Publications by authors named "David B Clifford"

164 Publications

Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease.

Clin Infect Dis 2021 Jan;72(1):1-8

Connecticut Children's Medical Center, Hartford, Connecticut, USA.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.
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http://dx.doi.org/10.1093/cid/ciab049DOI Listing
January 2021

Herpesvirus Infections and Risk of Parkinson's Disease.

Neurodegener Dis 2020 18;20(2-3):97-103. Epub 2021 Jan 18.

Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.

Introduction: Herpesviruses might play a role in the pathogenesis of neurodegenerative disorders. We sought to examine a possible association between alpha herpesvirus infections and Parkinson's disease.

Methods: We conducted a population-based case-control study of incident Parkinson's disease in 2009 Medicare beneficiaries age 66-90 years (89,790 cases, 118,095 randomly selected comparable controls). We classified beneficiaries with any diagnosis code for "herpes simplex" and/or "herpes zoster" in the previous 5 years as having had the respective alpha herpesviruses. In beneficiaries with Part D prescription coverage, we also identified those prescribed anti-herpetic medications. We calculated odds ratios (OR) and 95% CI between alpha herpesvirus diagnosis/treatment and Parkinson's disease with logistic regression, with adjustment for age, sex, race/ethnicity, smoking, and use of medical care.

Results: Parkinson's disease risk was inversely associated with herpes simplex (OR 0.79, 95% CI 0.74-0.84), herpes zoster (OR 0.88, 95% CI 0.85-0.91), and anti-herpetic medications (OR 0.87, 95% CI 0.80-0.96).

Conclusion: Herpesvirus infection or treatment might reduce risk of Parkinson's disease, but future studies will be required to explore whether this inverse association is causal.
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http://dx.doi.org/10.1159/000512874DOI Listing
January 2021

Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease.

Clin Infect Dis 2021 Jan;72(1):e1-e48

Connecticut Children's Medical Center, Hartford, Connecticut, USA.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.
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http://dx.doi.org/10.1093/cid/ciaa1215DOI Listing
January 2021

Clinical Practice Guidelines by the Infectious Diseases Society of America, American Academy of Neurology, and American College of Rheumatology: 2020 Guidelines for the Prevention, Diagnosis, and Treatment of Lyme Disease.

Neurology 2021 02 30;96(6):262-273. Epub 2020 Nov 30.

From the Duke University School of Medicine (P.M.L.), Durham, NC; Pathway Neurology (J. Rumbaugh), Tampa, FL; Yale University (L.K.B., L.E.R.), New Haven, CT; Case Western Reserve University, VA Northeast Ohio Healthcare System (Y.T.F.-Y.), Cleveland; New York University School of Medicine (M.E.A.-R.), New York; Johns Hopkins University School of Medicine (P.G.A.), Baltimore, MD; Geisinger Medical Center (K.B.), Danville, PA; Tufts Medical Center (R.R.B., H.C.M., M.C.O., E.E.V.), Boston, MA; Childrens Hospital and Clinical of Minnesota (K.K.B.), Minneapolis; University of British Columbia (W.R.B.), Vancouver Canada; Massachusetts General Hospital (J.A.B., A.C.S.), Boston; Washington University School of Medicine (D.B.C.), St. Louis, Missouri; Connecticut Children's Medical Center (F.J.D.M., L.S.Z.), Hartford, CT; Atlantic Health System (J.J.H.), Summit, NJ; Yale School of Public Health (P.J.K.), New Haven, CT; University of Montreal (V.L.), Quebec, Canada; Brigham and Women's Hospital (M.H.L.), Boston, MA; Boston Children's Hospital (L.E.N., R.S.), Massachusetts; Medical College of Wisconsin (J.(J.)J.N.), Waowatosa; University of Pennsylvania (A.A.P.), Philadelphia; Consumer Representative (J. Rips), Omaha, NE; Temple University (M.L.S.), Philadelphia, PA; Northwell Health (S.K.S.), New York, NY; University Medical Centre Ljubljana (F.S.), Slovenia; Michigan State University (J.T.), East Lansing; and New York Medical College (G.P.W.), Valhalla.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.
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http://dx.doi.org/10.1212/WNL.0000000000011151DOI Listing
February 2021

Higher iron stores and the HFE 187C>G variant delay onset of peripheral neuropathy during combination antiretroviral therapy.

PLoS One 2020 15;15(10):e0239758. Epub 2020 Oct 15.

Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.

Objective: People with HIV (PWH) continue to experience sensory neuropathy and neuropathic pain in the combination antiretroviral therapy (cART) era for unclear reasons. This study evaluated the role of iron in a previously reported association of iron-loading hemochromatosis (HFE) gene variants with reduced risk of neuropathy in PWH who received more neurotoxic cART, since an iron-related mechanism also might be relevant to neuropathic symptoms in PWH living in low-resource settings today.

Design: This time-to-event analysis addressed the impact of systemic iron levels on the rapidity of neuropathy onset in PWH who initiated cART.

Methods: Soluble transferrin receptor (sTFR), the sTFR-ferritin index of iron stores, and high-sensitivity C-reactive protein (hsCRP) levels were determined in stored baseline sera from participants of known HFE genotype from AIDS Clinical Trials Group (ACTG) Study 384, a multicenter randomized clinical trial that evaluated cART strategies. Associations with incident neuropathy were evaluated in proportional-hazards, time-to-event regression models, adjusting for potential confounders.

Results: Of 151 eligible participants with stored serum who were included in the original genetic study, 43 had cART-associated neuropathy; 108 had sufficient serum for analysis, including 30 neuropathy cases. Carriers of HFE variants had higher systemic iron (lower sTFR and sTFR-ferritin index) and lower hsCRP levels than non-carriers (all p<0.05). Higher sTFR or iron stores, the HFE 187C>G variant, and lower baseline hsCRP were associated with significantly delayed neuropathy in self-reported whites (n = 28; all p-values<0.05), independent of age, CD4+ T-cell count, plasma HIV RNA, and cART regimen.

Conclusions: Higher iron stores, the HFE 187C>G variant, and lower hsCRP predicted delayed onset of neuropathy among self-reported white individuals initating cART. These findings require confirmation but may have implications for cART in HIV+ populations in areas with high endemic iron deficiency, especially those PWH in whom older, more neurotoxic antiretroviral drugs are occasionally still used.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239758PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561201PMC
November 2020

Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum.

Am J Med Genet A 2021 01 7;185(1):15-25. Epub 2020 Oct 7.

Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.
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http://dx.doi.org/10.1002/ajmg.a.61907DOI Listing
January 2021

Predictors of worsening neuropathy and neuropathic pain after 12 years in people with HIV.

Ann Clin Transl Neurol 2020 07 3;7(7):1166-1173. Epub 2020 Jul 3.

Departments of Medicine and Psychiatry, University of California, San Diego, La Jolla, California.

Objective: Distal sensory polyneuropathy (DSP) and neuropathic pain are important clinical concerns in virally suppressed people with HIV. We determined how these conditions evolved, what factors influenced their evolution, and their clinical impact.

Methods: Ambulatory, community-dwelling HIV seropositive individuals were recruited at six research centers. Clinical evaluations at baseline and 12 years later determined neuropathy signs and distal neuropathic pain (DNP). Additional assessments measured activities of daily living and quality of life (QOL). Factors potentially associated with DSP and DNP progression included disease severity, treatment, demographics, and co-morbidities. Adjusted odds ratios were calculated for follow-up neuropathy outcomes.

Results: Of 254 participants, 21.3% were women, 57.5% were non-white. Mean baseline age was 43.5 years. Polyneuropathy prevalence increased from 25.7% to 43.7%. Of 173 participants initially pain-free, 42 (24.3%) had incident neuropathic pain. Baseline risk factors for incident pain included unemployment (OR [95% CI], 5.86 [1.97, 17.4]) and higher baseline body mass index (BMI) (1.78 [1.03, 3.19] per 10-units). Participants with neuropathic pain at follow-up had significantly worse QOL and greater dependence in activities of daily living than those who remained pain-free.

Interpretation: HIV DSP and neuropathic pain increased in prevalence and severity over 12 years despite high rates of viral suppression. The high burden of neuropathy included disability and poor life quality. However, substantial numbers remained pain-free despite clear evidence of neuropathy on exam. Protective factors included being employed and having a lower BMI. Implications for clinical practice include promotion of lifestyle changes affecting reversible risk factors.
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http://dx.doi.org/10.1002/acn3.51097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359117PMC
July 2020

Seven-Year Experience From the National Institute of Neurological Disorders and Stroke-Supported Network for Excellence in Neuroscience Clinical Trials.

