Changes in cerebrospinal fluid proteins across the spectrum of untreated and treated chronic HIV-1 infection.

Using the Olink Explore 1536 platform, we measured 1,463 unique proteins in 303 cerebrospinal fluid (CSF) specimens from four clinical centers contributed by uninfected controls and 12 groups of people living with HIV-1 infection representing the spectrum of progressive untreated and treated chronic infection. We present three initial analyses of these measurements: an overview of the CSF protein features of the sample; correlations of the CSF proteins with CSF HIV-1 RNA and neurofilament light chain protein (NfL) concentrations; and comparison of CSF proteins in HIV-associated dementia (HAD) and neurosymptomatic CSF escape (NSE). These reveal a complex but coherent picture of CSF protein changes with highest concentrations of many proteins during CNS injury in the HAD and NSE groups and variable protein changes across the course of systemic HIV-1 progression that included two common patterns, designated as lymphoid and myeloid patterns, related to principal involvement of their underlying inflammatory cell lineages. Antiretroviral therapy reduced CSF protein perturbations, though not always to control levels. The dataset of these CSF protein measurements, along with background clinical information, is posted online. Extended studies of this unique dataset will supplement this report to provide more detailed characterization of the dynamic impact of HIV-1 infection on the CSF proteome across the spectrum of HIV-1 infection, advancing the mechanistic understanding of HIV-1-related CNS pathobiology.

Serum and CSF biomarkers in asymptomatic patients during primary HIV infection: a randomized study.

It is debated whether central nervous system involvement begins during acute HIV infection in persons without meningitis/encephalitis and if specific antiretroviral drugs or combinations would be beneficial. Neurologically asymptomatic participants enrolled in a randomized and controlled study comparing three combination antiretroviral regimens (tenofovir alafenamide/emtricitabine plus dolutegravir, darunavir or both) during primary HIV infection were enrolled. Serum and cerebrospinal fluid (CSF) were collected at baseline, 12 and 48 (serum only) weeks after treatment initiation. Single Molecule Array was used to measure neurofilament light chain (NFL), total tau protein (Tau), Brain-Derived Neurotrophic Factor (BDNF), Glial Fibrillary Acidic Protein (GFAP), Ubiquitin C-terminal Hydrolase (UCH-L1). We assessed the longitudinal change in biomarkers over time as well as the change in the prevalence of serum NFL concentrations above previously published age-adjusted cut-offs (7 pg/mL if 5-18 years, 10 pg/mL if 18-51 years, 15 pg/mL if 51-61 years, 20 pg/mL if 61-70 years and 35 pg/mL if >70 years). Serum was available from 47 participants at all time points while CSF was in 13 and 7 participants (baseline/W12). We observed a significant direct serum-to-CSF correlation for NFL (rho = 0.692, p = 0.009), GFAP (rho = 0.659, p = 0.014) and BDNF (rho = 0.587, p = 0.045). Serum (rho = 0.560, p = 0.046) and CSF NFL (rho = 0.582, p = 0.037) concentrations were directly associated with CSF HIV RNA levels. We observed a significant decrease over time in serum NFL (p = 0.006) and GFAP (p = 0.006) but not in the other biomarkers. No significant difference was observed among the treatment arms. At baseline, serum and CSF age-adjusted NFL levels were above age-adjusted cut-offs in 23 (48.9%) and 4 participants (30.8%); considering serum NFL, this proportion was lower at weeks 12 (31.9%, p = 0.057) and 48 (27.7%, p = 0.13). A relevant proportion of neurologically asymptomatic participants had abnormal CSF and serum NFL levels during primary HIV infection. NFL and GFAP decreased in serum following combination antiretroviral therapy without significant differences among the treatment arms.

Otitis in Patients With Community-Acquired Bacterial Meningitis: A Nationwide Prospective Cohort Study.

