Benjamin B Gelman

Publications (30)127.64 Total impact

• Article: Neurovirological correlation with HIV-associated neurocognitive disorders and encephalitis in a HAART-era cohort.

  Benjamin B Gelman, Joshua G Lisinicchia, Susan Morgello, Eliezer Masliah, Deborah Commins, Cristian L Achim, Howard S Fox, Dennis L Kolson, Igor Grant, Elyse Singer, Constantin T Yiannoutsos, Seth Sherman, Gary Gensler, David J Moore, Tiansheng Chen, Vicki M Soukup
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  ABSTRACT: OBJECTIVE:: Replicating HIV-1 in the brain is present in HIV encephalitis (HIVE) and microglial nodule encephalitis (MGNE) and is putatively linked with HIV-associated neurocognitive disorders (HAND). A clinico-neurovirological correlation was conducted to elucidate the relationship between brain viral load and clinical phenotype. SUBJECTS: and assays: HIV gag/pol RNA and DNA copies were quantified with RT-PCR or PCR in 148 HAART-era brain specimens. Comparison to HAND, HIVE and MGNE and correlation with neuropsychological (NP) test scores were done using one-way ANOVA with Tukey-Kramer and Spearman's tests respectively. RESULTS:: Brain HIV RNA was higher in subjects with HAND plus HIVE vs without HAND (delta = 2.48 log10 units, n = 27 vs 36, p < 0.001). In HAND without HIVE or MGNE, brain HIV RNA was not significantly different vs without HAND (p = 0.314). Worse NP scores correlated significantly with higher HIV RNA and interferon responses in brain specimens (p<0.001), but not with HIV RNA levels in premortem blood plasma (n = 114) or cerebrospinal fluid (n = 104). In subjects with MGNE, brain HIV RNA was slightly higher versus without MGNE (p<0.01), and much lower versus with HIVE (p<0.001). CONCLUSION:: Brain HIV RNA and to a lesser extent HIV DNA are correlated with worse NP performance in the 6 months before death. Linkage occurs primarily in patients with HIVE and MGNE; while on HAART these patients could obtain added NP improvement by further reducing brain HIV. Patients not in those groups are less certain to obtain added NP benefit.
  JAIDS Journal of Acquired Immune Deficiency Syndromes 12/2012; · 4.43 Impact Factor
• Article: Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90% inhibitory concentration.

  David Croteau, Steven S Rossi, Brookie M Best, Edmund Capparelli, Ronald J Ellis, David B Clifford, Ann C Collier, Benjamin B Gelman, Christina M Marra, Justin McArthur, J Allen McCutchan, Susan Morgello, David M Simpson, Igor Grant, Scott Letendre
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  ABSTRACT: OBJECTIVES: Higher CSF antiretroviral concentrations may be associated with better control of HIV replication and neurocognitive performance, but only the unbound fraction of antiretrovirals is available to inhibit HIV. Therefore, the objective of this study was to determine total and unbound darunavir concentrations in CSF and compare findings with plasma concentrations as well as the wild-type HIV-1 90% inhibitory concentration (IC(90)). METHODS: Subjects with HIV infection were selected based on the use of darunavir-containing regimens with a twice-daily dosing schedule and availability of stored CSF and matched plasma. Total darunavir was measured by HPLC for plasma or liquid chromatography-tandem mass spectroscopy (LC/MS/MS) for CSF. Plasma unbound darunavir was measured by ultrafiltration and LC/MS/MS. CSF protein binding was determined by competitive binding exchange with radiolabelled darunavir. RESULTS: Twenty-nine matched CSF-plasma pairs were analysed and darunavir was detected in all CSF specimens (median total concentration 55.8 ng/mL), with a CSF unbound fraction of 93.5%. Median fractional penetrance was 1.4% of median total and 9.4% of median unbound plasma concentrations. Unbound darunavir concentrations in CSF exceeded the median IC(90) for wild-type HIV in all subjects by a median of 20.6-fold, despite the relatively low fractional penetrance. Total darunavir concentrations in CSF correlated with both total and unbound darunavir concentrations in plasma. CONCLUSIONS: Darunavir should contribute to the control of HIV replication in the CNS as a component of effective combination antiretroviral regimens.
  Journal of Antimicrobial Chemotherapy 11/2012; · 5.07 Impact Factor
• Article: Concurrent Classification Accuracy of the HIV Dementia Scale for HIV-associated Neurocognitive Disorders in the CHARTER Cohort.