JAMA Neurol 2020 06;77(6):755-763

University of Rochester, Rochester, New York.

Importance: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders.

Observations: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings.

Conclusions And Relevance: NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.
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http://dx.doi.org/10.1001/jamaneurol.2020.0367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483960PMC
June 2020

Treatment of Progressive Multifocal Leukoencephalopathy Using Immune Restoration.

Neurotherapeutics 2020 07;17(3):955-965

Department of Neurology, Washington University in St Louis, St. Louis, MO, USA.

Progressive multifocal leukoencephalopathy (PML) is a viral disease of the brain associated with immunodeficiency, immune suppressing medications, and malignancy. In the absence of effective anti-viral therapy for the causative JC virus, immune restoration has emerged as the critical therapeutic alternative. The evolving treatment of PML (and other rare JC virus-associated neurologic syndromes) requires consideration of baseline immune functioning and comorbid diseases while selecting from a number of therapeutic options to restore an effective immune response. This review focuses on the current options for management of PML in typical situations where this disease presents, including several where immune restoration is a standard therapeutic approach such as in PML associated with HIV/AIDS and in multiple sclerosis associated with natalizumab. Other circumstances in which PML occurs including associated with primary immunodeficiencies, malignancies, and transplants present greater challenges to immune reconstitution, but emerging concepts may enhance therapeutic options for these situations. Particular attention is focused on recent experience with checkpoint inhibitors, guidance for MS drug discontinuation, and strategies to monitor and facilitate immune restoration.
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http://dx.doi.org/10.1007/s13311-020-00848-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641288PMC
July 2020

Use of Neuroimaging to Inform Optimal Neurocognitive Criteria for Detecting HIV-Associated Brain Abnormalities.

J Int Neuropsychol Soc 2020 02 2;26(2):147-162. Epub 2019 Oct 2.

Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.

Objective: Frascati international research criteria for HIV-associated neurocognitive disorders (HAND) are controversial; some investigators have argued that Frascati criteria are too liberal, resulting in a high false positive rate. Meyer et al. recommended more conservative revisions to HAND criteria, including exploring other commonly used methodologies for neurocognitive impairment (NCI) in HIV including the global deficit score (GDS). This study compares NCI classifications by Frascati, Meyer, and GDS methods, in relation to neuroimaging markers of brain integrity in HIV.

Method: Two hundred forty-one people living with HIV (PLWH) without current substance use disorder or severe (confounding) comorbid conditions underwent comprehensive neurocognitive testing and brain structural magnetic resonance imaging and magnetic resonance spectroscopy. Participants were classified using Frascati criteria versus Meyer criteria: concordant unimpaired [Frascati(Un)/Meyer(Un)], concordant impaired [Frascati(Imp)/Meyer(Imp)], or discordant [Frascati(Imp)/Meyer(Un)] which were impaired via Frascati criteria but unimpaired via Meyer criteria. To investigate the GDS versus Meyer criteria, the same groupings were utilized using GDS criteria instead of Frascati criteria.

Results: When examining Frascati versus Meyer criteria, discordant Frascati(Imp)/Meyer(Un) individuals had less cortical gray matter, greater sulcal cerebrospinal fluid volume, and greater evidence of neuroinflammation (i.e., choline) than concordant Frascati(Un)/Meyer(Un) individuals. GDS versus Meyer comparisons indicated that discordant GDS(Imp)/Meyer(Un) individuals had less cortical gray matter and lower levels of energy metabolism (i.e., creatine) than concordant GDS(Un)/Meyer(Un) individuals. In both sets of analyses, the discordant group did not differ from the concordant impaired group on any neuroimaging measure.

Conclusions: The Meyer criteria failed to capture a substantial portion of PLWH with brain abnormalities. These findings support continued use of Frascati or GDS criteria to detect HIV-associated CNS dysfunction.
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http://dx.doi.org/10.1017/S1355617719000985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015796PMC
February 2020

Dosing interval of natalizumab in MS: Do good things come to those who wait?

Neurology 2019 10 12;93(15):655-656. Epub 2019 Sep 12.

From the Department of Neurology (D.B.C.), Washington University in St Louis, MO; and Department of Medicine and Immunology-Microbiology (K.L.T.), University of Colorado School of Medicine, Aurora.

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http://dx.doi.org/10.1212/WNL.0000000000008238DOI Listing
October 2019

Thinking About Getting Older With Human Immunodeficiency Virus.

