Insights into Treatment Alternatives for Neurosyphilis: Systematic Literature Review and Meta-Analysis.

ABSTRACT: We conducted a systematic literature review and meta-analysis to assess the efficacy of alternative treatments for neurosyphilis. We searched MEDLINE, CINAHL, Embase, Cochrane, Scopus, and Web of Science from database inception to September, 2023, for studies in neurosyphilis that compared penicillin monotherapy to other treatments. We focused on the impact of these therapies on treatment response, but also assessed data regarding reinfection and adverse drug events. Random-effect models were used to obtain pooled mean differences. Of 3,415 screened studies, six met the inclusion criteria for the systematic literature review. Three studies provided quantitative data that allowed for inclusion in the meta-analysis. Our analysis revealed that the efficacy of intravenous ceftriaxone 2 g daily for 10 days (51 patients) did not appear statistically different compared to intravenous penicillin G 18-24 million units daily for 10 days (185 patients) for neurosyphilis (pooled OR, 2.85; 95% CI, 0.41-19.56; I2 = 49%). No statistical difference between ceftriaxone and penicillin was identified in people living with HIV (pooled OR, 4.51; 95% CI, 0.50-40.49; I2 = 34%). We concluded that alternative therapy with IV ceftriaxone appears similar to penicillin, potentially expanding treatment options for neurosyphilis. Other treatment options including doxycycline warrant further study.

Twelve-year neurocognitive decline in HIV is associated with comorbidities, not age: a CHARTER study.

Modern antiretroviral therapy (ART) has increased longevity of people with HIV and shifted the age distribution of the HIV pandemic upward toward that of the general population. This positive development has also led to concerns about premature and/or accelerated neurocognitive and physical ageing due to the combined effects of chronic HIV, accumulating comorbidities, adverse effects or possible toxicities of ART and biological ageing. Here we present results of comprehensive assessments over 12 years of 402 people with HIV in the CNS HIV ART Effects Research (CHARTER) programme, who at follow-up were composed of younger (<60 years) and older (≥60 years) subgroups. Over the 12 years, ART use and viral suppression increased in both subgroups as did systemic and psychiatric comorbidities; participants in both subgroups also evidenced neurocognitive decline beyond what is expected in typical ageing. Contrary to expectations, all these adverse effects were comparable in the younger and older CHARTER subgroups, and unrelated to chronological age. Neurocognitive decline was unrelated to HIV disease or treatment characteristics but was significantly predicted by the presence of comorbid conditions, specifically diabetes, hypertension, chronic pulmonary disease, frailty, neuropathic pain, depression and lifetime history of cannabis use disorder. These results are not consistent with premature or accelerated neurocognitive ageing due to HIV itself but suggest important indirect effects of multiple, potentially treatable comorbidities that are more common among people with HIV than in the general population. Good medical management of HIV disease did not prevent these adverse outcomes, and increased attention to a range of comorbid conditions in people with HIV may be warranted in their care.

Higher Levels of Cerebrospinal Fluid and Plasma Neurofilament Light in Human Immunodeficiency Virus-Associated Distal Sensory Polyneuropathy.