BACKGROUND: Otitis is commonly associated with community-acquired bacterial meningitis, but the role of ear surgery as treatment is debated. In this study, we investigated the impact of otitis and ear surgery on outcome of adults with community-acquired bacterial meningitis. METHODS: We analyzed episodes of adults with community-acquired bacterial meningitis from a nationwide prospective cohort study in the Netherlands, between March 2006 and July 2021. RESULTS: A total of 2548 episodes of community-acquired bacterial meningitis were evaluated. Otitis was present in 696 episodes (27%). In these patients the primary causative pathogen was Streptococcus pneumoniae (615 of 696 [88%]), followed by Streptococcus pyogenes (5%) and Haemophilus influenzae (4%). In 519 of 632 otitis episodes (82%) an ear-nose-throat specialist was consulted, and surgery was performed in 287 of 519 (55%). The types of surgery performed were myringotomy with ventilation tube insertion in 110 of 287 episodes (38%), mastoidectomy in 103 of 287 (36%), and myringotomy alone in 74 of 287 (26%). Unfavorable outcome occurred in 210 of 696 episodes (30%) and in 65 of 696 episodes was fatal (9%). Otitis was associated with a favorable outcome in a multivariable analysis (odds ratio 0.74; 95% confidence interval [CI] .59-.92; P = .008). There was no association between outcome and ear surgery. CONCLUSIONS: Otitis is a common focus of infection in community-acquired bacterial meningitis in adults, with S. pneumoniae being the most common causative pathogen. Presence of otitis is associated with a favorable outcome. Ear surgery's impact on the outcome of otogenic meningitis patients remains uncertain.

A Digital Platform for Home-Based Exercise Prescription for Older People with Sarcopenia.

Digital therapeutics refers to smartphone applications, software, and wearable devices that provide digital solutions to improve healthcare delivery. We developed a digital platform to support the GYM (Grow Your Muscle) study, an ongoing 48-week randomized, controlled trial on reduction of sarcopenia through a home-based, app-monitored physical exercise intervention. The GYM platform consists of a smartphone application including the exercise program and video tutorials of body-weight exercises, a wearable device to monitor heart rate during training, and a website for downloading training data to remotely monitor the exercise. The aim of this paper is to describe the platform in detail and to discuss the technical issues emerging during the study and those related to usability of the smartphone application through a retrospective survey. The main technical issue concerned the API level 33 upgrade, which did not enable participants using the Android operating systems to use the wearable device. The survey revealed some problems with viewing the video tutorials and with internet or smartphone connection. On the other hand, the smartphone application was reported to be easy to use and helpful to guide home exercising. Despite the issues encountered during the study, this digital-supported physical exercise intervention could provide useful to improve muscle measures of sarcopenia.

Biotypes of Central Nervous System Complications in People With Human Immunodeficiency Virus: Virology, Immunology, and Neuropathology.

Despite viral suppression with antiretroviral therapy (ART), people with human immunodeficiency virus (HIV) continue to experience central nervous system (CNS) complications, primarily in the form of mild cognitive impairment and mental health disorders (eg, depression, anxiety, other neuropsychiatric problems). The multifactorial pathogenesis and heterogeneity of mechanisms likely underlying CNS complications must be addressed in the development of preventive interventions and effective treatments. The biotyping approach has previously been useful to define phenotypes of other CNS diseases based on underlying mechanisms and could be translated to the field of neuroHIV. The purpose of the Biotype Workshop series, and the Virology, Immunology and Neuropathology Working Group in particular, is to capitalize on current and new technologies and guide future research efforts using the wealth of available immunological, virologic, and neuropathological data collected from people with HIV on and off ART.

Major revision version 12.0 of the European AIDS Clinical Society guidelines 2023.

BACKGROUND: The European AIDS Clinical Society (EACS) guidelines were revised in 2023 for the 19th time, and all aspects of HIV care were updated. KEY POINTS OF THE GUIDELINES UPDATE: Version 12.0 of the guidelines recommend the same six first-line treatment options for antiretroviral treatment (ART)-naïve adults as versions 11.0 and 11.1: tenofovir-based backbone plus an unboosted integrase inhibitor or doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with lamivudine or emtricitabine plus dolutegravir. The long-acting section has been expanded in the ART and drug-drug interaction (DDI) panels. Tables for preferred and alternative ART in children and adolescents have been updated, as has the section on prevention of vertical transmission, particularly with new guidance for breastfeeding. A new DDI table has been included for the ART and anti-infective drugs used for opportunistic infections, sexually transmitted infections, and other infectious conditions; lenacapavir has been included in all DDI tables. New sections on alcohol use and patient-reported outcome measures (PROMs) have been included in the comorbidity panel, in addition to updates on many relevant topics, such as new resource guidance for deprescribing in people with HIV. Other sections, including travel, cognitive impairment, cancer screening, sexual health, and diabetes have also been revised extensively. The algorithm for the management of acute hepatitis C virus infection has been removed, as current guidelines recommend immediate treatment of all people with recently acquired hepatitis C virus. Updates on vaccination for hepatitis B virus and recommendations for simplification to tenofovir-free two-drug regimens in people with isolated anti-hepatitis B core antibodies are provided. In the opportunistic infections and COVID-19 panel, guidance on the management of COVID-19 in people with HIV has been updated according to the most up-to-date evidence, and a new section on monkeypox has been added. CONCLUSIONS: In 2023, the EACS guidelines were updated extensively and now include several new sections. The recommendations are available as a free app, in interactive web format, and as a pdf online.