  Maiko Sakamoto, Thomas D Marcotte, Anya Umlauf, Donald Franklin, Robert K Heaton, Ronald J Ellis, Scott Letendre, Terry Alexander, J Allen McCutchan, Erin E Morgan, Steven Paul Woods, Ann C Collier, Christina M Marra, David B Clifford, Benjamin B Gelman, Justin C McArthur, Susan Morgello, David Simpson, Igor Grant
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  ABSTRACT: BACKGROUND:: The HIV Dementia Scale (HDS) was developed to screen for HIV-associated Neurocognitive Disorders (HAND), but concerns have persisted regarding its substandard sensitivity. This study aimed to examine the classification accuracy of the HDS using raw and norm-based cutpoints, and to evaluate the contribution of the HDS subtests to predicting HAND. METHODS:: 1,580 HIV-infected participants from 6 U.S. sites completed the HDS, and a gold standard neuropsychological battery, on which 51% of participants were impaired. RESULTS:: Sensitivity and specificity to HAND using the standard raw HDS cutpoint were 24% and 92%, respectively. The raw HDS subtests of attention, recall, and psychomotor speed significantly contributed to classification of HAND, while visuomotor construction contributed the least. A modified raw cutpoint of 14 yielded sensitivity of 66% and specificity of 61%, with cross-validation. Using norms also significantly improved sensitivity to 69% with a concomitant reduction of specificity to 56%, while the positive predictive value declined from 75% to 62% and negative predictive value improved from 54% to 64%. The HDS showed similarly modest rates of sensitivity and specificity among subpopulations of individuals with minimal comorbidity and successful viral suppression. CONCLUSIONS:: Findings indicate that while the HDS is a statistically significant predictor of HAND, particularly when adjusted for demographic factors, its relatively low diagnostic classification accuracy continues to hinder its clinical utility. A raw cutpoint of 14 greatly improved the sensitivity of the previously established raw cutscore, but may be subject to ceiling effects, particularly on repeat assessments.
  JAIDS Journal of Acquired Immune Deficiency Syndromes 10/2012; · 4.43 Impact Factor
• Article: Mitochondrial DNA variation and HIV-associated sensory neuropathy in CHARTER.

  Emily R Holzinger, Todd Hulgan, Ronald J Ellis, David C Samuels, Marylyn D Ritchie, David W Haas, Asha R Kallianpur, Cinnamon S Bloss, David B Clifford, Ann C Collier, [......], Christina M Marra, Justin C McArthur, J Allen McCutchan, Susan Morgello, David M Simpson, Donald R Franklin, Debralee Rosario, Doug Selph, Scott Letendre, Igor Grant
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  ABSTRACT: HIV-associated sensory neuropathy remains an important complication of combination antiretroviral therapy and HIV infection. Mitochondrial DNA haplogroups and single nucleotide polymorphisms (SNPs) have previously been associated with symptomatic neuropathy in clinical trial participants. We examined associations between mitochondrial DNA variation and HIV-associated sensory neuropathy in CNS HIV Antiretroviral Therapy Effects Research (CHARTER). CHARTER is a USA-based longitudinal observational study of HIV-infected adults who underwent a structured interview and standardized examination. HIV-associated sensory neuropathy was determined by trained examiners as ≥1 sign (diminished vibratory and sharp-dull discrimination or ankle reflexes) bilaterally. Mitochondrial DNA sequencing was performed and haplogroups were assigned by published algorithms. Multivariable logistic regression of associations between mitochondrial DNA SNPs, haplogroups, and HIV-associated sensory neuropathy were performed. In analyses of associations of each mitochondrial DNA SNP with HIV-associated sensory neuropathy, the two most significant SNPs were at positions A12810G [odds ratio (95 % confidence interval) = 0.27 (0.11-0.65); p = 0.004] and T489C [odds ratio (95 % confidence interval) = 0.41 (0.21-0.80); p = 0.009]. These synonymous changes are known to define African haplogroup L1c and European haplogroup J, respectively. Both haplogroups were associated with decreased prevalence of HIV-associated sensory neuropathy compared with all other haplogroups [odds ratio (95 % confidence interval) = 0.29 (0.12-0.71); p = 0.007 and odds ratio (95 % confidence interval) = 0.42 (0.18-1.0); p = 0.05, respectively]. In conclusion, in this cohort of mostly combination antiretroviral therapy-treated subjects, two common mitochondrial DNA SNPs and their corresponding haplogroups were associated with a markedly decreased prevalence of HIV-associated sensory neuropathy.
  Journal of NeuroVirology 10/2012; · 2.31 Impact Factor
• Article: Cerebral β-amyloid deposition predicts HIV-associated neurocognitive disorders in APOE ε4 carriers.