BACKGROUND: Neurofilament light (NFL) chain concentrations, reflecting axonal damage, are seen in several polyneuropathies but have not been studied in human immunodeficiency virus (HIV) distal sensory polyneuropathy (DSP). We evaluated NFL in cerebrospinal fluid (CSF) and plasma in relation to DSP in people with HIV (PWH) from 2 independent cohorts and in people without HIV (PWoH). METHODS: Cohort 1 consisted of PWH from the CHARTER Study. Cohort 2 consisted of PWH and PWoH from the HIV Neurobehavioral Research Center (HNRC). We evaluated DSP signs and symptoms in both cohorts. Immunoassays measured NFL in CSF for all and for plasma as well in Cohort 2. RESULTS: Cohort 1 consisted of 111 PWH, mean ± SD age 56.8 ± 8.32 years, 15.3% female, 38.7% Black, 49.6% White, current CD4+ T-cells (median, interquartile range [IQR]) 532/µL (295, 785), 83.5% with plasma HIV RNA ≤50 copies/mL. Cohort 2 consisted of 233 PWH of similar demographics to PWH in Cohort 1 but also 51 PWoH, together age 58.4 ± 6.68 years, 41.2% female, 18.0% Black, Hispanic, non-Hispanic White 52.0%, 6.00% White. In both cohorts of PWH, CSF and plasma NFL were significantly higher in both PWH with DSP signs. Findings were similar, albeit not significant, for PWoH. The observed relationships were not explained by confounds. CONCLUSIONS: Both plasma and CSF NFL were elevated in PWH and PWoH with DSP. The convergence of our findings with others demonstrates that NFL is a reliable biomarker reflecting peripheral nerve injury. Biomarkers such as NFL might provide, validate, and optimize clinical trials of neuroregenerative strategies in HIV DSP.

Antiretroviral Therapy Intensification for Neurocognitive Impairment in Human Immunodeficiency Virus.

BACKGROUND: Neurocognitive impairment (NCI) in people with HIV (PWH) on antiretroviral therapy (ART) is common and may result from persistent HIV replication in the central nervous system. METHODS: A5324 was a randomized, double-blind, placebo-controlled, 96-week trial of ART intensification with dolutegravir (DTG) + MVC, DTG + Placebo, or Dual - Placebo in PWH with plasma HIV RNA <50 copies/mL on ART and NCI. The primary outcome was the change on the normalized total z score (ie, the mean of individual NC test z scores) at week 48. RESULTS: Of 357 screened, 191 enrolled: 71% male, 51% Black race, 22% Hispanic ethnicity; mean age 52 years; mean CD4+ T-cells 681 cells/µL. Most (65%) had symptomatic HIV-associated NC disorder. Study drug was discontinued due to an adverse event in 15 (8%) and did not differ between arms (P = .17). Total z score, depressive symptoms, and daily functioning improved over time in all arms with no significant differences between them at week 48 or later. Adjusting for age, sex, race, study site, efavirenz use, or baseline z score did not alter the results. Body mass index modestly increased over 96 weeks (mean increase 0.32 kg/m2, P = .006) and did not differ between arms (P > .10). CONCLUSIONS: This is the largest, randomized, placebo-controlled trial of ART intensification for NCI in PWH. The findings do not support empiric ART intensification as a treatment for NCI in PWH on suppressive ART. They also do not support that DTG adversely affects cognition, mood, or weight.

Neuropathic pain correlates with worsening cognition in people with human immunodeficiency virus.

Neuropathic pain and cognitive impairment are among the HIV-related conditions that have most stubbornly resisted amelioration by virally suppressive antiretroviral therapy. Overlaps between the regional brain substrates and mechanisms of neuropathic pain and cognitive disorders are increasingly recognized, yet no studies have examined the longitudinal relationship between these two disorders. Participants in the prospective, observational CNS HIV AntiRetroviral Therapy Effects Research (CHARTER) cohort underwent standardized clinical evaluations for clinical examination findings of distal sensory polyneuropathy, reporting distal neuropathic pain and neurocognitive performance at study entry (baseline) and an average of 12 years later. Change in neuropathic pain and neuropathy status from baseline to follow-up was by self-report and repeat examination, and change in neurocognitive performance was assessed using a previously published summary regression-based change score. Relationships between incident or worsened neuropathic pain and neurocognitive change were evaluated using uni- and multivariable regressions, including age at baseline and other relevant covariates. Participants were 385 people with HIV, 91 (23.6%) females, mean ± standard deviation (SD) age at baseline 43.5 (7.81) years, ethnicity 44.9% African American, 10.6% Hispanic, 42.6% non-Hispanic white and 1.82% other. Baseline median (interquartile range) nadir CD4 was 175 (34 309) cells/µl and current CD4 was 454 (279 639). Incident or worsened distal neuropathic pain occurred in 98 (25.5%) over the follow-up period. People with HIV with incident or worsened distal neuropathic pain had significantly worsened neurocognitive performance at follow-up compared to those without incident or worsened distal neuropathic pain (summary regression-based change score mean ± SD -0.408 ± 0.700 versus -0.228 ± 0.613; P = 0.0158). This effect remained significant when considering viral suppression on antiretroviral therapy, incident diabetes and other covariates as predictors. Overall neurocognitive change related to neuropathic pain was driven primarily by changes in the domains of executive function and speed of information processing. Those with incident distal neuropathy signs did not have neurocognitive worsening, nor did individuals who used opioid analgesics or other pain-modulating drugs such as amitriptyline. Worsened neurocognitive performance in people with HIV was associated with worsened neuropathic pain but not with changes in physical signs of neuropathy, and this was not attributable to therapies for pain or depression or to differences in viral suppression. This finding implies that incident or worsened pain may signal increased risk for neurocognitive impairment, and deserves more investigation, particularly if better pain management might stabilize or improve neurocognitive performance.

