in plasma associated with cognitive impairment was studied, in order to characterize discriminatory factors of these two patient populations. Blood and CSF samples were collected at the time of neurological disorders for 227 patients in 22 centres in France and 1 centre in Switzerland. Genotypic HIV resistance tests were performed on CSF. The genotypic susceptibility score was calculated according to the last Agence Nationale de Recherche sur le Sida et les hépatites virales Action Coordonnée 11 (ANRS AC11) genotype interpretation algorithm. Among the 227 studied patients with VL > 1.7 log 10 copies/mL in CSF, 195 had VL detectable in plasma [median (IQR) HIV RNA was 3.7 (2.7-4.7) log 10 copies/mL] and 32 had discordant VL in plasma (VL < 1.7 log 10 copies/mL). The CSF VL was lower (median 2.8 versus 4.0 log 10 copies/mL; P < 0.001) and the CD4 cell count was higher (median 476 versus 214 cells/mm 3 ; P < 0.001) in the group of patients with VL < 1.7 log 10 copies/mL in plasma compared with patients with plasma VL > 1.7 log 10 copies/mL. Resistance to antiretrovirals was observed in CSF for the two groups of patients. Fourteen percent of this population of patients with cognitive impairment and detectable VL in CSF had well controlled VL in plasma. Thus, it is important to explore CSF HIV (VL and genotype) even if the HIV VL is controlled in plasma because HIV resistance may be observed.

The dopamine-related polymorphisms BDNF, COMT, DRD2, DRD3, and DRD4 are not linked with changes in CSF dopamine levels and frequency of HIV infection.

We showed previously that higher levels in CSF dopamine in HIV patients are associated with the presence of the dopamine transporter (DAT) 10/10-repeat allele which was also detected more frequently in HIV-infected individuals compared to uninfected subjects. In the current study, we investigated further whether other genetic dopamine (DA)-related polymorphisms may be related with changes in CSF DA levels and frequency of HIV infection in HIV-infected subjects. Specifically, we studied genetic polymorphisms of brain-derived neurotrophic factor, catechol-O-methyltransferase, and dopamine receptors DRD2, DRD3, and DRD4 genetic polymorphisms in uninfected and HIV-infected people in two different ethnical groups, a German cohort (Caucasian, 72 individuals with HIV infection and 22 individuals without HIV infection) and a South African cohort (Xhosan, 54 individuals with HIV infection and 19 individuals without HIV infection). We correlated the polymorphisms with CSF DA levels, HIV dementia score, CD4+ T cell counts, and HIV viral load. None of the investigated DA-related polymorphisms was associated with altered CSF DA levels, CD4+ T cell count, viral load, and HIV dementia score. The respective allele frequencies were equally distributed between HIV-infected patients and controls. Our findings do not show any influence of the studied genetic polymorphisms on CSF DA levels and HIV infection. This is in contrast to what we found previously for the DAT 3'UTR VNTR and highlights the specific role of the DAT VNTR in HIV infection and disease.

Blood-brain barrier integrity, intrathecal immunoactivation, and neuronal injury in HIV.

Objective:Although blood–brain barrier (BBB) impairment has been reported in HIV-infected individuals, characterization of this impairment has not been clearly defined.Methods:BBB integrity was measured by CSF/plasma albumin ratio in this cross-sectional study of 631 HIV-infected individuals and 71 controls. We also analyzed CSF and blood HIV RNA and neopterin, CSF leukocyte count, and neurofilament light chain protein (NFL) concentrations. The HIV-infected participants included untreated neuroasymptomatic patients, patients with untreated HIV-associated dementia (HAD), and participants on suppressive antiretroviral treatment (ART).Results:The albumin ratio was significantly increased in patients with HAD compared to all other groups. There were no significant differences between untreated neuroasymptomatic participants, treated participants, and controls. BBB integrity, however, correlated significantly with CSF leukocyte count, CSF HIV RNA, serum and CSF neopterin, and age in untreated neuroasymptomatic participants. In a multiple linear regression analysis, age, CSF neopterin, and CSF leukocyte count stood out as independent predictors of albumin ratio. A significant correlation was found between albumin ratio and CSF NFL in untreated neuroasymptomatic patients and in participants on ART. Albumin ratio, age, and CD4 cell count were confirmed as independent predictors of CSF NFL in multivariable analysis.Conclusions:BBB disruption was mainly found in patients with HAD, where BBB damage correlated with CNS immunoactivation. Albumin ratios also correlated with CSF inflammatory markers and NFL in untreated neuroasymptomatic participants. These findings give support to the association among BBB deterioration, intrathecal immunoactivation, and neuronal injury in untreated neuroasymptomatic HIV-infected individuals.

