Neurocognitive impairment is worse in HIV/HCV-coinfected individuals with liver dysfunction.

Infections with HIV and hepatitis C virus (HCV) can individually and jointly contribute to neurocognitive impairment (NCI). Rates of NCI in HIV/HCV-coinfected persons range from 40 to 63% but its correlates have not been described. In this study, we examined HIV/HCV-coinfected adults on antiretroviral therapy (ART) with undetectable HIV RNA in blood (n = 412) who were assessed using a comprehensive neuropsychological test battery. Demographics, host and viral biomarkers, and markers of liver dysfunction were compared between impaired (n = 198) and unimpaired (n = 214) participants using logistic regression. The cohort was predominantly middle-aged men, half of whom (48%) had NCI. The odds of NCI increased by almost two-fold when serum albumin was < 4 g/dL, 1.7-fold when alanine aminotransferase (ALT) levels were > 50 IU/L, and 2.2-fold with every unit increase in log10 AST to Platelet Ratio Index (APRI). These readily available clinical biomarkers of NCI measure hepatic injury and/or dysfunction, suggesting a mechanism for the effects of HCV infection on NCI. They may identify patients at increased risk of NCI who could be prioritized for early initiation of HCV treatment to protect or improve cognition.

Cerebrospinal fluid cell-free mitochondrial DNA is associated with HIV replication, iron transport, and mild HIV-associated neurocognitive impairment.

BACKGROUND: Mitochondria are abundant organelles critical for energy metabolism and brain function. Mitochondrial DNA (mtDNA), released during cellular injury and as part of the innate immune response to viral pathogens, contains CpG motifs that act as TLR-9 ligands. We investigated relationships between cerebrospinal fluid (CSF) cell-free mtDNA levels and HIV viral load (VL), biomarkers of inflammation and iron transport, and neurocognitive (NC) function in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort. METHODS: We quantified cell-free mtDNA in CSF by droplet digital PCR in 332 CHARTER participants who underwent comprehensive neuropsychiatric evaluation. NC performance was assessed using the global deficit score (GDS) as either a continuous or a binary measure (GDS ≥ 0.5, impaired vs. GDS < 0.5, unimpaired). CSF, clinical, and biomarker data from the earliest available time point were analyzed. Cell-free mtDNA associations with CSF inflammation and iron-related biomarkers [CXCL10, IL-6, IL-8, TNF-a, transferrin (TF), ceruloplasmin (CP), and vascular endothelial growth factor (VEGF)], VL, and GDS were evaluated by multivariable regression. RESULTS: CSF cell-free mtDNA levels were significantly lower in participants with undetectable (vs. detectable) VL in either plasma (p < 0.001) or CSF (p < 0.001) and in those on antiretroviral therapy (ART; p < 0.001). Participants on ART with undetectable VL in both CSF and plasma had lower mtDNA levels than those with detectable VL in both compartments (p = 0.001). Higher mtDNA levels were observed in participants in the highest vs. lowest tertile (T3 vs. T1) of CSF CXCL10 (T3 vs. T1, p < 0.001) and TNF-a (T3 vs. T1, p < 0.05) in unadjusted analyses. MtDNA levels also correlated with CSF leukocyte count. After adjusting for CSF leukocyte count and VL, mtDNA levels were also associated with other inflammation- and iron-related biomarkers in CSF, including TF (T3 vs. T1, p < 0.05) and CP (T3 vs. T1, p < 0.05). With additional correction for ART use, mtDNA was also negatively associated with CSF VEGF (p < 0.05) and IL-6 (p = 0.05). We observed no associations of CSF mtDNA levels with age or GDS-defined NC impairment. CONCLUSIONS: CSF cell-free mtDNA levels were associated with HIV RNA and ART status, as well as with biomarkers of iron transport and VEGF, a growth factor with known effects on mitochondrial integrity and autophagy. CSF mtDNA may be a biomarker of iron dysregulation and/or neuroinflammation during HIV infection.

Neurocognitive functioning among HIV-positive adults in southern India.

