Christina M Marra

Publications (40)237.8 Total impact

• Article: Two Mutations Associated With Macrolide Resistance in Treponema pallidum: Increasing Prevalence and Correlation With Molecular Strain Type in Seattle, Washington.

  Matthew Grimes, Sharon K Sahi, B Charmie Godornes, Lauren C Tantalo, Neal Roberts, David Bostick, Christina M Marra, Sheila A Lukehart
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  ABSTRACT: Although azithromycin promised to be a safe and effective single-dose oral treatment of early syphilis, azithromycin treatment failure has been documented and is associated with mutations in the 23S rDNA of corresponding Treponema pallidum strains. The prevalence of strains harboring these mutations varies throughout the United States and the world. We examined T. pallidum strains circulating in Seattle, Washington, from 2001 to 2010 to determine the prevalence of 2 mutations associated with macrolide resistance and to determine whether these mutations were associated with certain T. pallidum strain types. Subjects were enrolled in a separate ongoing study of cerebrospinal fluid abnormalities in patients with syphilis. T. pallidum DNA purified from blood and T. pallidum strains isolated from blood or cerebrospinal fluid were analyzed for two 23S rDNA mutations and for the molecular targets used in an enhanced molecular stain typing system. Nine molecular strain types of T. pallidum were identified in Seattle from 2001 to 2010. Both macrolide resistance mutations were identified in Seattle strains, and the prevalence of resistant T. pallidum exceeded 80% in 2005 and increased through 2010. Resistance mutations were associated with discrete molecular strain types of T. pallidum. Macrolide-resistant T. pallidum strains are highly prevalent in Seattle, and each mutation is associated with discrete strain types. Macrolides should not be considered for treatment of syphilis in regions where prevalence of the mutations is high. Combining the resistance mutations with molecular strain typing permits a finer analysis of the epidemiology of syphilis in a community.
  Sexually transmitted diseases 12/2012; 39(12):954-8. · 2.58 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: Health-related quality of life 'well-being' in HIV distal neuropathic pain is more strongly associated with depression severity than with pain intensity.

  John R Keltner, Florin Vaida, Ronald J Ellis, Tobias Moeller-Bertram, Chelsea Fitzsimmons, Nichole A Duarte, Jessica Robinson-Papp, Robert H Dworkin, David B Clifford, Justin C McArthur, David M Simpson, Ann C Collier, Christina M Marra, J Hampton Atkinson, Igor Grant
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  ABSTRACT: Despite modern antiretroviral treatment, HIV-associated distal neuropathic pain (DNP) remains one of the most prevalent and debilitating complications of HIV disease. Neuropathic pain is often accompanied by depressed mood, and both pain and depression have been associated with decreased health-related quality of life (HRQOL) well-being. The relative contribution of depression and pain to worse life quality has not been addressed, however, even though a better understanding might sharpen intervention strategies. We used the Medical Outcomes Study HIV (MOS-HIV) Health Survey and the Beck depression inventory-II and linear regression models to investigate HRQOL well-being in HIV-infected patients with DNP (n = 397) participating in an observational cohort study at six U.S. sites (CNS HIV Antiretroviral Treatment Effects Research Study, CHARTER). For this sample of patients with HIV DNP, severity of depressed mood was more highly correlated with HRQOL well-being than was pain intensity. These results suggest that interventions to improve HRQOL well-being in individuals with HIV-associated DNP may need to address not only pain intensity but mood state as well.
  Psychosomatics 07/2012; 53(4):380-6. · 2.12 Impact Factor
• Article: The rapid plasma reagin test cannot replace the venereal disease research laboratory test for neurosyphilis diagnosis.

