Diagnostic accuracy of new and old cognitive screening tools for HIV-associated neurocognitive disorders.

OBJECTIVES: Considering the similarities between HIV-associated neurocognitive disorders (HAND) and neurodegenerative dementias and the frequency of executive dysfunctions among HIV-positive patients, we evaluated the accuracy of the Frontal Assessment Battery and Clock-Drawing Test together with the Three Questions Test and International HIV Dementia Scale to screen for HAND. METHODS: A cross-sectional monocentric study was conducted from 2010 to 2017. The index tests were represented by the four screening tools; the reference standard was represented by a comprehensive neurocognitive battery used to investigate 10 cognitive domains. Patients were screened by a trained infectious diseases physician and those showing International HIV Dementia Scale scores ≤ 10 and/or complaining of neurocognitive symptoms were then evaluated by a trained neuropsychologist. RESULTS: A total of 650 patients were screened and 281 received the full neurocognitive evaluation. HAND was diagnosed in 140 individuals. The sensitivity, specificity, correct classification rate and area under the receiver operating characteristic curve (AUROC) were, respectively, as follows: Frontal Assessment Battery, 40.7%, 95.1%, 68.3% and 0.81; International HIV Dementia Scale, 74.4%, 56.8%, 65.4% and 0.73; Clock-Drawing Test, 30.9%, 73.4%, 53.8% and 0.56; and Three Questions Test, 37.3%, 54.1% and 45.7%. Raising the Frontal Assessment Battery's cut-off to ≤ 16 improved its sensitivity, specificity and correct classification rate to 78.0%, 63.9% and 70.8%, respectively. CONCLUSIONS: We observed poor screening performances of the Three Questions and Clock-Drawing Tests. While the International HIV Dementia Scale showed a poor specificity, the Frontal Assessment Battery showed the highest correct classification rate and a promising performance at different exploratory cut-offs.

Detectable cerebrospinal fluid JCV DNA in late-presenting HIV-positive patients: beyond progressive multifocal leukoencephalopathy?

In the absence of effective prophylaxis and treatment, therapeutic options in HIV-positive patients with progressive multifocal leukoencephalopathy (PML) are limited to antiretroviral therapy: nevertheless, outcome is poor. We conducted a retrospective study (2009-2015) describing the outcome of 25 HIV-positive patients with detectable cerebrospinal fluid JC virus DNA: 14 had a probable PML while the others had evidence of other inflammatory central nervous system (CNS) affecting disorders. In the former group, 6-month mortality was 45.5% vs 21.4 in the latter one: survival was higher than previously described but no predictor of poor outcome was identified. Two patients treated with 5HT2-inhibitors survived. The contributing role of JCV replication in other CNS-affecting disorders needs to be assessed as well as the benefits of 5HT2-inhibitors in HIV-positive patients with proven PML.

Blood Brain Barrier Impairment in HIV-Positive Naïve and Effectively Treated Patients: Immune Activation Versus Astrocytosis.

Blood brain barrier (BBB) damage is a common feature in central nervous system infections by HIV and it may persist despite effective antiretroviral therapy. Astrocyte involvement has not been studied in this setting. Patients were enrolled in an ongoing prospective study and subjects with central nervous system-affecting disorders were excluded. Patients were divided into two groups: treated subjects with cerebrospinal fluid (CSF) HIV RNA <50 copies/mL (CSF-controllers) and in late-presenters CD4+ T lymphocytes <100/uL. CSF biomarkers of neuronal or astrocyte damage were measured and compared to CSF serum-to-albumin ratio. 134 patients were included; 67 subjects in each group (50 %) with similar demographic characteristics (with the exception of older age in CSF controllers). CD4 (cells/uL), plasma and CSF HIV RNA (Log10 copies/mL) were 43 (20-96), 5.6 (5.2-6) and 3.9 (3.2-4.7) in LPs and 439 (245-615), <1.69 (9 patients <2.6) and <1.69 in CSFc. BBB impairment was observed in 17 late-presenters (25.4 %) and in 9 CSF-controllers (13.4 %). CSF biomarkers were similar but for higher CSF neopterin values in late-presenters (2.3 vs. 0.6 ng/mL, p < 0.001). CSARs were associated with CSF neopterin (rho = 0.31, p = 0.03) and HIV RNA (rho = 0.24, p = 0.05) in late-presenters and with CSF tau (rho = 0.51, p < 0.001), p-tau (rho = 0.47, p < 0.001) and S100beta (rho = 0.33, p = 0.009) in CSF-controllers. In HAART-treated subjects with suppressed CSF HIV RNA, BBB altered permeability was associated with markers of neuronal damage and astrocytosis. Additional treatment targeting astrocytosis and/or viral protein production might be needed in order to reduce HIV effects in the central nervous system.