Outcome of Progressive Multifocal Leukoencephalopathy Treated by Interleukin-7.

OBJECTIVE: Restoring anti-JC virus (JCV) immunity is the only treatment of progressive multifocal leukoencephalopathy (PML). Interleukin-7 is a cytokine that increases number and function of T cells. We analyzed a population of PML patients who received recombinant human IL-7 (rhIL-7) to estimate survival and its determinants. METHODS: After exclusion of patients with missing data or receiving other immunotherapies, findings from 64 patients with proven PML who received rhIL-7 between 2007 and 2020 were retrospectively analyzed. Logistic regression was used to analyze variables associated with one-year survival. RESULTS: Underlying conditions were HIV/AIDS (n = 27, 42%), hematological malignancies (n = 16, 25%), primary immunodeficiencies (n = 13, 20%), solid organ transplantation (n = 4, 6%) and chronic inflammatory diseases (n = 4, 6%). One-year survival was 54.7% and did not differ by underlying condition. Survival was not associated with baseline characteristics, but with a >50% increase in blood lymphocytes (OR 4.1, 95%CI 1.2-14.9) and CD4+ T cells (OR 5.9, 95%CI 1.7-23.3), and a > 1 log copies/mL decrease in cerebrospinal fluid JCV DNA (OR 7.6, 95%CI 1.6-56.1) during the first month after rhIL-7 initiation. Side effects were mainly local and flu-like symptoms (n = 8, 12.5%) and PML-immune reconstitution inflammatory syndrome (IRIS) (n = 5, 8%). INTERPRETATION: In this non-controlled retrospective study, survival did not differ from that expected in HIV/AIDS patients, but might have been improved in those with hematological malignancies, primary immunodeficiencies and transplant recipients. RhIL-7 might have contributed to the increase in blood lymphocytes and decrease in CSF JCV replication that were associated with better survival. ANN NEUROL 2022;91:496-505.

High-dose anakinra in addition to standard of care including corticosteroids in patients with severe COVID-19 treated with non-invasive ventilation.

Management of COVID-19 patients experiencing persisting respiratory failure despite corticosteroids remains challenging. Data on high-dose intravenous anakinra (HD-ANK) in this context are lacking. We aimed to investigate the impact of HD-ANK on mortality in COVID-19 patients progressing to non-invasive ventilation (NIV) while receiving corticosteroids. We retrospectively analyzed the impact of HD-ANK on 28-day mortality in individuals hospitalized with COVID-19 necessitating NIV after corticosteroid initiation. A total of 256 patients were identified: 146 received standard-of-care only (SOC), and 110 received HD-ANK+SOC. The groups were well-balanced at baseline. In-hospital mortality at 28 days did not differ between the two groups. HD-ANK is not beneficial in patients with severe COVID-19 deteriorating despite corticosteroids.

Failure of Digital Device Performance in Monitoring Physical Exercise in a Pilot Study in Sedentary Persons with HIV.