The validity of a comprehensive international neuropsychological (NP) test battery for detection of HIV-associated neurocognitive disorders (HAND) in a Tamil speaking southern Indian cohort (69 HIV+ and 67 HIV-) was explored. The prevalence of HAND was significantly higher in the HIV+ vs. HIV- group (33 vs.13%; p < 0.01). Impairment rates were highest in the motor and speed of information processing domains. An NP battery translated into Tamil appears to be a valid tool for assessing HAND because the prevalence it found of HAND in southern India is similar to that found elsewhere.

Latent Toxoplasma Infection and Higher Toxoplasma gondii Immunoglobulin G Levels Are Associated With Worse Neurocognitive Functioning in HIV-Infected Adults.

BACKGROUND: Human immunodeficiency virus (HIV)-associated neurocognitive disorders persist despite suppressive antiretroviral therapy (ART). Because latent Toxoplasma infection (LTI) may adversely impact brain function, we investigated its impact on neurocognitive impairment (NCI) in people living with HIV disease. METHODS: Two hundred sixty-three HIV-infected adults underwent comprehensive neurocognitive assessments and had anti-Toxoplasma gondii immunoglobulin G (anti-Toxo IgG) measured by qualitative and quantitative enzyme-linked immunosorbent assays. RESULTS: Participants were mostly middle-aged white men who were taking ART (70%). LTI was detected in 30 (11.4%) participants and was associated with a significantly greater prevalence of global NCI (LTI positive [LTI+] = 57% and LTI negative [LTI-] = 34%) (odds ratio, 1.67; 95% confidence interval, 1.17-2.40; P = .017). Deficits were more prevalent in the LTI+ vs the LTI- group in 6 of 7 cognitive domains with statistical significance reached for delayed recall (P < .01). The probability of NCI increased with higher CD4+ T-cell counts among LTI+ individuals but with lower CD4+ T-cell counts in LTI- persons. A strong correlation (r = .93) between anti-Toxo IgG levels and global deficit score was found in a subgroup of 9 patients. Biomarkers indicative of central nervous system inflammation did not differ between LTI+ and LTI- participants. CONCLUSIONS: In this cross-sectional analysis, LTI was associated with NCI, especially in those with higher CD4+ T-cell counts. Longitudinal studies to investigate the role of neuroinflammation and neuronal injury in LTI patients with NCI and trials of anti-Toxoplasma therapy should be pursued.

Total raltegravir concentrations in cerebrospinal fluid exceed the 50-percent inhibitory concentration for wild-type HIV-1.

HIV-associated neurocognitive disorders continue to be common. Antiretrovirals that achieve higher concentrations in cerebrospinal fluid (CSF) are associated with better control of HIV and improved cognition. The objective of this study was to measure total raltegravir (RAL) concentrations in CSF and to compare them with matched concentrations in plasma and in vitro inhibitory concentrations. Eighteen subjects with HIV-1 infection were enrolled based on the use of RAL-containing regimens and the availability of CSF and matched plasma samples. RAL was measured in 21 CSF and plasma pairs by liquid chromatography-tandem mass spectrometry, and HIV RNA was detected by reverse transcription-PCR (RT-PCR). RAL concentrations were compared to the 50% inhibitory concentration (IC(50)) for wild-type HIV-1 (3.2 ng/ml). Volunteers were predominantly middle-aged white men with AIDS and without hepatitis C virus (HCV) coinfection. The median concurrent CD4(+) cell count was 276/µl, and 28% of CD4(+) cell counts were below 200/µl. HIV RNA was detectable in 38% of plasma specimens and 4% of CSF specimens. RAL was present in all CSF specimens, with a median total concentration of 14.5 ng/ml. The median concentration in plasma was 260.9 ng/ml, with a median CSF-to-plasma ratio of 0.058. Concentrations in CSF correlated with those in with plasma (r(2), 0.24; P, 0.02) but not with the postdose sampling time (P, >0.50). RAL concentrations in CSF exceeded the IC(50) for wild-type HIV in all specimens by a median of 4.5-fold. RAL is present in CSF and reaches sufficiently high concentrations to inhibit wild-type HIV in all individuals. As a component of effective antiretroviral regimens or as the main antiretroviral, RAL likely contributes to the control of HIV replication in the nervous system.

Cerebrospinal fluid human immunodeficiency virus viral load in patients with neurosyphilis.