  Virawudh Soontornniyomkij, David J Moore, Ben Gouaux, Benchawanna Soontornniyomkij, Erick T Tatro, Anya Umlauf, Eliezer Masliah, Andrew J Levine, Elyse J Singer, Harry V Vinters, Benjamin B Gelman, Susan Morgello, Mariana Cherner, Igor Grant, Cristian L Achim
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  ABSTRACT: OBJECTIVE:: The apolipoprotein E (APOE) ε4 allele enhances cerebral accumulation of β-amyloid (Aβ) and is a major risk factor for sporadic Alzheimer's disease (AD). We hypothesized that HIV-associated neurocognitive disorders (HAND) would be associated with the APOE ε4 genotype and cerebral Aβ deposition. DESIGN:: Clinico-pathological study of HIV-infected adults from four prospective cohorts in the U.S. National NeuroAIDS Tissue Consortium. METHODS:: We used multivariable logistic regressions to model outcomes (Aβ plaques [immunohistochemistry] and HAND [standard criteria]) on predictors (APOE ε4 [allelic discrimination assay], older age [≥50 years], Aβ plaques, and their two-way interactions) and co-morbid factors. RESULTS:: Isocortical Aβ deposits generally occurred as diffuse plaques and mild to moderate amyloid angiopathy. Isocortical phospho-Tau-immunoreactive neurofibrillary lesions were sparse. The APOE ε4 and older age were independently associated with the presence of Aβ plaques (adjusted odds ratio [OR] 10.16 and 5.77 [95% confidence interval (CI) 2.89 - 35.76 and 1.91-17.48], P = 0.0003 and 0.0019, respectively, n = 96). The probability of HAND was increased in the presence of Aβ plaques among APOE ε4 carriers (adjusted OR 30.00 [95% CI 1.41-638.63], P = 0.029, n = 15), but not in non-ε4 carriers (n = 57). CONCLUSION:: The APOE ε4 and older age increased the likelihood of cerebral Aβ plaque deposition in HIV-infected adults. Generally Aβ plaques in HIV brains were immunohistologically different from those in symptomatic AD brains. Nonetheless, Aβ plaques were associated with HAND among APOE ε4 carriers. The detection of APOE ε4 genotype and cerebral Aβ deposition biomarkers may be useful in identifying living HAND subjects who could benefit from Aβ-targeted therapies.
  AIDS (London, England) 09/2012; · 4.91 Impact Factor
• Article: Substance abuse increases the risk of neuropathy in an HIV-infected cohort.

  Jessica Robinson-Papp, Benjamin B Gelman, Igor Grant, Elyse Singer, Gary Gensler, Susan Morgello
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  ABSTRACT: Human immunodeficiency virus (HIV)-infected patients commonly develop distal symmetric polyneuropathy (DSP). Age, ethnicity, and toxic exposures may influence the risk. In this study we examined the association between substance use, antiretrovirals, ethnicity, and incident neuropathy in an HIV-infected cohort. Data were obtained from the National NeuroAIDS Tissue Consortium (NNTC), an ongoing, prospective cohort started in 1998. Cox proportional hazards models were used to examine the association of substance use, demographics, neurotoxic antiretrovirals, and laboratory parameters with incident neuropathy in 636 participants who were neuropathy-free at baseline. The cumulative incidence of DSP was 41%. Substance use (P = 0.04), number of substances used (P = 0.04), and longer duration of HIV infection (P = 0.05) were associated with incident DSP, but demographic factors, use of neurotoxic antiretrovirals, and laboratory parameters were not. Substance use and longer duration of HIV infection are risk factors for DSP in HIV-infected patients. Use of multiple substances may be particularly risky.
  Muscle & Nerve 04/2012; 45(4):471-6. · 2.37 Impact Factor
• Article: Genetic features of cerebrospinal fluid-derived subtype B HIV-1 tat.

  Jun Yong Choi, George K Hightower, Joseph K Wong, Robert Heaton, Steven Woods, Igor Grant, Thomas D Marcotte, Ronald J Ellis, Scott L Letendre, Ann C Collier, Christina M Marra, David B Clifford, Benjamin B Gelman, Justin C McArthur, Susan Morgello, David M Simpson, J Allen McCutchan, Douglas D Richman, Davey M Smith
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  ABSTRACT: Since HIV-1 Tat has been associated with neurocognitive dysfunction, we investigated 60 HIV-1 subtype B-infected individuals who were characterized for neurocognitive functioning and had paired CSF and blood plasma samples available. To avoid issues with repeated sampling, we generated population-based HIV-1 tat sequences from each compartment and evaluated these data using a battery of phylogenetic, statistical, and machine learning tools. These analyses identified position HXB2 5905 within the cysteine-rich domain of tat as a signature of CSF-derived HIV-1, and a higher number of mixed bases in CSF, as measure of diversity, was associated with HIV-associated neurocognitive disorder. Since identified mutations were synonymous, we evaluated the predicted secondary RNA structures, which showed that this mutation altered secondary structure. As a measure of divergence, the genetic distance between the blood and CSF-derived tat was inversely correlated with current and nadir CD4+ T cell counts. These data suggest that specific HIV-1 features of tat influence neurotropism and neurocognitive impairment.
  Journal of NeuroVirology 04/2012; 18(2):81-90. · 2.31 Impact Factor
• Article: Lower than expected maraviroc concentrations in cerebrospinal fluid exceed the wild-type CC chemokine receptor 5-tropic HIV-1 50% inhibitory concentration.