Digital devices have gained popularity in the last 10 years as a tool for exercise prescription, the monitoring of daily physical activity, and nutrition for the management of a health-related parameter. Therefore, the aim of this study was to assess the effectiveness of the use of digital devices to monitor exercise data in sedentary persons with HIV who exercise following an individualized activity pacing (AP) protocol on cardiorespiratory fitness body composition, blood lipid profile, and psychological parameters. Twenty-four PLWH were enrolled in an 18-week randomized, open-label, pilot AP exercise protocol. All participants were monitored by a Health Band connected to a mobile app that transmitted the data to a server. At week 3, they were randomized either in an experimental group (EG), in which an open device configuration enabled them to receive training data feedback (n = 12), or continued with no data feedback (control group, n = 12). The primary endpoint was improvement from the baseline of 15% of steady-state oxygen consumption (V˙O2) during a 6-min walking test. Technical issues occurred when pairing the health band with the app, which prevented EG participants from regularly receiving data feedback, and with data transmission to the server, which enabled only 40% monitoring of the total training days. Consequently, the study outcomes could not be compared between the two groups, and participants also lost confidence in the study. However, 19 out of 24 participants completed the AP program. Overall, only 6 (32%) improved steady-state V˙O2, with no significant changes at W18 from the baseline. Significant reductions were observed of BMI (p = 0.040), hip circumference (p = 0.027), and total-(p = 0.049) and HDL-cholesterol (p = 0.045). The failure of digital device performance substantially affected study procedures, monitoring, and participants' engagement, and likely limited the potential benefits of the AP exercise program.

Cerebrospinal Fluid Viral Load Across the Spectrum of Untreated Human Immunodeficiency Virus Type 1 (HIV-1) Infection: A Cross-Sectional Multicenter Study.

BACKGROUND: The aim of this large multicenter study was to determine variations in cerebrospinal fluid (CSF) HIV-RNA in different phases of untreated human immunodeficiency virus type 1 (HIV-1) infection and its associations with plasma HIV-RNA and other biomarkers. METHODS: Treatment naive adults with available CSF HIV-RNA quantification were included and divided into groups representing significant disease phases. Plasma HIV-RNA, CSF white blood cell count (WBC), neopterin, and albumin ratio were included when available. RESULTS: In total, 1018 patients were included. CSF HIV-RNA was in median (interquartile range [IQR]) 1.03 log10 (0.37-1.86) copies/mL lower than in plasma, and correlated with plasma HIV-RNA (r = 0.44, P < .01), neopterin concentration in CSF (r = 0.49, P < .01) and in serum (r = 0.29, P < .01), CSF WBC (r = 0.34, P < .01) and albumin ratio (r = 0.25, P < .01). CSF HIV-RNA paralleled plasma HIV-RNA in all groups except neuroasymptomatic patients with advanced immunodeficiency (CD4 < 200) and patients with HIV-associated dementia (HAD) or opportunistic central nervous system (CNS) infections. Patients with HAD had the highest CSF HIV-RNA (in median [IQR] 4.73 (3.84-5.35) log10 copies/mL). CSF > plasma discordance was found in 126 of 972 individuals (13%) and varied between groups, from 1% in primary HIV, 11% in neuroasymptomatic groups, up to 30% of patients with HAD. CONCLUSIONS: Our study confirms previous smaller observations of variations in CSF HIV-RNA in different stages of HIV disease. Overall, CSF HIV-RNA was approximately 1 log10 copies/mL lower in CSF than in plasma, but CSF discordance was found in a substantial minority of subjects, most commonly in patients with HAD, indicating increasing CNS compartmentalization paralleling disease progression.

Seasonal Betacoronavirus Antibodies' Expansion Post-BNT161b2 Vaccination Associates with Reduced SARS-CoV-2 VoC Neutralization.

SARS-CoV-2 vaccination is known to induce antibodies that recognize also variants of concerns (VoCs) of the virus. However, epidemiological and laboratory evidences indicate that these antibodies have a reduced neutralization ability against VoCs. We studied binding and neutralizing antibodies against the Spike protein domains and subunits of the Wuhan-Hu-1 virus and its alpha, beta, delta VoCs and of seasonal betacoronaviruses (HKU1 and OC43) in a cohort of 31 health care workers prospectively followed post-vaccination with BNT162b2-Comirnaty. The study of sequential samples collected up to 64 days post-vaccination showed that serological assays measuring IgG against Wuhan-Hu-1 antigens were a poor proxy for VoC neutralization. In addition, in subjects who had asymptomatic or mild COVID-19 prior to vaccination, the loss of nAbs following disease could be rapid and accompanied by post-vaccination antibody levels similar to those of naïve vaccinees. Interestingly, in health care workers naïve for SARS-CoV-2 infection, vaccination induced a rapid and transient reactivation of pre-existing seasonal coronaviruses IgG responses that was associated with a subsequent reduced ability to neutralize alpha and beta VoCs.