Syphilis is a frequent coinfection with human immunodeficiency virus (HIV). Whereas systemic syphilis infection increases plasma HIV RNA levels (viral load; VL), effects of syphilis on cerebrospinal fluid (CSF) VL are unknown. We hypothesized that intrathecal immune activation in neurosyphilis would selectively increase CSF VL in coinfected patients. In this study, HIV-infected research subjects (N = 225) were categorized into three groups based on serum rapid plasma reagin (RPR), microhemaglutination for Treponema pallidum (MHA-TP) MHA-TP, and CSF VDRL: 23 with neurosyphilis (NS+; reactive serum RPR and MHA-TP and positive CSF VDRL); 42 with systemic syphilis but not neurosyphilis (Syph+; reactive serum RPR and MHA-TP; negative CSF VDRL), and 160 without syphilis (Syph-; nonreactive serum RPR). Plasma and CSF HIV VL were quantified by reverse transcriptase-ploymerase chain reaction (RT-PCR) (Amplicor, Roche) in log(10) copies/ml. To adjust for covariates previously shown to influence CSF HIV VL (i.e., plasma VL, CD4, pleocytosis, and highly active antiretroviral therapy [HAART]), multivariable linear regression was used. Lumbar punctures (LP) done for research purposes diagnosed 23 with neurosyphilis; most (83%) of these reported prior syphilis treatment. Among subjects with detectable plasma VL, CSF VL was highest in NS+, followed by Syph+ and Syph- (P =.006). This relationship was independent of the level of plasma VL or CSF pleocytosis. By contrast, among subjects with undetectable plasma HIV VL, CSF VLs were similar in the three syphilis subgroups (P = .50). Neurosyphilis may amplify intrathecal HIV replication, possibly through immune activation that persists even after syphilis treatment. Because elevated CSF VL is associated with subsequent neurocognitive decline, future studies should evaluate the impact of neurosyphilis on the course of central nervous system (CNS) HIV infection.

Impact of Latent Tuberculosis Infection on Neurocognitive Functioning and Inflammation in HIV-Infected and Uninfected South Indians.

BACKGROUND: HIV-associated neurocognitive disorder persists in some people living with HIV despite optimal antiretroviral therapy. Latent tuberculosis infection (LTBI) may cause systemic inflammation and immune activation that may impair brain function. We assessed cognition and biomarkers of inflammation in both HIV+ and HIV- South Indians with and without LTBI. METHODS: Adults (≥18 years old) with and without HIV infection were screened for LTBI by interferon-gamma release assays, completed comprehensive neurocognitive assessments, and underwent measurement of serum inflammatory biomarker levels. RESULTS: The participants (n = 119) were HIV+/LTBI+ (n = 15), HIV+/LTBI- (n = 50), HIV-/LTBI+ (n = 26), and HIV-/LTBI- (n = 28). HIV+ participants, regardless of LTBI status, had more impaired global deficit scores than HIV- participants (odds ratio = 3.42, P = 0.028, adjusted for sex and education differences). Neither global deficit scores nor impairment rates differed in the LTBI+ group compared with the LTBI- group (P = 0.79 and P = 0.41, respectively). The mean log10 interleukin (IL)-6 and monocyte chemoattractant protein-1 values were significantly higher and high sensitivity C-reactive protein lower in the LTBI+ group than the LTBI- group (P = 0.044, 0.023, and 0.03, respectively, adjusting for HIV status and sex). CONCLUSIONS: In this cross-sectional study of South Indians, HIV infection, but not LTBI, was associated with increased neurocognitive impairment. Proinflammatory biomarkers (IL-6 and monocyte chemoattractant protein-1, but not tumor necrosis factor-α) were elevated in the LTBI+ groups compared with the LTBI- groups. Biomarkers of immune activation (interferon-γ, macrophage inflammatory protein-1ß, IL-2, interferon gamma inducible protein-10, RANTES, and IL-22) did not differ between these groups. Larger longitudinal studies should be conducted to confirm our findings that the effect of LTBI on systemic inflammation or neurocognitive impairment is likely small.

Metabolic Syndrome and Neurocognitive Deficits in HIV Infection.