Peripheral Blood Mononuclear Cells HIV DNA Levels Impact Intermittently on Neurocognition

ObjectivesTo determine the contribution of peripheral blood mononuclear cells’ (PBMCs) HIV DNA levels to HIV-associated dementia (HAD) and non-demented HIV-associated neurocognitive disorders (HAND) in chronically HIV-infected adults with long-term viral suppression on combined antiretroviral treatment (cART).MethodsEighty adults with chronic HIV infection on cART (>97% with plasma and CSF HIV RNA <50 copies/mL) were enrolled into a prospective observational cohort and underwent assessments of neurocognition and pre-morbid cognitive ability at two visits 18 months apart. HIV DNA in PBMCs was measured by real-time PCR at the same time-points.ResultsAt baseline, 46% had non-demented HAND; 7.5% had HAD. Neurocognitive decline occurred in 14% and was more likely in those with HAD (p<.03). Low pre-morbid cognitive ability was uniquely associated with HAD (p<.05). Log10 HIV DNA copies were stable between study visits (2.26 vs. 2.22 per 106 PBMC). Baseline HIV DNA levels were higher in those with lower pre-morbid cognitive ability (p<.04), and higher in those with no ART treatment during HIV infection 1st year (p = .03). Baseline HIV DNA was not associated with overall neurocognition. However, % ln HIV DNA change was associated with decline in semantic fluency in unadjusted and adjusted analyses (p = .01-.03), and motor-coordination (p = .02-.12) to a lesser extent.ConclusionsPBMC HIV DNA plays a role in HAD pathogenesis, and this is moderated by pre-morbid cognitive ability in the context of long-term viral suppression. While the HIV DNA levels in PBMC are not associated with current non-demented HAND, increasing HIV DNA levels were associated with a decline in neurocognitive functions associated with HAND progression.

CSF LPV concentrations and viral load in viral suppressed patients on LPV/r monotherapy given once daily.

Introduction Plasma trough concentrations of lopinavir (LPV) given as LPV/r 800/200 mg once daily (OD) are reduced in comparison with 400/100 mg twice daily (BID). While OD dosage of LPV/r is sufficient to achieve viral suppression in plasma, data about drug penetration and viral suppression in central nervous system (CNS) is needed, mainly if LPVr is used as maintenance monotherapy strategy in selected patients. The objective of this study was to evaluate CSF HIV-1 RNA and CSF LPV concentrations in patients receiving LPV/r monotherapy OD (LPVrMOD).Material and Methods This is a cross-sectional sub-study within a prospective, open-label pilot simplification study to evaluate the efficacy and safety of LPV/rMOD in virologically suppressed patients previously receiving a BID LPV/r monotherapy regimen (LPV/rMBID), the “Kmon study” (NCT01581853). To assess LPV concentrations and HIV-1 RNA in CSF, a lumbar puncture (LP) was performed in a subgroup of patients after at least one month of LPVrMOD treatment. Plasma-paired samples of all patients were also obtained. HIV-1 RNA was determined by real-time PCR (limit of detection 40 copies/mL). Liquid chromatography-tandem mass spectrometry (Tandem labs, NJ) was used to determine CSF and blood plasma LPV concentrations.Results Nine patients were included. Median (range) age was 48 (34–56) years, median CD4 cell count 672 (252–1,408) cells/mL, median nadir CD4 count 125 (35–537) cells/mL and 40% of subjects were HCV-positive. Before starting LPV/rMOD median time on a LPV/r-containing regimen and on LPV/rMBID were 9 (4–11) years and 15 (7–24) months respectively, median time with undetectable HIV viral load was 5 (3–12) years and 2 patients had a previous documented blip. LP was performed a median of 24 (8–36) weeks after starting LPV/rMOD and 24 (11–28) hours after the last LPV/rMOD dose CSF and plasma HIV RNA was 40 copies/mL in all patients. Median LPV CSF concentration was 9.78 (1.93–78.3) ng/mL, median LPV plasma concentration 1,103 (377–16,700) ng/mL and median LPV CSF/plasma ratio 0.3% (0.1–1.2).Conclusions No CSF viral escape was detected and LPV concentrations were above the IC50 for wtHIV-1 (1.9 ng/mL). However, as concentrations were close to IC50 in some patients, a careful clinical follow up of patients receiving this regimen would be advisable. Larger longitudinal studies will be helpful for a better understanding of the CNS antiviral activity of LPVr monotherapy.