Major revision version 11.0 of the European AIDS Clinical Society Guidelines 2021.

BACKGROUND: The European AIDS Clinical Society (EACS) Guidelines were revised in 2021 for the 17th time with updates on all aspects of HIV care. KEY POINTS OF THE GUIDELINES UPDATE: Version 11.0 of the Guidelines recommend six first-line treatment options for antiretroviral treatment (ART)-naïve adults: tenofovir-based backbone plus an unboosted integrase inhibitor or plus doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with lamivudine or emtricitabine plus dolutegravir. Recommendations on preferred and alternative first-line combinations from birth to adolescence were included in the new paediatric section made with Penta. Long-acting cabotegravir plus rilpivirine was included as a switch option and, along with fostemsavir, was added to all drug-drug interaction (DDI) tables. Four new DDI tables for anti-tuberculosis drugs, anxiolytics, hormone replacement therapy and COVID-19 therapies were introduced, as well as guidance on screening and management of anxiety disorders, transgender health, sexual health for women and menopause. The sections on frailty, obesity and cancer were expanded, and recommendations for the management of people with diabetes and cardiovascular disease risk were revised extensively. Treatment of recently acquired hepatitis C is recommended with ongoing risk behaviour to reduce transmission. Bulevirtide was included as a treatment option for the hepatitis Delta virus. Drug-resistant tuberculosis guidance was adjusted in accordance with the 2020 World Health Organization recommendations. Finally, there is new guidance on COVID-19 management with a focus on continuance of HIV care. CONCLUSIONS: In 2021, the EACS Guidelines were updated extensively and broadened to include new sections. The recommendations are available as a free app, in interactive web format and as an online pdf.

The risk of infection in patients with multiple sclerosis treated with disease-modifying therapies: A Delphi consensus statement.

The risk of infection associated with immunomodulatory or immunosuppressive disease-modifying drugs (DMDs) in patients with multiple sclerosis (MS) has been increasingly addressed in recent scientific literature. A modified Delphi consensus process was conducted to develop clinically relevant, evidence-based recommendations to assist physicians with decision-making in relation to the risks of a wide range of infections associated with different DMDs in patients with MS. The current consensus statements, developed by a panel of experts (neurologists, infectious disease specialists, a gynaecologist and a neuroradiologist), address the risk of iatrogenic infections (opportunistic infections, including herpes and cryptococcal infections, candidiasis and listeria; progressive multifocal leukoencephalopathy; human papillomavirus and urinary tract infections; respiratory tract infections and tuberculosis; hepatitis and gastrointestinal infections) in patients with MS treated with different DMDs, as well as prevention strategies and surveillance strategies for the early identification of infections. In the discussion, more recent data emerged in the literature were taken into consideration. Recommended risk reduction and management strategies for infections include screening at diagnosis and before starting a new DMD, prophylaxis where appropriate, monitoring and early diagnosis.

Vaccinations in patients with multiple sclerosis: A Delphi consensus statement.

BACKGROUND: Patients with multiple sclerosis (MS) are at increased risk of infection. Vaccination can mitigate these risks but only if safe and effective in MS patients, including those taking disease-modifying drugs. METHODS: A modified Delphi consensus process (October 2017-June 2018) was used to develop clinically relevant recommendations for making decisions about vaccinations in patients with MS. A series of statements and recommendations regarding the efficacy, safety and timing of vaccine administration in patients with MS were generated in April 2018 by a panel of experts based on a review of the published literature performed in October 2017. RESULTS: Recommendations include the need for an 'infectious diseases card' of each patient's infectious and immunisation history at diagnosis in order to exclude and eventually treat latent infections. We suggest the implementation of the locally recommended vaccinations, if possible at MS diagnosis, otherwise with vaccination timing tailored to the planned/current MS treatment, and yearly administration of the seasonal influenza vaccine regardless of the treatment received. CONCLUSION: Patients with MS should be vaccinated with careful consideration of risks and benefits. However, there is an urgent need for more research into vaccinations in patients with MS to guide evidence-based decision making.