Epidemiology, Pathophysiology, Diagnosis, and Management of Cerebral Toxoplasmosis.

Toxoplasma gondii is known to infect a considerable number of mammalian and avian species and a substantial proportion of the world's human population. The parasite has an impressive ability to disseminate within the host's body and employs various tactics to overcome the highly regulatory blood-brain barrier and reside in the brain. In healthy individuals, T. gondii infection is largely tolerated without any obvious ill effects. However, primary infection in immunosuppressed patients can result in acute cerebral or systemic disease, and reactivation of latent tissue cysts can lead to a deadly outcome. It is imperative that treatment of life-threatening toxoplasmic encephalitis is timely and effective. Several therapeutic and prophylactic regimens have been used in clinical practice. Current approaches can control infection caused by the invasive and highly proliferative tachyzoites but cannot eliminate the dormant tissue cysts. Adverse events and other limitations are associated with the standard pyrimethamine-based therapy, and effective vaccines are unavailable. In this review, the epidemiology, economic impact, pathophysiology, diagnosis, and management of cerebral toxoplasmosis are discussed, and critical areas for future research are highlighted.

Previous Syphilis Alters the Course of Subsequent Episodes of Syphilis.

BACKGROUND: The influence of previous syphilis on the course of a subsequent episode is unknown. METHODS: Individuals enrolled in a study of cerebrospinal fluid (CSF) abnormalities in syphilis were allowed to enroll in the study again with subsequent syphilis. For each participant, the index episode was defined as the most recent syphilis episode for which the study entry visit was performed within 30 days of the syphilis diagnosis date. Venipuncture and lumbar puncture (LP) were performed. Total number of syphilis episodes was determined by review of medical and public health records. T. pallidum DNA in blood and rRNA in CSF were detected by polymerase chain reaction (PCR) and reverse transcriptase PCR. Odds ratios (ORs) with 95% confidence intervals (95% CI) were determined by logistic regression. RESULTS: 651 individuals had one (n = 482), two (n = 121) or three or more (n = 48) episodes of syphilis. The proportion of individuals whose index episode was early latent stage was significantly higher in those with ≥3 syphilis episodes; this relationship was reduced to a trend when rate of testing was taken into account. Adjusted odds (aOR) of detection of T. pallidum DNA in blood or rRNA in CSF at the index episode were significantly lower in those with previous syphilis (0.17 [95% CI, 0.09-0.31] and 0.15 [95% CI, 0.07-0.35]). The aOR for neurosyphilis at the index episode was also significantly lower in individuals with previous syphilis (0.54 [95% CI, 0.34-0.87]). CONCLUSIONS: Previous syphilis attenuates the manifestations of subsequent infection with T. pallidum.

Higher buccal mitochondrial DNA and mitochondrial common deletion number are associated with markers of neurodegeneration and inflammation in cerebrospinal fluid.