  Christina M Marra, Lauren C Tantalo, Clare L Maxwell, Emily L Ho, Sharon K Sahi, Trudy Jones
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  ABSTRACT: The cerebrospinal fluid (CSF) Venereal Disease Research Laboratory (VDRL) test is a mainstay for neurosyphilis diagnosis, but it lacks diagnostic sensitivity and is logistically complicated. The rapid plasma reagin (RPR) test is easier to perform, but its appropriateness for use on CSF is controversial. RPR reactivity was determined for CSF from 149 individuals with syphilis using 2 methods. The CSF-RPR was performed according to the method for serum. The CSF-RPR-V was performed using the method recommended for the CSF-VDRL. Laboratory-defined neurosyphilis included reactive CSF-fluorescent treponemal antibody absorption test and CSF white blood cells >20/uL. Symptomatic neurosyphilis was defined as vision loss or hearing loss. CSF-VDRL was reactive in 45 (30.2%) patients. Of these, 29 (64.4%) were CSF-RPR reactive and 37 (82.2%) were CSF-RPR-V reactive. There were no instances where the CSF-VDRL was nonreactive but the CSF-RPR or CSF-RPR-V was reactive. Among the 28 samples that were reactive in all 3 tests, CSF-VDRL titers (median [IQR], 1:4 [1:4-1:16]) were significantly higher than CSF-RPR (1:2 [1:1-1:4], P = 0.0002) and CSF-RPR-V titers (1:4 [1:2-1:8], P = 0.01). The CSF RPR and the CSF-RPR-V tests had lower sensitivities than the CSF-VDRL: 56.4% and 59.0% versus 71.8% for laboratory-diagnosed neurosyphilis and 51.5% and 57.6% versus 66.7% for symptomatic neurosyphilis. Compared with the CSF-VDRL, the CSF-RPR has a high false-negative rate, thus not improving upon this known limitation of the CSF-VDRL for neurosyphilis diagnosis. Adapting the RPR procedure to mimic the CSF-VDRL decreased, but did not eliminate, the number of false negatives and did not avoid all the logistical complications of the CSF-VDRL.
  Sexually transmitted diseases 06/2012; 39(6):453-7. · 2.58 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: 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: Lifetime suicidal ideation and attempt are common among HIV+ individuals.

  Jayraan Badiee, David J Moore, J Hampton Atkinson, Florin Vaida, Mickey Gerard, Nichole A Duarte, Donald Franklin, Ben Gouaux, J Allen McCutchan, Robert K Heaton, Justin McArthur, Susan Morgello, David Simpson, Ann Collier, Christina M Marra, Benjamin Gelman, David Clifford, Igor Grant
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  ABSTRACT: Estimates of the prevalence of lifetime suicidal ideation and attempt, and risks for new-onset suicidality, among HIV-infected (HIV+) individuals are not widely available in the era of modern combined antiretroviral treatment (cART). Participants (n=1560) were evaluated with a comprehensive battery of tests that included the depression and substance use modules of the Composite International Diagnostic Interview (CIDI) and the Beck Depression Inventory-II (BDI-II) as part of a large prospective cohort study at six U.S. academic medical centers. Participants with possible lifetime depression (n=981) were classified into five categories: 1) no thoughts of death or suicide (n=352); 2) thoughts of death (n=224); 3) thoughts of suicide (n=99); 4) made a suicide plan (n=102); and 5) attempted suicide (n=204). Twenty-six percent (405/1560) of participants reported lifetime suicidal ideation and 13% (204/1560) reported lifetime suicide attempt. Participants who reported suicidal thoughts or plans, or attempted suicide, reported higher scores on the BDI-II (p<0.0001), and higher rates of current major depressive disorder (p=0.01), than those who did not. Attempters reported higher rates of lifetime substance abuse (p=0.02) and current use of psychotropic medications (p=0.01) than non-attempters. Study assessments focused on lifetime, rather than current, suicide. Data was not collected on the timing of ideation or attempt, frequency, or nature of suicide attempt. High rates of lifetime suicidal ideation and attempt, and the relationship of past report with current depressed mood, suggest that mood disruption is still prevalent in HIV. Findings emphasize the importance of properly diagnosing and treating psychiatric comorbidities among HIV persons in the cART era.
  Journal of affective disorders 07/2011; 136(3):993-9. · 3.76 Impact Factor
• Source

  Available from: Donald Ray Franklin

  Article: Neurocognitive impact of substance use in HIV infection.