BACKGROUND: The adverse consequences of HIV and related comorbidities on the central nervous system remain prevalent in the era of combination antiretroviral therapy. Metabolic syndrome (MetS) is a common comorbidity in HIV and has been linked to increased neurocognitive impairment in the general population. We investigated the association between MetS and neurocognition among persons living with HIV (PLHIV). METHODS: Participants included 109 PLHIV and 92 HIV-uninfected adults (HIV-) from the Multi-dimensional Successful Aging cohort study at the University of California San Diego (age: M = 50.8, SD = 8.0). Participants completed neuromedical, psychiatric, and neurocognitive assessments. Based on a comprehensive neurocognitive battery, we examined global neurocognitive deficits (based on the entire battery) and neurocognitive deficits in 7 domains (verbal fluency, learning, recall, executive function, working memory, speed of information processing, and fine motor skills). MetS was determined via the standard criteria by the National Cholesterol Education Program's Adult Treatment Panel-III. Covariates examined included demographics and psychiatric comorbidities (and HIV disease characteristics among PLHIV). RESULTS: MetS had an independent significant effect on global neurocognitive deficits among PLHIV (P = 0.03) but not among their HIV- counterparts (P = 0.93). Among PLHIV, MetS was most strongly associated with the neurocognitive domains of learning, fine motor skills, and executive function. Diabetes and elevated triglycerides were the MetS components most strongly linked with increased global neurocognitive deficits in PLHIV. CONCLUSIONS: The present findings underscore the need for early identification of PLHIV at risk for MetS and the implementation of preventive and treatment approaches to lessen the development of MetS and neurocognitive impairment among PLHIV.

Saccharomyces cerevisiae Laryngitis and Oral Lesions in a Patient with Laryngeal Carcinoma.

Saccharomyces cerevisiae is increasingly being promoted as a nutritional supplement by health food enthusiasts and is also recommended as prophylaxis against antibiotic-associated diarrhea. However, severe opportunistic infections due to S. cerevisiae have been reported in patients with chronic disease, cancer, and immunosuppression. Fungemia, endocarditis, pneumonia, peritonitis, urinary tract infections, skin infections, and esophagitis have been described. It is important to consider infections due to S. cerevisiae in appropriate clinical settings. Here, we describe the first case of S. cerevisiae laryngitis in a patient with a history of laryngeal carcinoma who also had oral lesions.

(1→3)-ß-D-Glucan Levels Correlate With Neurocognitive Functioning in HIV-Infected Persons on Suppressive Antiretroviral Therapy: A Cohort Study.

Microbial translocation from the gut is associated with immune dysfunction, persistent inflammation, and likely plays a role in the pathogenesis of neurocognitive dysfunction during HIV infection. (1→3)-ß-D-Glucan (BDG) is a component of most fungal cell walls and might be a useful indicator of gut mucosal barrier impairment. The objective of this study was to evaluate whether higher blood BDG levels correlate with impaired neurocognitive functioning in a cohort of HIV-infected adults with suppressed levels of HIV RNA in blood plasma. In this cross-sectional cohort study, we measured levels of BDG in blood plasma and cerebrospinal fluid (CSF) supernatant samples in a cohort of adults with acute/early HIV infection, who initiated antiretroviral therapy (ART) during the earliest phase of infection and achieved suppressed levels of HIV RNA in blood plasma (<50 copies/mL) thereafter. We compared BDG with established biomarkers of microbial translocation, immune activation, and cognitive dysfunction (evaluated by global deficit score). We found that higher blood BDG levels were significantly related to higher global deficit scores, reflecting worse neurocognitive performance (Spearman r = 0.47; P = 0.042) among HIV-infected adults with suppressed viral loads who initiated ART early in infection. Two CSF samples presented elevated BDG levels. Interestingly, these 2 samples originated from the 2 subjects with the highest global deficit scores of the cohort. BDG may be a promising independent biomarker associated with neurocognitive functioning in virologically suppressed HIV-infected individuals.

Dynamics of monocyte chemoattractant protein type one (MCP-1) and HIV viral load in human cerebrospinal fluid and plasma.