Human immunodeficiency virus (HIV) infection is potentially associated with premature aging, but demonstrating this is difficult due to a lack of reliable biomarkers. The mitochondrial (mt) DNA "common deletion" mutation (mtCDM) is a 4977-bp deletion associated with aging and neurodegenerative diseases. We examined how mtDNA and mtCDM correlate with markers of neurodegeneration and inflammation in people with and without HIV (PWH and PWOH). Data from 149 adults were combined from two projects involving PWH (n = 124) and PWOH (n = 25). We measured buccal mtDNA and mtCDM by digital droplet PCR and compared them to disease and demographic characteristics and soluble biomarkers in cerebrospinal fluid (CSF) and blood measured by immunoassay. Participants had a median age of 52 years, with 53% white and 81% men. Median mtDNA level was 1,332 copies/cell (IQR 1,201-1,493) and median mtCDM level was 0.36 copies × 102/cell (IQR 0.31-0.42); both were higher in PWH. In the best model adjusting for HIV status and demographics, higher mtDNA levels were associated with higher CSF amyloid-ß 1-42 and 8-hydroxy-2'-deoxyguanosine and higher mtCDM levels were associated with higher plasma soluble tumor necrosis factor receptor II. The differences in mtDNA markers between PWH and PWOH support potential premature aging in PWH. Our findings suggest mtDNA changes in oral tissues may reflect CNS processes, allowing the use of inexpensive and easily accessible buccal biospecimens as a screening tool for CSF inflammation and neurodegeneration. Confirmatory and mechanistic studies on mt genome alterations by HIV and ART may identify interventions to prevent or treat neurodegenerative complications.

HIV Viremia and Risk of Stroke Among People Living with HIV Who Are Using Antiretroviral Therapy.

BACKGROUND: Rates of stroke are higher in people living with HIV compared with age-matched uninfected individuals. Causes of elevated stroke risk, including the role of viremia, are poorly defined. METHODS: Between 1 January 2006 and 31 December 2014, we identified incident strokes among people living with HIV on antiretroviral therapy at five sites across the United States. We considered three parameterizations of viral load (VL) including (1) baseline (most recent VL before study entry), (2) time-updated, and (3) cumulative VL (copy-days/mL of virus). We used Cox proportional hazards models to estimate hazard ratios (HRs) for stroke risk comparing the 75th percentile ("high VL") to the 25th percentile ("low VL") of baseline and time-updated VL. We used marginal structural Cox models, with most models adjusted for traditional stroke risk factors, to estimate HRs for stroke associated with cumulative VL. RESULTS: Among 15,974 people living with HIV, 139 experienced a stroke (113 ischemic; 18 hemorrhagic; eight were unknown type) over a median follow-up of 4.2 years. Median baseline VL was 38 copies/mL (interquartile interval: 24, 3,420). High baseline VL was associated with increased risk of both ischemic (HR: 1.3; 95% CI = 0.96-1.7) and hemorrhagic stroke (HR: 3.1; 95% CI = 1.6-5.9). In time-updated models, high VL was also associated with an increased risk of any stroke (HR: 1.8; 95% CI = 1.4-2.3). We observed no association between cumulative VL and stroke risk. CONCLUSIONS: Our findings are consistent with the hypothesis that elevated HIV VL may increase stroke risk, regardless of previous VL levels.

Alternatives to the Cerebrospinal Fluid Venereal Disease Research Laboratory Test for Neurosyphilis Diagnosis.