Blood brain barrier impairment is associated with cerebrospinal fluid markers of neuronal damage in HIV-positive patients.

Blood brain barrier impairment occurs early in the course of infection by HIV and it may persist in a subset of patients despite effective antiretroviral treatment. We tested the hypothesis that HIV-positive patients with dysfunctional blood brain barrier may have altered biomarkers of neuronal damage. In adult HIV-positive highly active antiretroviral treatment (HAART)-treated patients (without central nervous system infections and undergoing lumbar punctures for clinical reasons) cerebrospinal fluid albumin to serum ratios (CSAR), total tau, phosphorylated tau, 1-42 beta amyloid, and neopterin were measured. In 101 adult patients, cerebrospinal fluid-to-serum albumin ratios were 4.8 (3.7-6.1) with 12 patients (11.9%) presenting age-defined impaired blood brain barrier. A significant correlation was observed between CSAR and total tau (p = 0.005), phosphorylated tau (p = 0.008), and 1-42 beta amyloid (p = 0.040). Patients with impaired blood brain barrier showed significantly higher total tau (201.6 vs. 87.3 pg/mL, p = 0.010), phosphorylated tau (35.3 vs. 32.1 ng/mL, p = 0.035), and 1-42 beta amyloid (1134 vs. 830 pg/mL, p = 0.045). Despite effective antiretroviral treatment, blood brain barrier impairment persists in some HIV-positive patients: it is associated with markers of neuronal damage and it was not associated with CSF neopterin concentrations.

Prevalence and predictors of blood-brain barrier damage in the HAART era.

Blood-brain barrier damage (BBBD) is prevalent in HIV-positive patients and may enhance cell trafficking to the central nervous system. A retrospective analysis in adult HIV-positive patients with no central nervous system disease was conducted in order to estimate the prevalence and risk factors of BBBD (according to cerebrospinal fluid to plasma albumin ratios). One hundred fifty-eight HIV-positive adult patients were included. BBBD impairment and intrathecal IgG synthesis were respectively observed in 45 (28.5 %) and 100 patients (63.3 %). Low CD4 nadir and high CSF HIV RNA were independently associated with both abnormalities. BBBD is common in HIV-positive patients, and its main determinants are advanced immune depression and compartmental viral replication.

A case of dengue type 3 virus infection imported from Africa to Italy, October 2009.

In October 2009, a traveller returning from Africa to Italy was hospitalised with symptoms suggestive of a haemorrhagic fever of unknown origin. The patient was immediately placed in a special biocontainment unit until laboratory investigations confirmed the infection to be caused by a dengue serotype 3 virus. This case reasserts the importance of returning travellers as sentinels of unknown outbreaks occurring in other countries, and highlights how the initial symptoms of dengue fever resemble those of other haemorrhagic fevers, hence the importance of prompt isolation of patients until a final diagnosis is reached.

Infective endocarditis in intravenous drug users from Italy: the increasing importance in HIV-infected patients.

BACKGROUND: Intravenous drug users (IDUs) are at increased risk of infective endocarditis (IE). PATIENTS AND METHODS: Episodes of IE in IDUs were retrospectively analyzed in this multicenter study. Cases were collected between 1986 and 1999. Only definite diagnosis according to the Duke criteria were analyzed. RESULTS: Two hundred and sixty-three cases, including 100 cases in HIV-positive patients, were observed in IDUs. Any right-sided involvement was detected in 167 out of 263 cases (63.5%) and any left-sided involvement in 115 out of 263 cases (43.7%). The tricuspid valve (TV) alone was affected in 135 cases (51.3%), the mitral valve alone in 32 patients (12.1%), the aortic valve alone in 41 cases (15.6%) and the pulmonic valve alone in 3 cases. Staphylococcus aureus was isolated in 156 cases (59.3%) and Streptococcus spp. in 33 cases (12.5%). No major differences were observed between HIV-negative and HIV-positive patients. Any TV valve involvement was significantly associated with female rather than male gender (p = 0.02). There was a significant association between S. aureus etiology and TV involvement (p < 0.0001). The mortality rate was 16%. On multivariate analysis, only left-side IE (p = 0.0006; OR 5.2; 95% CI 2.0-13.5) and age greater than 35 years (p = 0.0068; OR 3.6; 95% CI 1.4-9.0) were independently associated with mortality. CONCLUSIONS: Infective endocarditis in IDUs is significantly associated with right-side localization (63.5% for any rightsided heart involvement vs 43.7% for any left-sided heart involvement; OR 2.24; 95% CI 1.55-3.23; p < 0.001). S. aureus is the microorganism most frequently isolated and is significantly associated with TV involvement. Any left-side involvement and age greater than 35 years are independently associated with mortality. HIV infection does not appear to have a significant effect on mortality.