  David Croteau, Brookie M Best, Scott Letendre, Steven S Rossi, Ronald J Ellis, David B Clifford, Ann C Collier, Benjamin B Gelman, Justin C McArthur, John Allen McCutchan, Susan Morgello, Igor Grant
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  ABSTRACT: To measure maraviroc total cerebrospinal fluid (CSF) concentrations and compare them with total and unbound plasma concentrations. Total maraviroc was measured by reverse-phase high-performance liquid chromatography with tandem mass spectrometry, whereas ultrafiltration was used for unbound maraviroc. Maraviroc was detected in all nine CSF/plasma pairs with a median CSF total concentration of 2.4 ng/ml. CSF concentrations exceeded the 50% inhibitory concentration of wild-type CC chemokine receptor 5-tropic HIV-1 in all specimens. CSF concentrations are lower than expected based on plasma concentrations and physicochemical characteristics. Unbound maraviroc plasma concentrations may be informative in estimating concentrations in CSF.
  AIDS (London, England) 02/2012; 26(7):890-3. · 4.91 Impact Factor
• Article: Therapeutic amprenavir concentrations in cerebrospinal fluid.

  David Croteau, Scott Letendre, Brookie M Best, Steven S Rossi, Ronald J Ellis, David B Clifford, Ann C Collier, Benjamin B Gelman, Christina M Marra, Justin McArthur, J Allen McCutchan, Susan Morgello, David M Simpson, Lauren Way, Edmund Capparelli, Igor Grant
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  ABSTRACT: Antiretrovirals that reach higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV in CSF and possibly better neurocognitive performance. The objective of this study was to determine whether amprenavir (APV) concentrations in CSF are in the therapeutic range. Individuals were selected based on the use of regimens that included fosamprenavir (FPV), a prodrug of APV, and the availability of stored CSF and matched plasma. Total APV was measured in 119 matched CSF-plasma pairs from 75 subjects by high-performance liquid chromatography (HPLC) (plasma) or liquid chromatography tandem mass spectrometry (LC/MS/MS) (CSF). Concentrations were compared to the 50% inhibitory concentration (IC₅₀) for wild-type HIV (5.6 ng/ml). Subjects were predominantly middle-aged (median 44 years) white (57%) men (78%) with AIDS (77%). APV was detected in all but 4 CSF specimens, with a median concentration of 24.8 ng/ml (interquartile range [IQR], 16.2 to 44.0). The median CSF-to-plasma ratio was 0.012 (IQR, 0.008 to 0.018). CSF concentrations correlated with plasma concentrations (rho = 0.61; P < 0.0001) and with postdose sampling interval (rho = -0.29; P = 0.0019). APV concentrations in CSF exceeded the median IC₅₀ for wild-type HIV in more than 97% of CSF specimens with detectable APV by a median of 4.4-fold (IQR, 2.9 to 7.9). We conclude that administration of fosamprenavir should contribute to control of HIV replication in the central nervous system (CNS) as a component of effective antiretroviral regimens.
  Antimicrobial Agents and Chemotherapy 01/2012; 56(4):1985-9. · 4.84 Impact Factor
• Article: Low cerebrospinal fluid concentrations of the nucleotide HIV reverse transcriptase inhibitor, tenofovir.