Authors:
David B Clifford

Clin Infect Dis 2020 06;70(12):2649-2651

Department of Neurology, St. Louis, Missouri.

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http://dx.doi.org/10.1093/cid/ciz675DOI Listing
June 2020

Is successful HIV therapy a Pyrrhic victory for the brain?

Authors:
David B Clifford

J Clin Invest 2019 07 15;129(8):3052-3053. Epub 2019 Jul 15.

Neurologic involvement of HIV remains an important concern for patients, physicians, and investigators. Catastrophic decline is rarely seen in patients on combination antiretroviral therapy (cART); however, neurological decline remains a critical clinical challenge. In this issue of the JCI, Spudich and associates investigated the status of HIV in the cerebral spinal fluid (CSF) and revealed ongoing presence of HIV in the nervous system. Surprisingly, even in the face of optimal treatment, including suppressed HIV RNA, almost half of the patients investigated showed cell-associated HIV (CA-HIV) DNA in the CSF. Spudich et al. find that persistence of HIV in CSF cells is associated with lower performance on neurocognitive testing. These findings emphasize the need to consider a viral-associated mechanism as playing a significant and potentially ongoing role in HIV-associated neurocognitive disorder (HAND).
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http://dx.doi.org/10.1172/JCI127831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668814PMC
July 2019

Correlates of HIV RNA concentrations in cerebrospinal fluid during antiretroviral therapy: a longitudinal cohort study.

Lancet HIV 2019 07 14;6(7):e456-e462. Epub 2019 Jun 14.

Department of Psychiatry, University of California San Diego, San Diego, CA, USA; Department of Medicine, University of California San Diego, San Diego, CA, USA. Electronic address:

Background: Few large projects have evaluated the factors that influence the HIV RNA concentrations (viral load) in cerebrospinal fluid (CSF) during antiretroviral therapy (ART) over time. We aimed to determine the correlates of HIV RNA in CSF in a large cohort.

Methods: We analysed longitudinal data from adults living with HIV in the US CHARTER cohort. Participants in the CHARTER study were recruited from six US academic medical centres-in Baltimore (MD), Galveston (TX), New York (NY), St Louis (MO), San Diego (C92A), and Seattle (WA). Participants in this study had been assessed at least three times between Sept 4, 2003, and Sept 14, 2010, and were taking ART and underwent venous and lumbar puncture with measurement of HIV RNA concentration at all assessments. The lower limit of quantification of the HIV RNA assays was 50 copies per mL. Data were analysed with longitudinal mixed effects logistic regression to identify correlates of HIV RNA concentration (as a binary [detectable or not] and as a continuous variable) in CSF over time. We tested demographic characteristics, plasma HIV RNA, nadir and current CD4 cell count in blood, current CD8 cell count in blood, estimated duration of HIV infection, AIDS diagnosis, duration of ART, adherence to ART, ART characteristics, and CSF characteristics as potential correlates.

Findings: At the time of analysis, 2207 assessments from 401 participants met the criteria for inclusion in this study. Mean duration of observation was 33·7 months (range 12-84). HIV RNA concentrations in 710 (32·2%) plasma specimens and in 255 (11·6%) CSF specimens were greater than the lower limit of quantification. The best multivariate model of HIV RNA concentration in CSF greater than the lower limit of quantification over time included increased plasma HIV RNA concentration (odds ratio 18·0 per 1 log copy per mL, 95% CI 11·3 to 28·8; p<0·0001), increased CSF leucocyte count (2·01 per 5 cells per μL, 1·61 to 2·39; p<0·0001), decreased CD4 cell count (0·53 per 5 square-root cells per μL, 0·35 to 0·79; p=0·0025), decreased CNS penetration-effectiveness value (0·71 per unit, 0·56 to 0·92; p=0·0078), increased CD8 cell count (1·51 per 5 square-root cells, 1·11 to 2·06; p=0·0089), and protease inhibitor use (3·26, 1·04 to 10·23; p=0·039; model R=0·22, p<0·0001). Analyses of continuous HIV RNA concentration in CSF that accounted for censoring below the lower limit of quantification had similar findings, although increased HIV RNA concentrations in CSF were also associated with black ethnicity (change in log HIV RNA concentration in CSF 0·205, 0·0367 to 0·3733; p=0·017), increased total protein in CSF (0·0025, -0·0002 to 0·0052; p=0·069), and the presence of addictive-drug metabolites in urine (0·103, -0·013 to 0·219; p=0·081).