Central nervous system penetration-effectiveness rank does not reliably predict neurocognitive impairment in HIV-infected individuals.

IntroductionCentral nervous system (CNS) penetration-effectiveness (CPE) rank was proposed in 2008 as an estimate of penetration of ARV regimen into the CNS, and validated as predictor of CSF HIV-1 replication. Results on predictive role of CPE on neurocognitive and clinical outcome were conflicting.Materials and MethodsRetrospective, cross-sectional analysis of neurocognitive profile in HIV-infected cART-treated patients. All patients underwent neuropsychological (NP) assessment by standardized battery of 14 tests on 5 different domains. People were classified as having NCI if they scored >1 standard deviation (SD) below the normal mean in at least two tests, or >2 SD below in one test. Linear and logistic regression analyses were fitted using as outcome Npz8 and impaired/not impaired respectively.ResultsA total of 660 HIV-infected cART-treated individuals from 2009 to 2014, contributing a total of 1003 tests (mean age 49 (IQR 43–56), male 82%; median current CD4 586/mm3; 18% HCV infected; HIV-RNA <40 cp/mL in 84%). Current ARV regimen was 2NRTIs+1NNRTI 50.3%, 2NRTI+1PI/r in 32.6%, NRTI sparing in 11.1%. Mean CPE of current regimens was 6.6 (95% CI 6.5–6.7). As per test multivariable analysis, higher CPE values were associated to poor NP tasks (Beta=−0,09; 95% CI −0,14 −0,03; p=0.002 at multivariable linear regression). The association between higher CPE and increased NCI risk was confirmed at multivariable logistic regression, with a 1.24-fold risk of NCI occurrence for each point increase of CPE of current regimen at the time of NP testing (see Table 1). In a sensitivity analysis performed only on patients at the first NP test, the association between higher CPE and poor NP tasks and enhanced NCI risk was only marginally confirmed (Beta=−0,05; [−0,12–0,02]; p=0,19; OR 1,13 [0,95–1,34]; p=0.17). Older age, longer time from HIV diagnosis, current CD4 count <350 cell/mm3 and lower education level were all associated to an increased risk of NCI. ConclusionsIn our analysis, higher CPE rank is associated to poorly performing at NP tasking. Even if selection bias could not be excluded due to retrospective cross-sectional design, these results fitted with the direct correlation between high CPE and HIV dementia recently recorded in a large observational database. We think that CPE use to guide ART in patients neurocognitively impaired should be revised.

Cerebrospinal fluid biomarkers in patients with plasma HIV RNA below 20 copies/mL.