  Brookie M Best, Scott L Letendre, Peter Koopmans, Steven S Rossi, David B Clifford, Ann C Collier, Benjamin B Gelman, Christina M Marra, Justin C McArthur, J Allen McCutchan, Susan Morgello, David M Simpson, Edmund V Capparelli, Ronald J Ellis, Igor Grant
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  ABSTRACT: Tenofovir is a nucleotide HIV reverse transcriptase inhibitor whose chemical properties suggest that it may not penetrate into the central nervous system in therapeutic concentrations. The study's objective was to determine tenofovir's penetration into cerebrospinal fluid (CSF). CNS HIV Antiretroviral Therapy Effects Research is a multicenter observational study to determine the effects of antiretroviral therapy on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within an hour of each other from subjects taking tenofovir between October 2003 and March 2007. All samples were assayed by mass spectrometry with a detection limit of 0.9 ng/mL. One hundred eighty-three participants (age 44 ± 8 years; 83 ± 32 kg; 33 females; CSF protein 44 ± 16 mg/dL) had plasma and CSF samples drawn 12.2 ± 6.9 and 11 ± 7.8 hours post dose, respectively. Median plasma and CSF tenofovir concentrations were 96 ng/mL [interquartile range (IQR) 47-153 ng/mL] and 5.5 ng/mL (IQR 2.7-11.3 ng/mL), respectively. Thirty-four of 231 plasma (14.7%) and 9 of 77 CSF samples (11.7%) were below detection. CSF to plasma concentration ratio from paired samples was 0.057 (IQR 0.03-0.1; n = 38). Median CSF to wild-type 50% inhibitory concentration ratio was 0.48 (IQR 0.24-0.98). Seventy-seven percent of CSF concentrations were below the tenofovir wild-type 50% inhibitory concentration. More subjects had detectable CSF HIV with lower (≤ 7 ng/mL) versus higher (>7 ng/mL) CSF tenofovir concentrations (29% versus 9%; P = 0.05). Tenofovir concentrations in the CSF are only 5% of plasma concentrations, suggesting limited transfer into the CSF, and possibly active transport out of the CSF. CSF tenofovir concentrations may not effectively inhibit viral replication in the CSF.
  JAIDS Journal of Acquired Immune Deficiency Syndromes 01/2012; 59(4):376-81. · 4.43 Impact Factor
• Article: The National NeuroAIDS Tissue Consortium Brain Gene Array: Two Types of HIV-Associated Neurocognitive Impairment.

  Benjamin B Gelman, Tiansheng Chen, Joshua G Lisinicchia, Vicki M Soukup, J Russ Carmical, Jonathan M Starkey, Eliezer Masliah, Deborah L Commins, Dianne Brandt, Igor Grant, Elyse J Singer, Andrew J Levine, Jeremy Miller, Jessica M Winkler, Howard S Fox, Bruce A Luxon
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  ABSTRACT: The National NeuroAIDS Tissue Consortium (NNTC) performed a brain gene expression array to elucidate pathophysiologies of Human Immunodeficiency Virus type 1 (HIV-1)-associated neurocognitive disorders. Twenty-four human subjects in four groups were examined A) Uninfected controls; B) HIV-1 infected subjects with no substantial neurocognitive impairment (NCI); C) Infected with substantial NCI without HIV encephalitis (HIVE); D) Infected with substantial NCI and HIVE. RNA from neocortex, white matter, and neostriatum was processed with the Affymetrix® array platform. With HIVE the HIV-1 RNA load in brain tissue was three log(10) units higher than other groups and over 1,900 gene probes were regulated. Interferon response genes (IFRGs), antigen presentation, complement components and CD163 antigen were strongly upregulated. In frontal neocortex downregulated neuronal pathways strongly dominated in HIVE, including GABA receptors, glutamate signaling, synaptic potentiation, axon guidance, clathrin-mediated endocytosis and 14-3-3 protein. Expression was completely different in neuropsychologically impaired subjects without HIVE. They had low brain HIV-1 loads, weak brain immune responses, lacked neuronally expressed changes in neocortex and exhibited upregulation of endothelial cell type transcripts. HIV-1-infected subjects with normal neuropsychological test results had upregulation of neuronal transcripts involved in synaptic transmission of neostriatal circuits. Two patterns of brain gene expression suggest that more than one pathophysiological process occurs in HIV-1-associated neurocognitive impairment. Expression in HIVE suggests that lowering brain HIV-1 replication might improve NCI, whereas NCI without HIVE may not respond in kind; array results suggest that modulation of transvascular signaling is a potentially promising approach. Striking brain regional differences highlighted the likely importance of circuit level disturbances in HIV/AIDS. In subjects without impairment regulation of genes that drive neostriatal synaptic plasticity reflects adaptation. The array provides an infusion of public resources including brain samples, clinicopathological data and correlative gene expression data for further exploration (http://www.nntc.org/gene-array-project).
  PLoS ONE 01/2012; 7(9):e46178. · 4.09 Impact Factor
• Article: Clinical factors related to brain structure in HIV: the CHARTER study.