BACKGROUND: Increased expression of monocyte chemoattractant protein type 1 (MCP-1) is associated with HIV CNS disease. This study evaluated the temporal relationships between MCP-1 expression and HIV replication in the CNS. METHODS: MCP-1 and HIV viral load (VL) were measured in serially obtained samples of plasma and cerebrospinal fluid (CSF) in subjects either interrupting (TI) or starting (TS) antiretroviral therapy. RESULTS: Following TI, plasma VL rebounded first, followed by increases in CSF MCP-1, which immediately preceded or coincided with a rebound of CSF VL. CONCLUSION: The close temporal relationship of the increase of MCP-1 and CSF VL suggests that they are co-regulated, or that one is a stimulus for the other.

Are HIV care providers talking with patients about safer sex and disclosure?: A multi-clinic assessment.

OBJECTIVES: To examine HIV-positive patients' reports of whether HIV care providers ever talked with them about practicing safer sex and disclosing seropositive status to sex partners. DESIGN: Cross-sectional survey (1998-1999) of HIV-positive men and women sampled randomly at six public HIV clinics in California. METHODS: Participants were interviewed and asked whether applicable clinic providers (physician, physician assistant, nurse practitioner, nurse, social worker, health educator, psychologist, psychiatrist) ever talked with them about safer sex or disclosure. Responses were analyzed by clinic site, HIV medical status (viral load), demographic, and behavioral variables (unprotected intercourse, non-disclosure). RESULTS: The sample (n = 839) included heterosexual men (n = 127), men who have sex with men (MSM; n = 607), and women (n = 105). Thirty-nine percent were white, 36% Hispanic, 17% black, and 8% other/mixed ethnicity. Overall, 71% reported that an applicable provider had talked with them at least once about safer sex (range across clinics, 52-94%); 50% reported discussion of disclosure (range across clinics, 31-78%). Discussion of safer sex was more prevalent with physicians than with other clinic staff. In multivariate analyses, in addition to significant clinic differences, MSM (versus heterosexual men) and whites (versus blacks or Hispanics) were less likely to receive prevention messages on these topics. Patients' behaviors (unsafe sex, non-disclosure) and HIV medical status were not independently associated with provider communication. CONCLUSIONS: HIV clinics differed substantially in the percentage of patients who reported that they received prevention messages from clinic staff. Care providers should assess and overcome barriers to providing prevention messages to patients.

Effect of brief safer-sex counseling by medical providers to HIV-1 seropositive patients: a multi-clinic assessment.

OBJECTIVE: To test the efficacy of brief, safer-sex counseling by medical providers of HIV-positive patients during medical visits. SETTING: Six HIV clinics in California. DESIGN: Clinics were randomized to intervention arms evaluated with cohorts of randomly selected patients measured before and after the intervention. PARTICIPANTS: Five-hundred and eighty-five HIV-positive persons, sexually active prior to enrollment. INTERVENTIONS: Prevention counseling from medical providers supplemented with written information. Two clinics used a gain-framed approach (positive consequences of safer-sex), two used a loss-frame approach (negative consequences of unsafe sex), and two were attention-control clinics (medication adherence). Interventions were given to all patients who attended the clinics. OUTCOME MEASURE: Self-reported unprotected anal or vaginal intercourse (UAV). RESULTS: Among participants who had two or more sex partners at baseline, UAV was reduced 38% (P < 0.001) among those who received the loss-frame intervention. UAV at follow-up was significantly lower in the loss-frame arm [odds ratio (OR), 0.42; 95% confidence interval (CI), 0.19-0.91; P = 0.03] compared with the control arm. Using generalized estimating equations (GEE) to adjust for clustering did not change the conclusions (OR, 0.34; 95% CI, 0.24-0.49; P = 0.0001). Similar results were obtained in participants with casual partners at baseline. No effects were seen in participants with only one partner or only a main partner at baseline. No significant changes were seen in the gain-frame arm. CONCLUSIONS: Brief provider counseling emphasizing the negative consequences of unsafe sex can reduce HIV transmission behaviors in HIV-positive patients presenting with risky behavioral profiles.

Localized osteomyelitis due to Mycobacterium avium complex in patients with Human Immunodeficiency Virus receiving highly active antiretroviral therapy.

We describe 3 patients who developed atypical manifestations of Mycobacterium avium complex (MAC) infection >10 months (range, 3-16 months) after attaining sustained CD4(+) T cell counts of >100 cells/microL while receiving antiretroviral therapy and not receiving MAC prophylaxis. The common features of these cases include the degree of immune reconstitution, the unusual locations of the infections, and the absence of a systemic inflammatory response. The low rate of these unusual MAC infections does not warrant continuation of primary or secondary prophylaxis after presumed immune reconstitution.

