Janis Durelle

Hepatitis C augments cognitive deficits associated with HIV infection and methamphetamine

Objective: To examine the contribution of hepatitis C virus (HCV) infection to neurocognitive dysfunction in individuals with comorbid HIV infection or methamphetamine (METH) dependence. Methods: Neurocognitive functioning was examined in 430 study participants who were either normal controls or had HCV infection, HIV infection, history of METH dependence, or combinations of these factors as risks for cognitive deficits. Results: Rates of global and domain-specific neuropsychological (NP) impairment increased with the number of risk factors. HCV serostatus was a significant predictor of NP performance both globally and in the areas of learning, abstraction, and motor skills, with trends in speeded information processing and delayed recall. HCV serostatus did not predict scores in attention/working memory or verbal fluency. Conclusion: Hepatitis C virus infection contributes to the neuropsychological deficits observed among HIV-infected and stimulant-dependent populations.

Genetic Composition of Human Immunodeficiency Virus Type 1 in Cerebrospinal Fluid and Blood without Treatment and during Failing Antiretroviral Therapy

ABSTRACT Human immunodeficiency virus (HIV) infection of the central nervous system (CNS) is a significant cause of morbidity. The requirements for HIV adaptation to the CNS for neuropathogenesis and the value of CSF virus as a surrogate for virus activity in brain parenchyma are not well established. We studied 18 HIV-infected subjects, most with advanced immunodeficiency and some neurocognitive impairment but none with evidence of opportunistic infection or malignancy of the CNS. Clonal sequences of C2-V3 env and population sequences of pol from HIV RNA in cerebrospinal fluid (CSF) and plasma were correlated with clinical and virologic variables. Most (14 of 18) subjects had partitioning of C2-V3 sequences according to compartment, and 9 of 13 subjects with drug resistance exhibited discordant resistance patterns between the two compartments. Regression analyses identified three to seven positions in C2-V3 that discriminated CSF from plasma HIV. The presence of compartmental differences at one or more of the identified positions in C2-V3 was highly associated with the presence of discordant resistance (P = 0.007), reflecting the autonomous replication of HIV and the independent evolution of drug resistance in the CNS. Discordance of resistance was associated with severity of neurocognitive deficits (P = 0.07), while low nadir CD4 counts were linked both to the severity of neurocognitive deficits and to discordant resistance patterns (P = 0.05 and 0.09, respectively). These observations support the study of CSF HIV as an accessible surrogate for HIV virions in the brain, confirm the high frequency of discordant resistance in subjects with advanced disease in the absence of opportunistic infection or malignancy of the CNS, and begin to identify genetic patterns in HIV env associated with adaptation to the CNS.

Lopinavir concentrations in cerebrospinal fluid exceed the 50% inhibitory concentration for HIV.

Introduction:Lopinavir (LPV) is highly bound to plasma proteins and is a substrate for active drugs transporters, which may greatly limit the access of LPV to the central nervous system (CNS). However, even low lopinavir concentrations may be sufficient to inhibit HIV replication. Prior anecdotal reports indicated that lopinavir concentrations were below detection in cerebrospinal fluid (CSF). Methods:LPV was measured by liquid chromatography/mass spectrometry in 31 CSF–plasma pairs from 26 HIV-infected individuals who were taking LPV-containing antiretroviral regimens. The lower limit of quantification was 3.7 μg/l. Results:Seven of the sample pairs had very low plasma (and CSF) LPV concentrations, with a mean estimated plasma trough of 274 μg/l (range, < 3.7 to 608; typical trough values ∼4000 μg/l), suggesting poor recent adherence. In the remaining 24 sample pairs, the median LPV concentration was 5889 μg/l [interquartile range (IQR), 4805–9620] and all CSF samples had measurable LPV concentrations: median 17.0 μg/l (IQR, 12.1–22.7). The median CSF–plasma ratio was 0.23% (range, 0.12–0.75). All CSF concentrations in these samples were more than double the 50% inhibitory concentration for wild-type HIV virus. Conclusions:In patients with typical plasma levels of LPV, the drug is detectable in the CSF at concentrations that exceed those needed to inhibit HIV replication. Despite being > 98% bound to plasma proteins, LPV penetrates into the CNS and may contribute to the control of HIV in this potential reservoir.