  Desiree A Byrd, Robert P Fellows, Susan Morgello, Donald Franklin, Robert K Heaton, Reena Deutsch, J Hampton Atkinson, David B Clifford, Ann C Collier, Christina M Marra, Benjamin Gelman, J Allen McCutchan, Nichole A Duarte, David M Simpson, Justin McArthur, Igor Grant
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  ABSTRACT: : To determine how serious a confound substance use (SU) might be in studies on HIV-associated neurocognitive disorder (HAND), we examined the relationship of SU history to neurocognitive impairment (NCI) in participants enrolled in the Central Nervous System HIV Antiretroviral Therapy Effects Research study. : After excluding cases with behavioral evidence of acute intoxication and histories of factors that independently could account for NCI (eg, stroke), baseline demographic, medical, SU, and neurocognitive data were analyzed from 399 participants. Potential SU risk for NCI was determined by the following criteria: lifetime SU Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis, self-report of marked lifetime SU, or positive urine toxicology. Participants were divided into 3 groups as follows: no SU (n = 134), nonsyndromic SU (n = 131), syndromic SU (n = 134) and matched on literacy level, nadir CD4, and depressive symptoms. : Although approximately 50% of the participants were diagnosed with HAND, a multivariate analysis of covariance of neurocogntive summary scores, covarying for urine toxicology, revealed no significant effect of SU status. Correlational analyses indicated weak associations between lifetime heroin dosage and poor recall and working memory and between cannabis and cocaine use and better verbal fluency. : These data indicate that HIV neurocognitive effects are seen at about the same frequency in those with and without historic substance abuse in cases that are equated on other factors that might contribute to NCI. Therefore, studies on neuroAIDS and its treatment need not exclude such cases. However, the effects of acute SU and current SU disorders on HAND require further study.
  JAIDS Journal of Acquired Immune Deficiency Syndromes 06/2011; 58(2):154-62. · 4.43 Impact Factor
• Source

  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: Stroke in a patient with human immunodeficiency virus and syphilis treated with penicillin and antiretroviral therapy.

  Joy B Bucher, Matthew R Golden, Alison E Heald, Christina M Marra
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  ABSTRACT: With the rising incidence and prevalence of syphilis, meningovascular syphilis and other forms of neurosyphilis have reappeared, particularly among persons infected with human immunodeficiency virus. We present a patient with meningovascular syphilis leading to stroke after treatment with penicillin and antiretroviral therapy.
  Sexually transmitted diseases 11/2010; 38(5):442-4. · 2.58 Impact Factor
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  Available from: sfcityclinic.org

  Article: Enhanced molecular typing of treponema pallidum: geographical distribution of strain types and association with neurosyphilis.

  Christina M Marra, Sharon K Sahi, Lauren C Tantalo, Charmie Godornes, Tara Reid, Frieda Behets, Anne Rompalo, Jeffrey D Klausner, Yue Ping Yin, Fiona Mulcahy, Matthew R Golden, Arturo Centurion-Lara, Sheila A Lukehart
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  ABSTRACT: Strain typing is a tool for determining the diversity and epidemiology of infections. Treponema pallidum DNA was isolated from 158 patients with syphilis from the United States, China, Ireland, and Madagascar and from 15 T. pallidum isolates. Six typing targets were assessed: (1) the number of 60‐bp repeats in the acidic repeat protein gene, (2) restriction fragment length polymorphism (RFLP) analysis of T. pallidum repeat (tpr) subfamily II genes, (3) RFLP analysis of the tprC gene, (4) determination of tprD allele in the tprD gene locus, (5) the presence of a 51‐bp insertion between tp0126 and tp0127, and (6) sequence analysis of an 84‐bp region of tp0548. The combination of targets 1 and 2 comprises the Centers for Disease Control and Prevention (CDC) T. pallidum subtyping method. Adding sequence analysis of tp0548 to the CDC method yielded the most discriminating typing system. Twenty‐five strain types were identified and designated as "CDC subtype/tp0548 sequence type." Type 14d/f was found in samples from 5 of 6 locations. In Seattle, Washington, strain types changed from 1999 through 2008 (P < .001). Twenty‐one (50%) of 42 patients infected with type 14d/f had neurosyphilis compared with 10 (24%) of 41 patients infected with any of the other types combined (P = .02). We describe an enhanced T. pallidum strain typing system that shows biological and clinical relevance.
  The Journal of Infectious Diseases 11/2010; 202(9):1380-8. · 6.41 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: CXCL13 as a cerebrospinal fluid marker for neurosyphilis in HIV-infected patients with syphilis.