Portable lactate analyzer for measuring lactate in cerebrospinal fluid (CSF) and plasma - method-comparison evaluations.

UNLABELLED: Increased plasma lactate levels can indicate the presence of metabolic disorders in HIV infected individuals. OBJECTIVE: To determine whether a portable analyzer is valid for measuring cerebrospinal fluid (CSF) and plasma lactate levels in HIV infected individuals. METHOD: CSF and plasma were collected from 178 subjects. Samples tested by the Accutrend portable analyzer were compared to those tested by a reference device (SYNCHRON LX 20). RESULTS: The portable analyzer had in plasma sensitivity of 0.95 and specificity 0.87. For CSF the specificity was 0.95; the sensitivity 0.33; the negative predictive value was 95% and the positive predictive value 33%. CONCLUSIONS: These findings support the validity of the portable analyzer in measuring lactate concentrations in CSF that fall within the normal range. The relatively poor positive predictive value indicates that a result above the reference range may represent a "false positive test", and should be confirmed by the reference device before concluding abnormality.

Clinical variables identify seronegative HCV co-infection in HIV-infected individuals.

BACKGROUND: A substantial number of people living with HIV (PLWH) are co-infected with Hepatitis C Virus (HCV) but have a negative screening HCV antibody test (seronegative HCV infection, or SN-HCV). OBJECTIVE: To identify a concise set of clinical variables that could be used to improve case finding for SN-HCV co-infection among PLWH. STUDY DESIGN: Two hundred HIV-infected participants of the CHARTER study were selected based on 7 clinical variables associated with HCV infection but were HCV seronegative. Data were analyzed using Fisher's exact tests, receiver-operating characteristic (ROC) curves, and logistic regression. RESULTS: Twenty-six (13%) participants had detectable HCV RNA. SN-HCV was associated with a history of IDU, elevated ALT and AST, low platelets, black ethnicity, and undetectable HIV RNA in plasma. Each of these clinical variables, except for abnormal AST, remained independently associated with SN-HCV in a multivariate logistic regression analysis. A composite risk score correctly identified SN-HCV with sensitivity up to 85% and specificity up to 88%. CONCLUSIONS: In a substantial minority of PLWH, seronegative HCV viremia can be predicted by a small number of clinical variables. These findings, after validation in an unselected cohort, could help focus screening in those at highest risk.

Effects of traumatic brain injury on cognitive functioning and cerebral metabolites in HIV-infected individuals.

We explored the possible augmenting effect of traumatic brain injury (TBI) history on HIV (human immunodeficiency virus) associated neurocognitive complications. HIV-infected participants with self-reported history of definite TBI were compared to HIV patients without TBI history. Groups were equated for relevant demographic and HIV-associated characteristics. The TBI group evidenced significantly greater deficits in executive functioning and working memory. N-acetylaspartate, a putative marker of neuronal integrity, was significantly lower in the frontal gray matter and basal ganglia brain regions of the TBI group. Together, these results suggest an additional brain impact of TBI over that from HIV alone. One clinical implication is that HIV patients with TBI history may need to be monitored more closely for increased risk of HIV-associated neurocognitive disorder signs or symptoms.

Risk perception and beliefs regarding HIV infection among Ethiopian immigrants.

In Ethiopia, approximately 7.5% of the urban population is HIV-positive, and countrywide 1.5 million people are living with HIV. Between 1990 and 2000, immigration into the United States by African-born immigrants increased by 130%. Of this immigrant population, individuals from Ethiopia make up a significant portion. Although there is a rich literature addressing the beliefs regarding HIV and risk perception among some immigrant populations in the United States, few studies target Ethiopian-born residents. Thus, a survey-based study addressing demographics, acculturation, awareness, beliefs and risk perception, attitudes toward susceptibility for infection, and risk behaviors targeted Ethiopian-born residents of San Diego, California. Results indicate a separation between understanding of HIV transmission and personal risk perception for infection in a young, highly educated, predominantly male participant pool. As an initial study of HIV beliefs and risk perception in the immigrant Ethiopian population, our results provide information on specific areas warranting further investigation.