BACKGROUND: The diagnosis of neurosyphilis relies in large part on the cerebrospinal fluid (CSF) Venereal Disease Research Laboratory (VDRL) test, which is diagnostically specific but not sensitive. METHODS: We determined the sensitivity and specificity of 3 CSF tests in addition to the CSF-VDRL in participants with syphilis enrolled in a research study: detection of Treponema pallidum ribosomal RNA, T. pallidum particle agglutination titer, and chemokine (C-X-C motif) ligand 13 (CXCL13) concentration. Neurosyphilis was defined as asymptomatic or symptomatic meningitis: CSF white blood cells >10/µL without or with neurological symptoms, including new vision or hearing loss. RESULTS: Cerebrospinal fluid-VDRL, CSF T. pallidum ribosomal RNA detection, and CSF T. pallidum particle agglutination titer ≥1:640 were specific (89%-96%) but not sensitive (12%-48%). In contrast, diagnostic sensitivity of CSF-CXCL13 thresholds established from receiver operating characteristic curves using the Youden index was 78% to 83% and specificity was 76% to 81%. In individuals with nonreactive CSF-VDRL, neurosyphilis diagnosis could be confirmed by CSF-CXCL13 concentration in 69% to 75%. CONCLUSIONS: Further studies of CSF-CXCL13 should include CSF samples from multiple cohorts and countries and should use standard neurosyphilis definitions to establish uniform thresholds for diagnosis.

A Comparison of Treponema pallidum Subspecies pallidum Molecular Typing Systems: Multilocus Sequence Typing vs. Enhanced Centers for Disease Control and Prevention Typing.

BACKGROUND: At least 3 syphilis typing systems are proposed. Recent work suggests that multilocus sequence typing (MLST) may be superior to enhanced Centers for Disease Control and Prevention typing (ECDCT) by yielding a higher discriminatory power. The goal of this study was to compare the 2 systems and identify associations between neurosyphilis and strain types. METHODS: Multilocus sequence typing for tp0136, tp0548, and tp0705 was determined for DNA from 78 Treponema pallidum subspecies pallidum isolates propagated in rabbits, 10 oral and 10 genital or non-genital lesion swabs, and 10 blood samples from patients with syphilis. These samples were chosen because they were completely typeable by ECDCT. Using both systems, association between strain types and neurosyphilis, defined as a reactive cerebrospinal fluid Venereal Disease Research Laboratory test, was determined. Partial and complete ECDCT types were also determined for samples from different anatomical sites in 35 patients, and from blood and blood isolates (rabbit propagated) from 13 patients. RESULTS: The MLST type could be fully determined for 100 (92.6%) of 108 samples. Although MLST subdivided 3 common ECDCT types, it failed to distinguish among others. Neurosyphilis was more common in individuals infected with type 1.1.2 and tp0705 type 2 using MLST, and tp0548 type f using ECDCT. Enhanced Centers for Disease Control and Prevention typing was stable among anatomical sites and between patient-derived and rabbit propagated organisms. CONCLUSIONS: Compared with ECDCT, MLST was not uniformly more discriminating. Both typing systems demonstrate that specific types may be more neurotropic than others.

Detection of Treponema pallidum DNA in Oropharyngeal Swabs and Whole Blood for Syphilis Diagnosis.

BACKGROUND: Syphilis diagnosis relies on serological tests, which may be falsely nonreactive or may be reactive but not reflect current syphilis. METHODS: Polymerase chain reaction for detection of T. pallidum DNA was performed on 123 oropharyngeal swabs, 120 whole bloods, and 46 lesion exudate swabs from 123 untreated individuals with syphilis (cases); oropharyngeal swabs from 148 at-risk controls without syphilis; and 73 oropharyngeal swabs and 36 whole bloods from 73 individuals recently treated for syphilis. RESULTS: Most (90.2%) cases had early syphilis. T. pallidum DNA was detected in 33 (26.8%) of 123 oropharyngeal swabs, 32 (26.7%) of 120 bloods, and 30 (65.2%) of 46 lesion exudate swabs. T. pallidum DNA was detected in 49 (40.8%) of 120 individuals in whom both oropharyngeal swabs and blood were tested. T. pallidum was more likely to be amplified from oropharyngeal swabs when it was amplified from blood than when it was not (15 of 32 [46.9%] vs. 17 of 88 [19.3%], P = 0.003). For each 2-fold increase in serum rapid plasma reagin titer, the odds of detection of T. pallidum DNA in oropharyngeal swabs increased by 1.44 (95% confidence interval, 1.14-1.82, P = 0.003). T. pallidum DNA was not detected in oropharyngeal samples from controls, but it was detected in 3 (8.3%) of 36 bloods from individuals recently treated for syphilis: 2 at 1 day and 1 at 5 days after initiation of syphilis treatment. CONCLUSIONS: Nucleic amplification tests can identify recent T. pallidum infection and may be particularly useful for diagnosis of very early or asymptomatic syphilis.