Distal Sensory Peripheral Neuropathy in Human Immunodeficiency Virus Type 1-Positive Individuals Before and After Antiretroviral Therapy Initiation in Diverse Resource-Limited Settings.

BACKGROUND: Distal sensory peripheral neuropathy (DSPN) is a complication of human immunodeficiency virus (HIV). We estimate DSPN prevalence in 7 resource-limited settings (RLSs) for combination antiretroviral therapy (cART)-naive people living with HIV (PLWH) compared with matched participants not living with HIV and in PLWH virally suppressed on 1 of 3 cART regimens. METHODS: PLWH with a CD4+ count <300 cells/mm3 underwent standardized neurological examination and functional status assessments before and every 24 weeks after starting cART. Matched individuals not living with HIV underwent the same examinations once.Associations between covariates with DSPN at entry were assessed using the χ2 test, and virally suppressed PLWH were assessed using generalized estimating equations. RESULTS: Before initiating cART, 21.3% of PLWH had DSPN compared with 8.5% of people not living with HIV (n = 2400; χ2(df = 1) = 96.5; P < .00001). PLWH with DSPN were more likely to report inability to work [χ2(df = 1) = 10.6; P = .001] and depression [χ2(df = 1) = 8.9; P = .003] than PLWH without DSPN. Overall prevalence of DSPN among those virally suppressed on cART decreased: 20.3%, week 48; 15.3%, week 144; and 10.3%, week 192. Incident DSPN was seen in 127 PLWH. Longitudinally, DSPN was more likely in older individuals (P < .001) and PLWH with less education (P = .03). There was no significant association between cART regimen and DSPN. CONCLUSIONS: Although the prevalence of DSPN decreased following cART initiation in PLWH, further research could identify strategies to prevent or ameliorate residual DSPN after initiating cART in RLSs.

HIV-DNA undetectability during chronic HIV infection: frequency and predictive factors.

BACKGROUND: HIV-DNA is a marker of HIV reservoirs. Objectives of the study were to determine prevalence of HIV-DNA < 100 copies/106 PBMCs in blood and to identify factors associated with this in a cohort of HIV-1-infected subjects treated with ART and with undetectable viral load (VL). METHODS: This was a cross-sectional study on chronic HIV-1-infected people living with HIV (PLWH) followed up at the Department of Infectious Diseases of San Raffaele Scientific Institute on current ART without change for 12 months, with available pre-ART HIV-RNA and with undetectable VL for ≥12 months. HIV-DNA was amplified and quantified by real-time PCR (ABI Prism 7900); limit of detectability was 100 copies/106 PBMCs. Logistic regression was used to identify predictive factors for HIV-DNA < 100 copies/106 PBMCs. RESULTS: Four hundred and sixty-eight PLWH were considered in the analyses, 119 (25%) with HIV-DNA < 100 copies/106 PBMCs. At multivariate analysis, we found that PLWH with lower zenith HIV-RNA, higher nadir CD4 and a shorter time between HIV diagnosis and ART start were more likely to have HIV-DNA < 100 copies/106 PBMCs, after adjustment for age, gender, calendar year of ART start, type of current ART regimen, percentage time spent with undetectable VL since ART start, current CD4 and CD4/CD8 ratio. CONCLUSIONS: In our chronic PLWH on virological suppression for 4 years, the prevalence of HIV-DNA < 100 copies/106 PBMCs was found to be 25%. Lower zenith HIV-RNA, shorter time between HIV diagnosis and starting ART and higher CD4 nadir were independently associated with low HIV-DNA.

Acquisition of human immunodeficiency virus infection in a patient with multiple sclerosis: could these conditions positively influence each other's course?

Patients with human immunodeficiency virus (HIV) infection have a decreased risk of developing multiple sclerosis (MS) and MS patients very rarely contract HIV infection. We report on a 35-year-old woman with relapsing-remitting MS, who acquired HIV infection 8 years after MS onset. During 7 years of follow-up without combined antiretroviral therapy (cART), CD4+ counts decreased and HIV viremia increased progressively, but slightly. These trends reverted after starting cART, with optimal viro-immunological control. While the patient had many MS relapses before acquiring HIV infection, she had then only one relapse, shortly after HIV infection, despite irregular or no MS therapy. This case contributes to the discussion about MS and HIV potential interactions and describes for the first time the effects of the MS-targeting drug natalizumab in an HIV-positive patient.