Interpretation: The identified correlates of HIV RNA concentration in CSF during ART could strengthen clinical prediction of risk for failure to achieve or maintain HIV RNA suppression in CSF. Because most participants in this analysis were ART-experienced and were taking a three-drug regimen that did not include an integrase inhibitor, future research should focus on participants who are taking their first ART regimens or regimens that include integrase inhibitors or two drugs.

Funding: The work was supported by the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.
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http://dx.doi.org/10.1016/S2352-3018(19)30143-2DOI Listing
July 2019

High alert!

Authors:
David B Clifford

Mult Scler 2019 10 18;25(12):1685. Epub 2019 Jun 18.

Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA.

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http://dx.doi.org/10.1177/1352458519858603DOI Listing
October 2019

Neurocognitive SuperAging in Older Adults Living With HIV: Demographic, Neuromedical and Everyday Functioning Correlates.

J Int Neuropsychol Soc 2019 05 20;25(5):507-519. Epub 2019 Mar 20.

2Department of Psychiatry,University of California,San Diego,San Diego,California.

Objectives: Studies of neurocognitively elite older adults, termed SuperAgers, have identified clinical predictors and neurobiological indicators of resilience against age-related neurocognitive decline. Despite rising rates of older persons living with HIV (PLWH), SuperAging (SA) in PLWH remains undefined. We aimed to establish neuropsychological criteria for SA in PLWH and examined clinically relevant correlates of SA.

Methods: 734 PLWH and 123 HIV-uninfected participants between 50 and 64 years of age underwent neuropsychological and neuromedical evaluations. SA was defined as demographically corrected (i.e., sex, race/ethnicity, education) global neurocognitive performance within normal range for 25-year-olds. Remaining participants were labeled cognitively normal (CN) or impaired (CI) based on actual age. Chi-square and analysis of variance tests examined HIV group differences on neurocognitive status and demographics. Within PLWH, neurocognitive status differences were tested on HIV disease characteristics, medical comorbidities, and everyday functioning. Multinomial logistic regression explored independent predictors of neurocognitive status.

Results: Neurocognitive status rates and demographic characteristics differed between PLWH (SA=17%; CN=38%; CI=45%) and HIV-uninfected participants (SA=35%; CN=55%; CI=11%). In PLWH, neurocognitive groups were comparable on demographic and HIV disease characteristics. Younger age, higher verbal IQ, absence of diabetes, fewer depressive symptoms, and lifetime cannabis use disorder increased likelihood of SA. SA reported increased independence in everyday functioning, employment, and health-related quality of life than non-SA.

Conclusions: Despite combined neurological risk of aging and HIV, youthful neurocognitive performance is possible for older PLWH. SA relates to improved real-world functioning and may be better explained by cognitive reserve and maintenance of cardiometabolic and mental health than HIV disease severity. Future research investigating biomarker and lifestyle (e.g., physical activity) correlates of SA may help identify modifiable neuroprotective factors against HIV-related neurobiological aging. (JINS, 2019, 25, 507-519).
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http://dx.doi.org/10.1017/S1355617719000018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705613PMC
May 2019

Effects of comorbidity burden and age on brain integrity in HIV.

AIDS 2019 06;33(7):1175-1185

Department of Psychiatry, University of California San Diego, La Jolla.

Objective: The influence of confounding neurocognitive comorbidities in people living with HIV (PLWH) on neuroimaging has not been systematically evaluated. We determined associations between comorbidity burden and brain integrity and examined the moderating effect of age on these relationships.

Design: Observational, cross-sectional substudy of the CNS HIV Antiretroviral Therapy Effects Research cohort.

Methods: A total of 288 PLWH (mean age = 44.2) underwent structural MRI and magnetic resonance spectroscopy as well as neurocognitive and neuromedical assessments. Consistent with Frascati criteria for HIV-associated neurocognitive disorders (HAND), neuromedical and neuropsychiatric comorbidity burden was classified as incidental (mild), contributing (moderate), or confounding (severe-exclusionary) to a diagnosis of HAND. Multiple regression modeling predicted neuroimaging outcomes as a function of comorbidity classification, age, and their interaction.