A Dual-Platform Point-of-Care Test for Neurosyphilis Diagnosis.

BACKGROUND: The diagnosis of neurosyphilis relies on cerebrospinal fluid (CSF) abnormalities (pleocytosis, elevated protein) and CSF-Venereal Disease Research Laboratory (VDRL) test. In resource-limited settings, the CSF-VDRL test may not be widely available. METHODS: We optimized a commercial immunochromatographic strip test, the DPP Chembio syphilis assay, for performance with CSF and tested centrifuged CSF samples of 71 patients with syphilis (35 with neurosyphilis and 36 without neurosyphilis). A CSF dilution of 1:4 was chosen based on agreement with CSF pools with documented results from the CSF-VDRL test and fluorescent treponemal antibody absorption test on CSF. Using an electronic reader, we obtained unit values of treponemal and nontreponemal antibodies for all study samples and generated a receiver operating characteristic curve; using the Youden index, we established diagnostic cutoffs with optimal sensitivity and specificity. RESULTS: Diagnostic sensitivity of the nontreponemal test was 80% (95% confidence interval, 63%-92%) and specificity was 97% (95% confidence interval, 85%-100%) for neurosyphilis diagnosis using a reactive CSF-VDRL that improved after neurosyphilis therapy as a criterion standard. CONCLUSIONS: In this small study, the DPP Chembio test showed promising results for neurosyphilis diagnosis. Further studies are needed to assess its performance in resource-limited settings.

Neurosyphilis Treatment Outcomes After Intravenous Penicillin G Versus Intramuscular Procaine Penicillin Plus Oral Probenecid.

BACKGROUND: Data comparing neurosyphilis treatment regimens are limited. METHODS: Participants were enrolled in a study of cerebrospinal fluid (CSF) abnormalities in syphilis that was conducted at the University of Washington between April 2003 to May 2014. They were diagnosed with syphilis and referred by their providers due to concerns for neurosyphilis. We evaluated 150 people with CSF abnormalities who were treated with either intravenous aqueous penicillin G (PenG) or intramuscular aqueous procaine penicillin G plus oral probenecid (APPG-P). An abnormal CSF diagnosis was defined as a white blood cell (WBC) count >20/µL, a CSF protein reading >50 mg/dL, or a reactive CSF-Venereal Disease Research Laboratory test (VDRL). Hazard ratios for normalization of CSF or serum measures were determined using Cox regression. RESULTS: In individuals treated with either PenG or APPG-P, CSF WBCs and CSF-VDRL reactivity normalized within 12 months after treatment, while protein normalized more slowly and less completely. There was no relationship between treatment regimen or human immunodeficiency virus (HIV) status and likelihood of normalization of any measure. Among those living with HIV, CSF WBC counts and CSF-VDRL reactivity were more likely to normalize in those treated with antiretrovirals. Unexpectedly, CSF WBCs were more likely to normalize in those with low CD4+ T cell counts. When neurosyphilis was more stringently defined as a reactive CSF-VDRL, the relationship with the CD4+ T cell count remained unchanged. CONCLUSIONS: In the current antiretroviral treatment era, neurosyphilis treatment outcomes are not different for PenG and APPG-P, regardless of HIV status. The relationship between the normalization of CSF WBC counts and CD4+ T cell counts may indicate continued imprecision in neurosyphilis diagnostic criteria, due to HIV-related CSF pleocytosis.

Previous Syphilis Alters the Course of Subsequent Episodes of Syphilis.