IntroductionLow level HIV-1 CSF replication (CsfLLV) is often found even in patients with controlled plasma viraemia. The clinical consequences of such finding are uncertain; however, both symptomatic neurological disturbances and neurocognitive disorders may arise in the context of CSF-escape. Two reports suggested that low level replication in the CSF may be associated with increased CSF neopterine although the impact on other markers of neuroinflammation/damage is currently unknown.Materials and MethodsPatients with neurocognitive disorders, new neurological symptoms or followed in longitudinal studies were included provided that they were on HAART, with last available viral load below 20 copies/mL and without central nervous system (CNS)-involving infections/neoplasms. After brain Magnetic Resonance (MR) CSF HIV RNA (CAP/CTM HIV-1 v2.0) and biomarkers [total tau (t-tau), phosphorylated tau (p-tau), 1–42 Beta amyloid (Beta42), neopterine and S100beta] were measured through validated methods. Data are presented as medians (IQR); non-parametric tests are used for all analysis.Results70 patients [66.7% male, median age 47.8 years (40–56), median BMI 22.2 kg/m2 (20–24)] were enrolled. Current and nadir CD4+ cell count were 379 (219–656) and 116 cell/mm3 (46–225); HIV RNA was undetectable since 19.7 months (9–53). CSF HIV RNA was undetectable in 24 (34.3%), below 20 copies/mL in 26 (37.1%), above 20 copies/mL in 25 patients [35.7%, median 69 copies/mL (41–134]). Median (IQR) CSF biomarkers values were as follows: t-tau 109 pg/mL (<75–161), p-tau 31.6 pg/mL (23.4–35.4), Beta42 818 pg/mL (623–973), neopterine 0.58 ng/mL (0.45–0.87) and S100beta 149 pg/mL (110–186). Patients with CsfLLV did not show significant differences as for demographic, therapeutic, virological, radiological variables. t-tau (134 vs 92.6, p=0.05) and Beta42 (953 vs 675, p=0.007) were higher in patients with CsfLLV. Neopterine levels were directly associated with p-tau (rho=0.42, p=0.01), with CSF HIV RNA (rho=0.24, p=0.06). and inversely with current CD4 cell count (rho=−0.29, p=03).ConclusionsIn patients with controlled HIV viraemia (below 20 copies/mL), CSF total tau, Beta42 and neopterine were higher in patients with detectable HIV RNA. Prospective and adequately powered studies are warranted for evaluating the clinical significance of compartmental viral replication and immune activation.

Prevalence and predictors of blood-brain barrier damage in the HAART era

Blood-brain barrier damage (BBBD) is prevalent in HIV-positive patients and may enhance cell trafficking to the central nervous system. A retrospective analysis in adult HIV-positive patients with no central nervous system disease was conducted in order to estimate the prevalence and risk factors of BBBD (according to cerebrospinal fluid to plasma albumin ratios). One hundred fifty-eight HIV-positive adult patients were included. BBBD impairment and intrathecal IgG synthesis were respectively observed in 45 (28.5 %) and 100 patients (63.3 %). Low CD4 nadir and high CSF HIV RNA were independently associated with both abnormalities. BBBD is common in HIV-positive patients, and its main determinants are advanced immune depression and compartmental viral replication.

Methamphetamine use and neuropsychiatric factors are associated with antiretroviral non-adherence

The present study assesses the impact of methamphetamine (METH) on antiretroviral therapy (ART) adherence among HIV+ persons, as well as examines the contribution of neurocognitive impairment and other neuropsychiatric factors [i.e., major depressive disorder (MDD), antisocial personality disorder (ASPD), and attention deficit disorder (ADHD)] for ART non-adherence. We examined HIV+ persons with DSM-IV-diagnosed lifetime history of METH abuse/dependence (HIV+ /METH+ ; n=67) as compared to HIV+ participants with no history of METH abuse/dependence (HIV+ /METH − ; n=50). Ancillary analyses compared these groups with a small group of HIV+ /METH+ persons with current METH abuse/dependence (HIV+ /CU METH+ ; n=8). Non-adherence was defined as self-report of any skipped ART dose in the last four days. Neurocognitive functioning was assessed with a comprehensive battery, covering seven neuropsychological domains. Lifetime METH diagnosis was associated with higher rates of detectable levels of plasma and CSF HIV RNA. When combing groups (i.e., METH+ and METH– participants), univariate analyses indicated co-occurring ADHD, ASPD, and MDD predicted ART non-adherence (p's < 0.10; not lifetime METH status or neurocognitive impairment). A significant multivariable model including these variables indicated that only MDD uniquely predicted ART non-adherence after controlling for the other variables (p<0.05). Ancillary analyses indicated that current METH users (use within 30 days) were significantly less adherent (50% prevalence of non-adherence) than lifetime METH+ users and HIV+ /METH− participants and that neurocognitive impairment was associated with non-adherence (p's < 0.05). METH use disorders are associated with worse HIV disease outcomes and ART medication non-adherence. Interventions often target substance use behaviors alone to enhance antiretroviral treatment outcomes; however, in addition to targeting substance use behaviors, interventions to improve ART adherence may also need to address coexisting neuropsychiatric factors and cognitive impairment to improve ART medication taking.