Results: Comorbidity classifications were 176 incidental, 77 contributing, and 35 confounded; groups did not differ in HIV disease characteristics. Relative to incidental and contributing participants, confounded participants had less cortical gray matter and more abnormal white matter and ventricular cerebrospinal fluid, alongside more neuroinflammation (choline, myo-inositol) and less neuronal integrity (N-acetylaspartate). Older age exacerbated the impact of comorbidity burden: to a greater extent in the confounded group, older age was associated with more abnormal white matter (P = 0.017), less total white matter (P = 0.015), and less subcortical gray matter (P = 0.014).

Conclusion: Neuroimaging in PLWH reveals signatures associated with confounding neurocognitive conditions, emphasizing the importance of evaluating these among individuals with suspected HAND. Older age amplifies subcortical and white matter tissue injury, especially in PLWH with severe comorbidity burden, warranting increased attention to this population as it ages.
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http://dx.doi.org/10.1097/QAD.0000000000002192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613389PMC
June 2019

Progressive multifocal leukoencephalopathy treated with nivolumab.

J Neurovirol 2019 04 12;25(2):284-287. Epub 2019 Mar 12.

Department of Neurology, Washington University in St. Louis, Box 8111, 660 South Euclid Avenue, Saint Louis, MO, 63110, USA.

Therapy for progressive multifocal leukoencephalopathy (PML) remains challenging since there are no antiviral therapies available for JC virus. Immune reconstitution has improved the prognosis in many settings where PML occurs, but it often is not possible in PML patients with hematologic malignancies. We describe the first biopsy proven PML case where the PD-1 inhibitor nivolumab appears to have stimulated immune activation resulting in effective control of PML in a patient with hematologic malignancy. This report supports further investigation of the utility of checkpoint inhibitors for treating PML where other immune reconstitution options are not available.
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http://dx.doi.org/10.1007/s13365-019-00738-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506384PMC
April 2019

Cerebrospinal fluid viral escape in aviremic HIV-infected patients receiving antiretroviral therapy: prevalence, risk factors and neurocognitive effects.

AIDS 2019 03;33(3):475-481

University of California, San Diego, San Diego, California.

Background: During antiretroviral therapy, HIV RNA can be detected in cerebrospinal fluid (CSF) when it is undetectable in plasma, a condition termed 'CSF viral escape'. The aim of the current study was to determine the prevalence and risk factors for CSF viral escape in two large cohorts in the USA.

Methods: A total of 1264 HIV-infected volunteers enrolled in two US cohorts at their most recent visit between 2003 and 2011 were included in this cross-sectional analysis if their HIV RNA level in plasma was less than 50 copies/ml while receiving stable antiretroviral therapy (ART) (>6 months) and if they had HIV RNA measured in CSF at their most recent visit between 2003 and 2011. Potential risk factors were identified using univariable and multivariable regression.

Results: CSF viral escape was detected in 55 adults (4.4%; 95% CI: 3.4-5.6), who had a median CSF HIV RNA of 155 copies/ml [interquartile range (IQR: 80-283)]. Patients with or without CSF viral escape had similar rates of neurocognitive impairment (38.2 vs. 37.7%; P = 0.91). CSF viral escape was independently associated with the use of ritonavir-boosted protease inhibitors [odds ratio (OR): 2.0; 95% CI: 1.1-3.8] or unboosted atazanavir (OR: 5.1; 95% CI: 1.3-16.1), CSF pleocytosis (OR: 7.6; 95% CI: 4.2-13.7) and abnormal CSF total protein (OR: 2.1; 95% CI: 1.1-3.7).

Conclusions: In this large study of aviremic patients receiving ART, CSF viral escape was uncommon and was linked to evidence of central nervous system inflammation and the use of protease inhibitors, but not with worse neurocognitive performance.
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http://dx.doi.org/10.1097/QAD.0000000000002074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361539PMC
March 2019

White matter damage, neuroinflammation, and neuronal integrity in HAND.

J Neurovirol 2019 02 5;25(1):32-41. Epub 2018 Oct 5.

University of California at San Diego, La Jolla, CA, USA.