BACKGROUND: Individuals with previous syphilis may be more likely to be asymptomatic when they are reinfected with Treponema pallidum. METHODS: Individuals enrolled in a study of cerebrospinal fluid (CSF) abnormalities in syphilis were allowed to enroll in the study again with subsequent syphilis. For each participant, the index episode was defined as the most recent syphilis episode for which the study entry visit was performed within 30 days of the syphilis diagnosis date. Venipuncture and lumbar puncture were performed. The total number of syphilis episodes was determined by review of medical and public health records. Treponema pallidum DNA in blood and rRNA in CSF were detected using polymerase chain reaction (PCR) and reverse transcriptase PCR. Odds ratios (ORs) with 95% confidence intervals (CIs) were determined using logistic regression. RESULTS: 701 individuals had 1 (n = 478), 2 (n = 155), or ≥3 (n = 68) episodes of syphilis. The proportion of individuals whose index episode was asymptomatic significantly increased with increased number of syphilis episodes (P < .001). This difference was not explained by frequency of serological tests. Adjusted ORs (aORs) of detection of T. pallidum DNA in blood or rRNA in CSF at the index episode were significantly lower in those with previous syphilis (0.13; 95% CI, .08-.23, and 0.06, 95% CI, .02-.17). The aOR of neurosyphilis at the index episode was also significantly lower in individuals with previous syphilis (0.43; 95% CI, .27-.68). CONCLUSIONS: Previous syphilis attenuates clinical and laboratory manifestations of infection with T. pallidum.

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

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

Otosyphilis: A Review of the Literature.

The number of cases of syphilis has increased in the United States and in many high-income nations. Otosyphilis is a less recognized complication of syphilis that can lead to irreversible sensorineural hearing loss. Different pathophysiological mechanisms have been proposed to explain hearing loss in otosyphilis. We review the literature on otosyphilis in adults and propose the need for future work in this field to identify better ways to diagnose, treat, and manage this disease. Patients with syphilis should be screened routinely for hearing loss, and all patients with new, sudden, or fluctuating sensorineural hearing loss should be evaluated for syphilis.

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

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.

Human Immunodeficiency Virus Type 1 and Tuberculosis Coinfection in Multinational, Resource-limited Settings: Increased Neurological Dysfunction.

BACKGROUND: AIDS Clinical Trial Group 5199 compared neurological and neuropsychological test performance of human immunodeficiency virus type 1 (HIV-1)-infected participants in resource-limited settings treated with 3 World Health Organization-recommended antiretroviral (ART) regimens. We investigated the impact of tuberculosis (TB) on neurological and neuropsychological outcomes. METHODS: Standardized neurological and neuropsychological examinations were administered every 24 weeks. Generalized estimating equation models assessed the association between TB and neurological/neuropsychological performance. RESULTS: Characteristics of the 860 participants at baseline were as follows: 53% female, 49% African; median age, 34 years; CD4 count, 173 cells/µL; and plasma HIV-1 RNA, 5.0 log copies/mL. At baseline, there were 36 cases of pulmonary, 9 cases of extrapulmonary, and 1 case of central nervous system (CNS) TB. Over the 192 weeks of follow-up, there were 55 observations of pulmonary TB in 52 persons, 26 observations of extrapulmonary TB in 25 persons, and 3 observations of CNS TB in 2 persons. Prevalence of TB decreased with ART initiation and follow-up. Those with TB coinfection had significantly poorer performance on grooved pegboard (P < .001) and fingertapping nondominant hand (P < .01). TB was associated with diffuse CNS disease (P < .05). Furthermore, those with TB had 9.27 times (P < .001) higher odds of reporting decreased quality of life, and had 8.02 times (P = .0005) higher odds of loss of productivity. CONCLUSIONS: TB coinfection was associated with poorer neuropsychological functioning, particularly the fine motor skills, and had a substantial impact on functional ability and quality of life. CLINICAL TRIALS REGISTRATION: NCT00096824.