Lithium improves HIV-associated neurocognitive impairment.

Objective:To determine the effects of low-dose oral lithium on the neuropsychological performance of individuals diagnosed with HIV-associated neurocognitive impairment. Design and methods:The project was a single-arm, open-label, 12-week pilot study at a university-based tertiary care center. The participants were adults who had been diagnosed with HIV-associated neurocognitive impairment and had been on stable antiretroviral therapy for at least 12 weeks. Conditions that could affect cognition, worsen adherence to study procedures, or increase the risk of lithium adverse reactions were excluded. Twenty-one individuals were screened and eight were enrolled, all of whom completed the study. Oral lithium was initiated at 300 mg daily and was titrated to maintain 12-h trough concentrations between 0.4 and 0.8 mEq/l. Global neuropsychological performance was assessed by the global deficit score. Results:At baseline, all participants had impaired neuropsychological performance and most had reduced CD4 cell counts (median 292 cells/μl), and HIV RNA levels in plasma below 400 copies/mL (seven of eight). Titrated lithium doses ranged between 600 and 1200 mg/day. Performance improved in all eight individuals after 12 weeks, and became unimpaired in six. The study treatment was well tolerated with no grade 3 or 4 adverse events and no premature discontinuations. Conclusions:Lithium resulted in improved neuropsychological performance in antiretroviral-treated, impaired individuals in this small, open-label study. Based on published in vitro data, lithium may exert this effect by inhibiting neuronal glycogen synthase kinase-3β.

Human Immunodeficiency Virus Protease Inhibitors and Risk for Peripheral Neuropathy

Two recent analyses found that exposure to protease inhibitors (PIs) in the context of antiretroviral (ARV) therapy increased the risk for distal sensory polyneuropathy (DSPN) in subjects with human immunodeficiency virus (HIV) infection. These findings were supported by an in vitro model in which PI exposure produced neurite retraction and process loss in dorsal root ganglion sensory neurons. Confirmation of peripheral nerve toxicity with PIs could substantially limit their long‐term use in highly active ARV therapy.

Enteric‐coated cysteamine for the treatment of paediatric non‐alcoholic fatty liver disease

Aliment Pharmacol Ther 2011; 33: 1036–1044

Lopinavir with Ritonavir Reduces the HIV RNA Level in Cerebrospinal Fluid

Background. Combination antiretroviral (ARV) therapy can reduce human immunodeficiency virus (HIV) RNA levels in cerebrospinal fluid (CSF) and plasma and improve immunocompetence. However, HIV-associated neurocognitive disorders persist, possibly because some ARV drugs do not reach therapeutic concentrations in the brain. The primary objective of this study was to determine whether lopinavir plus ritonavir (LPV-rtv) used alone reduced the HIV RNA level in CSF. Methods. The study was an open-label, 24-week trial of sequential ARV therapy. Fifteen subjects were enrolled and received LPV-rtv therapy. Ten subjects reached the primary study end point at week 3, before at least 2 other ARV drugs were added to the treatment regimen. CSF and blood samples were obtained before treatment and after 3, 12, and 24 weeks of treatment. Results. LPV-rtv therapy alone reduced the HIV RNA level in CSF in all subjects (median change in HIV RNA level, -1.42 log 10 copies/mL), including 5 who had slower decreases in HIV RNA level in CSF than in plasma-an indicator of autonomous central nervous system infection. Among 9 subjects who completed 12 weeks of LPV-rtv-containing therapy, the HIV RNA level was below quantitation in the CSF samples from 8 subjects and in the plasma samples from 6 subjects. By week 24, HIV RNA levels were below quantitation in samples of both fluids from all 8 subjects. Conclusions. LPV-rtv therapy alone for 3 weeks consistently reduces the HIV RNA level in CSF by at least 10-fold in most individuals, including those likely to have autonomous HIV replication in the central nervous system. Because it penetrates the central nervous system in therapeutic concentrations and appears to reduce HIV replication in the central nervous system, LPV-rtv may benefit subjects who receive a diagnosis of or are at risk for HIV-associated neurocognitive disorders.