HIV-1 group N: travelling beyond Cameroon

On Jan 21, 2011, a 57-year-old man living in France attended our emergency unit with fever, rash, lymphadenopathy, and genital ulceration, 8 days after returning from Togo. He reported sexual contact with a Togolese partner, and HIV primary infection was suspected. Fourth-generation ELISA (ARCHITECT HIV Ag/Ab Combo, Abbott, Chicago, IL) was weakly positive, and HIV-1 western blot (New Lav Blot I, Biorad, Paris, France) showed weak reactivity with the p55 and p24 antigens. On Feb 1, 2011, his HIV-1 RNA load was 4∙2 log10 copies per mL (Cobas TaqMan HIV-1 v2.0 assay, Roche Molecular Systems, Branchburg, NJ, USA). On Feb 9, 2011, he developed facial paralysis. At this time his CD4 cell count was 219 per μL and his plasma and CSF HIV-1 RNA concentrations were 4∙4 log10 and 4∙5 log10 copies per mL, respectively. In keeping with French guidelines on new cases of HIV infection, we undertook resistance genotyping before starting treatment. We were surprised that we could not amplify the reverse transcriptase and protease genes with the ViroSeq HIV-1 genotyping assay (Abbott, Chicago, IL, USA) and the French National Agency for AIDS Research consensus primers, despite the high viral load. This fi nding prompted us to serotype the samples. Clear reactivity against group-N-specifi c antigens was obtained and we therefore did full-length genome sequencing. Phylogenetic analysis confi rmed that the new sequence clustered strictly within available group-N sequences (sequence designated N1.FR.2011, GenBank accession number JN572926). When last seen for followup after 4 weeks of antiretroviral combination therapy with tenofovir, emtricitabine, darunavir/ritonavir, raltegravir, and maraviroc, our patient’s plasma HIV-1 RNA load was below 20 copies per mL and his CD4 cell count was 483 per μL. HIV-1 group N (non-M, non-O) was fi rst identifi ed in 1998 in a Cameroonian woman with AIDS. This highly divergent HIV variant is more closely related to SIV isolated from wild chimpanzees than to HIV-1 groups M (major), O (outlier), and P. Group-N infection has previously been reported only in HIV-infected patients living in Cameroon. More than 12 000 HIVinfected patients living in Cameroon have been tested for group-N infection, but only 12 cases, including two couples infected by the same strains, have been identifi ed. Although our patient was diagnosed in Paris, the infection was probably acquired in Togo, which suggests that group-N viruses are now circulating outside Cameroon. This case of primary HIV-N infection is particularly important because of the severe clinical manifestations and early decline in the CD4 cell count. A fi ve-drug antiretroviral com bination showed good initial effi cacy, but longer-term immunological and virological follow-up is needed. The viral load of this HIV-N infected patient was positive during the primary infection as assessed by the Cobas TaqMan HIV-1 v2.0 assay, but the validity of the quantitative result is uncertain. The viral load was also assessed using the Abbott RealTime HIV-1 assay (Chicago, IL, USA), but was under-quantifi ed by about 1 log10. Whether other commercial assays can quantify these variants remains to be shown. Standard resistance genotyping methods used for group M failed to amplify the group-N virus, as happened with the fi rst case of group-P virus detected in 2009. Discrepancies between the results of HIV viral load assays and molecular tests should alert clinicians and virologists to the possibility of infection by a variant virus, which has important implications for management of the patient. This case of HIV-1 group-N primary infection indicates that this rare group is now circulating outside Cameroon, which emphasises the need for rigorous HIV epidemiological monitoring.