Serum neurofilaments increase at progressive multifocal leukoencephalopathy onset in natalizumab-treated multiple sclerosis patients.

This study analyzed serum neurofilament light chains (NfL) in 2 European cohorts of 312 multiple sclerosis (MS) patients to investigate whether NfL are biomarkers of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment. The cohort comprised 25 PML, 136 natalizumab-treated, and 151 untreated MS patients. Patients subsequently developing PML had similar NfL to other natalizumab-treated MS patients. At PML onset, NfL were 10-fold higher than in the pre-PML condition and in natalizumab-treated or untreated MS patients, and NfL continued to increase until onset of immune reconstitution inflammatory syndrome. The results suggest that in natalizumab-treated patients, NfL may represent an early and accessible marker of PML. Ann Neurol 2019;85:606-610.

Relapse of Symptomatic Cerebrospinal Fluid HIV Escape.

PURPOSE OF REVIEW: Symptomatic cerebrospinal fluid (CSF) HIV escape defines the presence of neurological disease in combination antiretroviral therapy (cART)-treated persons due to HIV replication in CSF despite systemic suppression or to higher viral replication in CSF than in plasma. The aim was to search for cases of recurrent symptomatic CSF escape and to define their characteristics. RECENT FINDINGS: By review of the literature, we identified symptomatic CSF escape relapses in three patients who had shown clinical remission of a first escape episode following cART optimization. By examination of our cohort of 21 patients with symptomatic CSF escape, we identified five additional patients. In the latter, viral escape relapsed over a median follow-up of 108 months because of low adherence or upon treatment simplification of a previously optimized regimen. cART reoptimization based on resistance profile and potential drug neuropenetration and efficacy led to relapse resolution with no further episodes after a median follow-up of 50 months from relapse. The observation that CSF escape may relapse highlights the importance of long-term neuro-suppressive regimens after a first episode and supports the role of the brain as a reservoir for HIV.

Analytical treatment interruption in chronic HIV-1 infection: time and magnitude of viral rebound in adults with 10 years of undetectable viral load and low HIV-DNA (APACHE study).

OBJECTIVES: Despite the fact that there are individuals who have chronic HIV infection, few studies have investigated ART interruption in this setting. The aim of this study was to evaluate the ability to spontaneously control viral replication during analytical treatment interruption (ATI) in adults with chronic HIV-1 infection, on ART, with suppressed viraemia for >10 years and with a low reservoir. PATIENTS AND METHODS: This was a prospective, open-label, single-arm, non-randomized, proof-of-concept study (NCT03198325) of subjects with chronic HIV-1 infection, HIV-RNA <50 copies/mL for ≥10 years, without residual viraemia for ≥5 years, CD4+ >500 cells/mm3, HIV-DNA <100 copies/106 PBMCs and without comorbidities or AIDS-defining diseases. Enrolled patients were strictly monitored. The ART regimen in use at ATI was resumed in the case of confirmed viral rebound (CVR, two consecutive HIV-RNA >50 copies/mL). Results are reported as median (IQR). RESULTS: Nine patients underwent ATI. All participants experienced CVR [4.84 (IQR: 3.47-6.47) HIV-RNA log10 copies/mL] after ATI at a median time of 21 days (range 14-56) and restarted ART. After ART resumption, all the subjects achieved HIV-RNA <50 copies/mL in a median of 88 days (range 15-197). No serious adverse event occurred; one subject experienced acute retroviral syndrome. No significant correlation between baseline factors and time to viral rebound was observed, while the magnitude of viral rebound was significantly associated with pre-ART HIV-1 RNA (Spearman r = 0.786, P = 0.036), nadir CD4+ (Spearman r = -0.800, P = 0.010), baseline CD4+ (Spearman r = -0.667, P = 0.049) and years with undetectable viral load (Spearman r = -0.717, P = 0.030). CONCLUSIONS: Despite a long period of HIV viral load suppression and a low viral reservoir, early and consistent viral rebound was observed during ATI in all subjects.