HIV-associated neurocognitive disorders (HANDs) persist even with virologic suppression on combination antiretroviral therapy (cART), and the underlying pathophysiological mechanisms are not well understood. We performed structural magnetic resonance imaging and MR spectroscopy (MRS) in HIV+ individuals without major neurocognitive comorbidities. Study participants were classified as neurocognitively unimpaired (NU), asymptomatic (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD). Using structural MRI, we measured volumes of cortical and subcortical gray matter and total and abnormal white matter (aWM). Using single-voxel MRS, we estimated metabolites in frontal gray matter (FGM) and frontal white matter (FWM) and basal ganglia (BG) regions. Adjusted odds ratios were used to compare HAND to NU. Among 253 participants, 40% met HAND criteria (21% ANI, 15% MND, and 4% HAD). Higher risk of HAND was associated with more aWM. Both HAD and MND also had smaller gray and white matter volumes than NU. Among individuals with undetectable plasma HIV RNA, structural volumetric findings were similar to the overall sample. MND had lower FWM creatine and higher FGM choline relative to NU, whereas HAD and ANI had lower BG N-acetyl aspartate relative to NU. In the virologically suppressed subgroup, however, ANI and MND had higher FGM choline compared to NU. Overall, HAND showed specific alterations (more aWM and inflammation; less gray matter volume and lower NAA). Some MR measures differentiated less severe subtypes of HAND from HAD. These MR alterations may represent legacy effects or accumulating changes, possibly related to medical comorbidities, antiretroviral therapy, or chronic effects of HIV brain infection.
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http://dx.doi.org/10.1007/s13365-018-0682-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416232PMC
February 2019

Definition and Consensus Diagnostic Criteria for Neurosarcoidosis: From the Neurosarcoidosis Consortium Consensus Group.

JAMA Neurol 2018 12;75(12):1546-1553

Department of Medicine, University of Cincinnati, Cincinnati, Ohio.

Importance: The Neurosarcoidosis Consortium Consensus Group, an expert panel of physicians experienced in the management of patients with sarcoidosis and neurosarcoidosis, engaged in an iterative process to define neurosarcoidosis and develop a practical diagnostic approach to patients with suspected neurosarcoidosis. This panel aimed to develop a consensus clinical definition of neurosarcoidosis to enhance the clinical care of patients with suspected neurosarcoidosis and to encourage standardization of research initiatives that address this disease.

Observations: The work of this collaboration included a review of the manifestations of neurosarcoidosis and the establishment of an approach to the diagnosis of this disorder. The proposed consensus diagnostic criteria, which reflect current knowledge, provide definitions for possible, probable, and definite central and peripheral nervous system sarcoidosis. The definitions emphasize the need to evaluate patients with findings suggestive of neurosarcoidosis for alternate causal factors, including infection and malignant neoplasm. Also emphasized is the need for biopsy, whenever feasible and advisable according to clinical context and affected anatomy, of nonneural tissue to document the presence of systemic sarcoidosis and support a diagnosis of probable neurosarcoidosis or of neural tissue to support a diagnosis of definite neurosarcoidosis.

Conclusions And Relevance: Diverse disease presentations and lack of specificity of relevant diagnostic tests contribute to diagnostic uncertainty. This uncertainty is compounded by the absence of a pathognomonic histologic tissue examination. The diagnostic criteria we propose are designed to focus investigations on NS as accurately as possible, recognizing that multiple pathophysiologic pathways may lead to the clinical manifestations we currently term NS. Research recognizing the clinical heterogeneity of this diagnosis may open the door to identifying meaningful biologic factors that may ultimately contribute to better treatments.
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http://dx.doi.org/10.1001/jamaneurol.2018.2295DOI Listing
December 2018

Progressive multifocal leukoencephalopathy with extended natalizumab dosing.

Neurol Clin Pract 2018 Jun;8(3):e12-e14

Mellen Center for Multiple Sclerosis (LEB, RJF) and Imaging Institute (SEJ), Cleveland Clinic, OH; and Department of Neurology (SEJ, DBC), Washington University School of Medicine, St. Louis, MO.

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http://dx.doi.org/10.1212/CPJ.0000000000000457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075974PMC
June 2018

Hemochromatosis (HFE) Gene Variants Are Associated with Increased Mitochondrial DNA Levels During HIV-1 Infection and Antiretroviral Therapy.

AIDS Res Hum Retroviruses 2018 11 22;34(11):942-949. Epub 2018 Aug 22.