  Terry L Jernigan, Sarah L Archibald, Christine Fennema-Notestine, Michael J Taylor, Rebecca J Theilmann, Michelle D Julaton, Randy J Notestine, Tanya Wolfson, Scott L Letendre, Ronald J Ellis, [......], Donald R Franklin, David B Clifford, Ann C Collier, Benjamin B Gelman, Christina Marra, Justin C McArthur, J Allen McCutchan, Susan Morgello, David M Simpson, Igor Grant
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  ABSTRACT: Despite the widening use of combination antiretroviral therapy (ART), neurocognitive impairment remains common among HIV-infected (HIV+) individuals. Associations between HIV-related neuromedical variables and magnetic resonance imaging indices of brain structural integrity may provide insight into the neural bases for these symptoms. A diverse HIV+ sample (n = 251) was studied through the CNS HIV Antiretroviral Therapy Effects Research initiative. Multi-channel image analysis produced volumes of ventricular and sulcal cerebrospinal fluid (CSF), cortical and subcortical gray matter, total cerebral white matter, and abnormal white matter. Cross-sectional analyses employed a series of multiple linear regressions to model each structural volume as a function of severity of prior immunosuppression (CD4 nadir), current CD4 count, presence of detectable CSF HIV RNA, and presence of HCV antibodies; secondary analyses examined plasma HIV RNA, estimated duration of HIV infection, and cumulative exposure to ART. Lower CD4 nadir was related to most measures of the structural brain damage. Higher current CD4, unexpectedly, correlated with lower white and subcortical gray and increased CSF. Detectable CSF HIV RNA was related to less total white matter. HCV coinfection was associated with more abnormal white matter. Longer exposure to ART was associated with lower white matter and higher sulcal CSF. HIV neuromedical factors, including lower nadir, higher current CD4 levels, and detectable HIV RNA, were associated with white matter damage and variability in subcortical volumes. Brain structural integrity in HIV likely reflects dynamic effects of current immune status and HIV replication, superimposed on residual effects associated with severe prior immunosuppression.
  Journal of NeuroVirology 06/2011; 17(3):248-57. · 2.31 Impact Factor
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  Available from: Donald Ray Franklin

  Article: HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors.

  Robert K Heaton, Donald R Franklin, Ronald J Ellis, J Allen McCutchan, Scott L Letendre, Shannon Leblanc, Stephanie H Corkran, Nichole A Duarte, David B Clifford, Steven P Woods, [......], Tanya Wolfson, Benjamin B Gelman, Justin C McArthur, David M Simpson, Ian Abramson, Anthony Gamst, Christine Fennema-Notestine, Terry L Jernigan, Joseph Wong, Igor Grant
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  ABSTRACT: Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV-) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV - participants from the pre-CART era (1988-1995; N = 857) and CART era (2000-2007; N = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation.
  Journal of NeuroVirology 02/2011; 17(1):3-16. · 2.31 Impact Factor
• Article: Family history of dementia predicts worse neuropsychological functioning among HIV-infected persons.

  David J Moore, Miguel Arce, Suzanne Moseley, J Allen McCutchan, Jennifer Marquie-Beck, Donald R Franklin, Florin Vaida, Cristian L Achim, Justin McArthur, Susan Morgello, David M Simpson, Benjamin B Gelman, Ann C Collier, Christina M Marra, David B Clifford, Robert K Heaton, Igor Grant
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  ABSTRACT: HIV-negative individuals with a family history of dementia (FHD) are more likely to develop dementia than those without FHD. Whether FHD increases risk for neuropsychological (NP) impairment in HIV+ persons is unknown. As part of a multisite study into HIV-associated neurocognitive disorders (HAND), the authors captured FHD with a free-response, self-report question, and assessed NP performance with a comprehensive battery of tests. The authors examined HIV+ persons with (N=190) and without (N=916) self-reported FHD. Despite the fact that the FHD group had factors typically associated with better NP performance (e.g., higher CD4 counts and estimated verbal IQ), persons with FHD had significantly worse NP ability than those without FHD as measured by a Global Deficit Score. Thus, FHD appears to be a risk factor for HAND; the mechanism(s) underlying how FHD contributes to NP impairment among HIV+ persons warrants study.
  The Journal of neuropsychiatry and clinical neurosciences 01/2011; 23(3):316-23. · 2.34 Impact Factor
• Article: Efavirenz concentrations in CSF exceed IC50 for wild-type HIV.

  Brookie M Best, Peter P Koopmans, Scott L Letendre, Edmund V Capparelli, Steven S Rossi, David B Clifford, Ann C Collier, Benjamin B Gelman, Gilbert Mbeo, J Allen McCutchan, David M Simpson, Richard Haubrich, Ronald Ellis, Igor Grant
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  ABSTRACT: HIV-associated neurocognitive disorders remain common despite use of potent antiretroviral therapy (ART). Ongoing viral replication due to poor distribution of antivirals into the CNS may increase risk for HIV-associated neurocognitive disorders. This study's objective was to determine penetration of a commonly prescribed antiretroviral drug, efavirenz, into CSF. CHARTER is an ongoing, North American, multicentre, observational study to determine the effects of ART on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within 1 h of each other from subjects taking efavirenz between September 2003 and July 2007. Samples were assayed by HPLC or HPLC/mass spectrometry with detection limits of 39 ng/mL (plasma) and <0.1 ng/mL (CSF). Eighty participants (age 44 ± 8 years; 79 ± 15 kg; 20 females) had samples drawn 12.5 ± 5.4 h post-dose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2-17] of therapy were 2145 ng/mL in plasma (IQR 1384-4423) and 13.9 ng/mL in CSF (IQR 4.1-21.2). The CSF/plasma concentration ratio from paired samples drawn within 1 h of each other was 0.005 (IQR 0.0026-0.0076; n = 69). The CSF/IC(50) ratio was 26 (IQR 8-41) using the published IC(50) for wild-type HIV (0.51 ng/mL). Two CSF samples had concentrations below the efavirenz IC(50) for wild-type HIV. Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC(50) in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.
  Journal of Antimicrobial Chemotherapy 11/2010; 66(2):354-7. · 5.07 Impact Factor
• Article: Continued high prevalence and adverse clinical impact of human immunodeficiency virus-associated sensory neuropathy in the era of combination antiretroviral therapy: the CHARTER Study.