  Christina M Marra, Lauren C Tantalo, Sharon K Sahi, Clare L Maxwell, Sheila A Lukehart
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  ABSTRACT: Asymptomatic neurosyphilis is more difficult to diagnose in human immunodeficiency virus (HIV)-infected patients because HIV itself can cause cerebrospinal fluid (CSF) pleocytosis. The proportion of CSF lymphocytes that are B cells is elevated in neurosyphilis, suggesting that the CSF concentration of the B cell chemoattractant, chemokine (C-X-C motif) ligand 13 (CXCL13) concentration may also be elevated. CSF and blood were collected from 199 HIV-infected patients with syphilis and neurosyphilis. Serum and CSF CXCL13 concentrations were determined. Patients with neurosyphilis had higher CSF and serum CXCL13 concentrations compared to patients with syphilis but not neurosyphilis. The odds of having symptomatic neurosyphilis were increased by 2.23-fold for every log increase in CSF CXCL13 concentration and were independent of CSF white blood cell and plasma HIV RNA concentrations, peripheral blood CD4+ T cell count and use of antiretroviral medications. A cut-off of 10 pg/mL CSF CXCL13 had high sensitivity and a cut-off of 250 pg/mL or evidence of intrathecal synthesis of CXCL13 had high specificity for diagnosis of both symptomatic and asymptomatic neurosyphilis. CSF concentrations of CXCL13 declined after treatment for neurosyphilis. CSF CXCL13 concentration may be particularly useful for diagnosis of neurosyphilis in HIV-infected patients because it is independent of CSF pleocytosis and markers of HIV disease.
  Sexually transmitted diseases 05/2010; 37(5):283-7. · 2.58 Impact Factor
• Article: Update on neurosyphilis.

  Christina M Marra
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  ABSTRACT: Neurosyphilis literally means syphilitic infection of the central nervous system, but it is often referred to incorrectly as "tertiary syphilis." Neurosyphilis can occur at any time in the course of syphilis, even in the earliest, primary, stage. Early forms of neurosyphilis primarily affect the meninges, cerebrospinal fluid, and cerebral or spinal cord vasculature. Late forms of neurosyphilis primarily affect the brain and spinal cord parenchyma. Uveitis and hearing loss related to syphilis are most common in early syphilis and may be accompanied by early neurosyphilis. The treatment for syphilis-related eye disease and hearing loss is the same as the treatment for neurosyphilis. Neurosyphilis is more commonly seen in patients infected with HIV, and much of the recent literature pertains to this risk group. This article provides a critical review of recent literature on the diagnosis, clinical findings, risk factors, and management of neurosyphilis.
  Current Infectious Disease Reports 04/2009; 11(2):127-34.
• Article: Normalization of serum rapid plasma reagin titer predicts normalization of cerebrospinal fluid and clinical abnormalities after treatment of neurosyphilis.

  Christina M Marra, Clare L Maxwell, Lauren C Tantalo, Sharon K Sahi, Sheila A Lukehart
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  ABSTRACT: Success of neurosyphilis treatment is defined by normalization of cerebrospinal fluid (CSF) and clinical abnormalities. The goal of this study was to determine whether normalization of serum rapid plasma reagin (RPR) titer could accurately predict treatment success. One hundred ten patients who were enrolled in a longitudinal study of CSF abnormalities in syphilis had asymptomatic syphilitic meningitis, symptomatic syphilitic meningitis, or syphilitic eye disease and were treated for neurosyphilis. At 4, 7, and 13 months after treatment, serum RPR titer and CSF and clinical abnormalities were analyzed for normalization. Odds ratios for normalization of each CSF and clinical abnormality when serum RPR titer had normalized and the positive predictive value of normalization of serum RPR titer for normalization of CSF and clinical abnormalities were determined. Serum RPR titer had normalized in 63 patients (57%) by 4 months after treatment, in 94 (85%) by 7 months, and in 97 (88%) by 13 months. Except for CSF protein concentration, normalization of serum RPR titer predicted normalization of other CSF and clinical abnormalities in >80% of patients at 4 months, >85% at 7 months, and >90% at 13 months. The odds of normalization of CSF and clinical abnormalities were 28-57-fold higher when serum RPR titer had normalized, compared with when it had not. Normalization of serum RPR titer was consistently less accurate in predicting treatment success in human immunodeficiency virus-infected patients who were not receiving antiretroviral therapy, compared with those who were receiving such therapy. In most instances, normalization of serum RPR titer correctly predicts success of treatment of neurosyphilis, and follow-up lumbar puncture can be avoided.
  Clinical Infectious Diseases 11/2008; 47(7):893-9. · 9.15 Impact Factor
• Article: Isolation and laboratory maintenance of Treponema pallidum.

  Sheila A Lukehart, Christina M Marra
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  ABSTRACT: The spirochetal bacteria that cause syphilis, yaws, and bejel cannot be cultivated in vitro. This unit describes methods for the isolation of subspecies of Treponema pallidum and other pathogenic treponemes from clinical specimens, the propagation of these isolates in rabbits, isolation of clonal populations of T. pallidum, and techniques for maintenance of frozen stocks of these treponemes.
  Current protocols in microbiology 12/2007; Chapter 12:Unit 12A.1.