9 Icahn School of Medicine of Mount Sinai , New York, New York.

Some HIV-associated complications involve mitochondrial dysfunction and may be less common in individuals with iron-loading HFE (hemochromatosis gene) variants. We evaluated HFE 845A and 187G alleles in relation to mitochondrial DNA (mtDNA) levels in peripheral blood mononuclear cells from 85 individuals with HIV infection on uninterrupted antiretroviral therapy (ART) for 15 or more consecutive weeks. Carriers of HFE gene variants (N = 24) had significantly higher mtDNA levels than noncarriers (N = 61), after adjusting for age, race, sex, and type of ART [adjusted β-coefficient 297, p-value < .001 for at least one HFE variant], but mtDNA declined among all individuals on study during 48 weeks on ART. Increased cellular mtDNA content may represent a compensatory response to mitochondrial stress that is influenced by iron-loading HFE variants.
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http://dx.doi.org/10.1089/AID.2018.0025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421985PMC
November 2018

A Programme for Risk Assessment and Minimisation of Progressive Multifocal Leukoencephalopathy Developed for Vedolizumab Clinical Trials.

Drug Saf 2018 08;41(8):807-816

Washington University School of Medicine, St. Louis, MO, USA.

Introduction: Over the past decade, the potential for drug-associated progressive multifocal leukoencephalopathy (PML) has become an increasingly important consideration in certain drug development programmes, particularly those of immunomodulatory biologics. Whether the risk of PML with an investigational agent is proven (e.g. extrapolated from relevant experience, such as a class effect) or merely theoretical, the serious consequences of acquiring PML require careful risk minimisation and assessment. No single standard for such risk minimisation exists. Vedolizumab is a recently developed monoclonal antibody to α4β7 integrin. Its clinical development necessitated a dedicated PML risk minimisation assessment as part of a global preapproval regulatory requirement.

Objective: The aim of this study was to describe the multiple risk minimisation elements that were incorporated in vedolizumab clinical trials in inflammatory bowel disease patients as part of the risk assessment and minimisation of PML programme for vedolizumab.

Methods: A case evaluation algorithm was developed for sequential screening and diagnostic evaluation of subjects who met criteria that indicated a clinical suspicion of PML. An Independent Adjudication Committee provided an independent, unbiased opinion regarding the likelihood of PML.

Results: Although no cases were detected, all suspected PML events were thoroughly reviewed and successfully adjudicated, making it unlikely that cases were missed.

Conclusion: We suggest that this programme could serve as a model for pragmatic screening for PML during the clinical development of new drugs.
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http://dx.doi.org/10.1007/s40264-018-0669-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061428PMC
August 2018

Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: a decade of lessons learned.

Lancet Neurol 2018 05;17(5):467-480

Department of Neurology, Washington University School of Medicine, St Louis, MO, USA. Electronic address:

Progressive multifocal leukoencephalopathy (PML) is a rare, devastating demyelinating disease of the CNS caused by the JC virus (JCV) that occurs in patients with compromised immune systems. Detection of PML in systemically immunocompetent patients with multiple sclerosis treated with natalizumab points to a role for this drug in the pathophysiology of PML. Emerging knowledge of the cellular and molecular biology of JCV infection and the pathogenesis of PML-including interplay of this common virus with the human immune system and features of natalizumab that might contribute to PML pathogenesis-provides new opportunities to monitor viral status and predict risk of JCV-associated disease. In the absence of an effective treatment for PML, early detection of the disease in patients with multiple sclerosis who are receiving natalizumab or other immunomodulatory treatments is vital to minimize CNS injury and avoid severe disability. Frequent MRI, stratified along a clinical and virus-specific immune risk profile, can be used to detect presymptomatic PML. Improved approaches to PML risk stratification are needed to guide treatment choices and surveillance of patients with multiple sclerosis.
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http://dx.doi.org/10.1016/S1474-4422(18)30040-1DOI Listing
May 2018

Could We Harness Human Immunodeficiency Virus Antibodies to Monitor the Brain?

Authors:
David B Clifford

J Infect Dis 2018 03;217(7):1017-1019

Melba and Forest Seay Professor of Clinical Neuropharmacology in Neurology, Washington University in St. Louis, Missouri.

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http://dx.doi.org/10.1093/infdis/jix663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939645PMC
March 2018

Progressive multifocal leukoencephalopathy: Are you aware of it?

Neurology 2018 02 10;90(6):255-256. Epub 2018 Jan 10.

From the Departments of Neurology and Medicine (D.B.C.), Washington University in St. Louis, MO; and Clinical Department of Neurology (T.B.), Medical University of Innsbruck, Austria.

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http://dx.doi.org/10.1212/WNL.0000000000004935DOI Listing
February 2018