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 log10 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.

Estimation of fish and ω-3 fatty acid intake in pediatric nonalcoholic fatty liver disease.

Aims: Fish and &ohgr;-3 fatty acids are reported to be beneficial in pediatric nonalcoholic fatty liver disease (NAFLD), but no studies have assessed their relation to histological severity. The objectives of this study were to evaluate the dietary intake of fish and &ohgr;-3 fatty acids in children with biopsy-proven NAFLD, and examine their association with serological and histological indicators of disease. Methods: This was a cross-sectional analysis of 223 children (6–18 years) who participated in the Treatment of Nonalcoholic Fatty Liver Disease in Children trial or the NAFLD Database study conducted by the Nonalcoholic Steatohepatitis Clinical Research Network. The distribution of fish and &ohgr;-3 fatty acid intake was determined from responses to the Block Brief 2000 Food Frequency Questionnaire, and analyzed for associations with serum alanine aminotransferase, histological features of fatty liver disease, and diagnosis of steatohepatitis after adjusting for demographic, anthropometric, and dietary variables. Results: The minority of subjects consumed the recommended 8 ounces of fish per week (22/223 [10%]) and 200 mg of long-chain &ohgr;-3 fatty acids per day (12/223 [5%]). Lack of fish and long-chain &ohgr;-3 fatty acid intake was associated with greater portal (P = 0.03 and P = 0.10, respectively) and lobular inflammation (P = 0.09 and P = 0.004, respectively) after controlling for potential confounders. Conclusions: Fish and &ohgr;-3 fatty acid intake was insufficient in children with NAFLD, which may increase susceptibility to hepatic inflammation. Patients with pediatric NAFLD should be encouraged to consume the recommended amount of fish per week.

Magnetic Resonance Elastography Measured Shear Stiffness as a Biomarker of Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease

Magnetic resonance elastography (MRE) is a promising technique for noninvasive assessment of fibrosis, a major determinant of outcome in nonalcoholic fatty liver disease (NAFLD). However, data in children are limited. The purpose of this study was to determine the accuracy of MRE for the detection of fibrosis and advanced fibrosis in children with NAFLD and to assess agreement between manual and novel automated reading methods. We performed a prospective, multicenter study of two‐dimensional (2D) MRE in children with NAFLD. MR elastograms were analyzed manually at two reading centers, and using a new automated technique. Analysis using each approach was done independently. Correlations were determined between MRE analysis methods and fibrosis stage. Thresholds for classifying the presence of fibrosis and of advanced fibrosis were computed and cross‐validated. In 90 children with a mean age of 13.1 ± 2.4 years, median hepatic stiffness was 2.35 kPa. Stiffness values derived by each reading center were strongly correlated with each other (r = 0.83). All three analyses were significantly correlated with fibrosis stage (center 1, ρ = 0.53; center 2, ρ = 0.55; and automated analysis, ρ = 0.52; P < 0.001). Overall cross‐validated accuracy for detecting any fibrosis was 72.2% for all methods (95% confidence interval [CI], 61.8%‐81.1%). Overall cross‐validated accuracy for assessing advanced fibrosis was 88.9% (95% CI, 80.5%‐94.5%) for center 1, 90.0% (95% CI, 81.9%‐95.3%) for center 2, and 86.7% (95% CI, 77.9%‐92.9%) for automated analysis. Conclusion: 2D MRE can estimate hepatic stiffness in children with NAFLD. Further refinement and validation of automated analysis techniques will be an important step in standardizing MRE. How to best integrate MRE into clinical protocols for the assessment of NAFLD in children will require prospective evaluation. (Hepatology 2017;66:1474–1485)