  Ronald J Ellis, Debralee Rosario, David B Clifford, Justin C McArthur, David Simpson, Terry Alexander, Benjamin B Gelman, Florin Vaida, Ann Collier, Christina M Marra, Beau Ances, J Hampton Atkinson, Robert H Dworkin, Susan Morgello, Igor Grant
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  ABSTRACT: To provide updated estimates of the prevalence and clinical impact of human immunodeficiency virus-associated sensory neuropathy (HIV-SN) and neuropathic pain due to HIV-SN in the combination antiretroviral therapy (CART) era. Prospective, cross-sectional analysis. Clinical correlates for HIV-SN and neuropathic pain, including age, exposure to CART, CD4 levels, plasma viral load, hepatitis C virus infection, and alcohol use disorders, were evaluated in univariate and multivariate models. Six US academic medical centers. One thousand five hundred thirty-nine HIV-infected individuals enrolled in the CNS (Central Nervous System) HIV Anti-Retroviral Therapy Effects Research study. The presence of HIV-SN, defined by 1 or more clinical signs (diminished vibration or sharp sensation in the legs and feet; reduced ankle reflexes) in a distal, symmetrical pattern. Neuropathic pain was defined as aching, stabbing, or burning in a similar distribution. The effect on quality of life was assessed with the Medical Outcomes Study HIV Health Survey. We found HIV-SN in 881 participants. Of these, 38.0% reported neuropathic pain. Neuropathic pain was significantly associated with disability in daily activities, unemployment, and reduced quality of life. Risk factors for HIV-SN after adjustment were advancing age (odds ratio, 2.1 [95% confidence interval, 1.8-2.5] per 10 years), lower CD4 nadir (1.2 [1.1-1.2] per 100-cell decrease), current CART use (1.6 [1.3-2.8]), and past "D-drug" use (specific dideoxynucleoside analogue antiretrovirals) (2.0 [1.3-2.6]). Risk factors for neuropathic pain were past D-drug use and higher CD4 nadir. Neuropathic pain and HIV-SN remain prevalent, causing substantial disability and reduced quality of life even with successful CART. The clinical correlates of HIV-SN have changed with the evolution of treatment. These findings argue for redoubled efforts to determine HIV-SN pathogenesis and the development of symptomatic and neuroregenerative therapies.
  Archives of neurology 05/2010; 67(5):552-8. · 6.31 Impact Factor
• Article: Persistent hijacking of brain proteasomes in HIV-associated dementia.

  Trung P Nguyen, Vicki M Soukup, Benjamin B Gelman
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  ABSTRACT: Immunoproteasome induction sustains class 1 antigen presentation and immunological vigilance against HIV-1 in the brain. Investigation of HIV-1-associated alterations in brain protein turnover by the ubiquitin-proteasome system was performed by (1) determining proteasome subunit changes associated with persistent brain inflammation due to HIV-1; (2) determining whether these changes are related to HIV-1 neurocognitive disturbances, encephalitis, and viral loads; and (3) localizing proteasome subunits in brain cells and synapses. On the basis of neurocognitive performance, virological, and immunological measurements obtained within 6 months before death, 153 autopsy cases were selected. Semiquantitative immunoblot analysis performed in the dorsolateral prefrontal cortex revealed up to threefold induction of immunoproteasome subunits LMP7 and PA28alpha in HIV-1-infected subjects and was strongly related to diagnoses of neuropsychological impairment and HIV encephalitis. Low performance on neurocognitive tests specific for dorsolateral prefrontal cortex functioning domains was selectively correlated with immunoproteasome induction. Immunohistochemistry and laser confocal microscopy were then used to localize immunoproteasome subunits to glial and neuronal elements including perikarya, dystrophic axons, and synapses. In addition, HIV loads in brain tissue, cerebrospinal fluid, and blood plasma were robustly correlated to immunoproteasome levels. This persistent "hijacking" of the proteasome by HIV-1-mediated inflammatory response and immunoproteasome induction in the brain is hypothesized to impede turnover of folded proteins in brain cells. This would disrupt neuronal and synaptic protein dynamics, contributing to HIV-1 neurocognitive disturbances.
  American Journal Of Pathology 02/2010; 176(2):893-902. · 4.89 Impact Factor
• Article: Molecular confirmation of Sappinia pedata as a causative agent of amoebic encephalitis.

  Yvonne Qvarnstrom, Alexandre J da Silva, Frederick L Schuster, Benjamin B Gelman, Govinda S Visvesvara
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  ABSTRACT: Pathogenic free-living amoebae, such as Acanthamoeba species, Balamuthia mandrillaris, and Naegleria fowleri, are known to cause infections of the central nervous system in human and other animals. In 2001, a case of human encephalitis was reported that was caused by another amoeba with morphological features suggestive of Sappinia. The amoeba originally identified as Sappinia diploidea was identified, most likely as S. pedata, by use of newly developed real-time polymerase chain reaction assays. This amoeba had previously been found only in environmental sources, such as soil and tree bark. The results illustrate the potential for other free-living amoebae, which are not normally associated with human disease, to cause occasional infections.
  The Journal of Infectious Diseases 05/2009; 199(8):1139-42. · 6.41 Impact Factor
• Article: Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy.

  Ronald J Ellis, Jennifer Marquie-Beck, Patrick Delaney, Terry Alexander, David B Clifford, Justin C McArthur, David M Simpson, Christopher Ake, Ann C Collier, Benjamin B Gelman, J Allen McCutchan, Susan Morgello, Igor Grant
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  ABSTRACT: Two recent analyses found that exposure to protease inhibitors (PIs) in the context of antiretroviral (ARV) therapy increased the risk for distal sensory polyneuropathy (DSPN) in subjects with human immunodeficiency virus (HIV) infection. These findings were supported by an in vitro model in which PI exposure produced neurite retraction and process loss in dorsal root ganglion sensory neurons. Confirmation of peripheral nerve toxicity with PIs could substantially limit their long-term use in highly active ARV therapy. We evaluated current and past exposure to PIs as a risk factor for DSPN in 1,159 HIV-infected individuals enrolled in a large, prospective, observational, multicenter study. Signs of DSPN were ascertained by neurological examination. Subjects were grouped into categories according to past and current exposure to any ARV and to PIs. We included disease indicators such as nadir CD4, plasma viral load, and duration of HIV infection, as well as advancing age and exposure to dideoxynucleoside ARVs in multivariate models. In univariate analyses, both past and current PI exposure significantly increased the risk for DSPN. However, after adjusting for previously validated concomitant risk factors in multivariate models, none of the PI exposure groups was more likely to have DSPN than ARV naive subjects. A secondary evaluation of duration of PI use and exposure to individual PI drugs was similarly nonsignificant in multivariate models, except for small effects of amprenavir and lopinavir. Evaluation of concomitant risks for HIV DSPN suggests that the independent risk attributable to PIs, if any, is small. This risk must be weighed against the important role of PIs in modern ARV therapy regimens.
  Annals of Neurology 12/2008; 64(5):566-72. · 11.09 Impact Factor
• Article: Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system.

  Scott Letendre, Jennifer Marquie-Beck, Edmund Capparelli, Brookie Best, David Clifford, Ann C Collier, Benjamin B Gelman, Justin C McArthur, J Allen McCutchan, Susan Morgello, David Simpson, Igor Grant, Ronald J Ellis
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  ABSTRACT: To evaluate whether penetration of a combination regimen into the central nervous system (CNS), as estimated by the CNS Penetration-Effectiveness (CPE) rank, is associated with lower cerebrospinal fluid (CSF) viral load. Data were analyzed from 467 participants who were human immunodeficiency virus (HIV) seropositive and who reported antiretroviral (ARV) drug use. Individual ARV drugs were assigned a penetration rank of 0 (low), 0.5 (intermediate), or 1 (high) based on their chemical properties, concentrations in CSF, and/or effectiveness in the CNS in clinical studies. The CPE rank was calculated by summing the individual penetration ranks for each ARV in the regimen. The median CPE rank was 1.5 (interquartile range, 1-2). Lower CPE ranks correlated with higher CSF viral loads. Ranks less than 2 were associated with an 88% increase in the odds of detectable CSF viral load. In multivariate regression, lower CPE ranks were associated with detectable CSF viral loads even after adjusting for total number of ARV drugs, ARV drug adherence, plasma viral load, duration and type of the current regimen, and CD4 count. Poorer penetration of ARV drugs into the CNS appears to allow continued HIV replication in the CNS as indicated by higher CSF HIV viral loads. Because inhibition of HIV replication in the CNS is probably critical in treating patients who have HIV-associated neurocognitive disorders, ARV treatment strategies that account for CNS penetration should be considered in consensus treatment guidelines and validated in clinical studies.
  Archives of Neurology 02/2008; 65(1):65-70. · 7.58 Impact Factor