A short course of pegylated interferon-alpha in acute HCV hepatitis.

Acute hepatitis C virus (HCV) infection evolves to chronicity in 50-84% cases. Treatment with interferon-alpha (IFN-alpha) was repeatedly found to provide sustained cure rates higher than that in chronic HCV infection, but the optimal treatment strategy has not yet been defined. In a multicentre open-label study, we investigated the therapeutic performance of a short course of pegylated (peg) IFN-alpha in patients with acute HCV hepatitis. Peg IFN-alpha2b, 1.0-1.5 micro g/kg weekly, was administered for 12 weeks. Forty-six patients were enrolled; 26 of them were intravenous drug users. Eleven patients had jaundice. Treatment was started within 1-90 days from the peak alanine aminotransferase. Treatment was well tolerated with a single dropout (2%). Thirty-three of 46 patients (72%) had a sustained virological response (SVR) after a 6 months post-treatment follow-up, 8 (17%) relapsed after treatment and 4 were nonresponders (9%). A lower peak viraemia, receiving at least 1.2 micro g/kg of peg IFN-alpha, and a negative HCV-RNA at week 4 and week 12 were predictors of SVR. Thus, in patients with early (week 4) viral response, a short course of peg IFN-alpha at a weekly dose >1.2 micro g/kg, may be a valuable option for the treatment of acute HCV hepatitis.

Penetration of didanosine in semen of HIV-1-infected men.

OBJECTIVES: The disposition of antiretroviral agents into genital tissue and fluids is one of the factors implicated in the control of viral replication within the male genital tract and should be an objective of highly active antiretroviral therapy. We have investigated didanosine penetration in seminal plasma of 16 HIV-infected patients. PATIENTS AND METHODS: A total of 16 patients on didanosine (200 mg every 12 h or 400 mg once daily) participated in the pharmacokinetic study. After the didanosine morning dose, peripheral blood plasma and semen plasma were collected within the intervals 0-4, 4-8 and 8-12 h in the twice-daily regimen and 0-4, 4-12 and 12-24 h in the once-daily regimen. RESULTS: Within each sampling time interval didanosine concentrations in seminal plasma were higher than in blood. The interquartile range of concentrations in seminal plasma was 292-1217 ng/mL, compared with 50-150 ng/mL in blood plasma. Didanosine could be detected in 14 of the 16 semen samples analysed and in 8 of the 16 blood samples. CONCLUSIONS: We have demonstrated that didanosine penetrates into the seminal plasma in higher concentrations than in blood plasma.

Clinical pharmacology of antiretroviral therapy.

Antiretroviral therapy represents by all means a new branch of anti-infective chemotherapy, and in order to describe the mode of action of antiretrovirals, a series of inferences from anti-bacterial chemotherapy were made. The currently available antiretroviral agents can be classified as time-dependent drugs, and therefore the key pharmacokinetic parameter adopted in their clinical-pharmacological assessment is the concentration at the end of the dosing interval (Ctrough). By focusing on this parameter, the application of Therapeutic Drug Monitoring (TDM) allows for the successful individual tailoring of the drug dosage in some clinical circumstances, such as treatment of drug-resistant infections, drug-drug interactions and side effects. While this procedure has now been sufficiently standardized for protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), no clinical applications are yet recognized for nucleoside/nucleotide reverse transcriptase inhibitors (N/NtRTIs) and fusion inhibitors. The main unfavourable peculiarity of HIV infection, such as the need for lifelong treatment, is one of the reasons why increasing attention is being paid to pharmacological aspects of antiretroviral therapy. Issues like treatment potency, maintenance over time of the immunovirological benefit and long-term side effects require intensive pharmacological investigation in order to obtain the information on which basing the most convenient strategy to be adopted for the therapeutical management of this condition.

Is a 3-month course of treatment with Peg-interferon effective in acute HCV hepatitis?

From February 2002, all the consecutive patients referring to the Department of Infectious Diseases, University of Turin, who were diagnosed as having acute HCV hepatitis were included in a prospective cohort study to evaluate if a 3-month course of Peg-Interferon alpha-2b (1.5 microg/kg once weekly) is effective to decrease the risk of progression to chronic disease. ALT and HCV-RNA measurements were scheduled at week 4 and 12 during treatment, and 24 weeks after the end of therapy. As of April 2003, ten patients were enrolled in the study. As to HCV genotype, seven patients had type 1 and 3 type non-1. At entry, median HCV-RNA level was 129500 (range: 3000-3100000 copies/mL) and six patients were symptomatic. Treatment was given within 20 days (range: 8-30) of the ALT peak. All patients completing 4 weeks (n = 9) and 12 weeks of treatment (n = 7) had undetectable HCV-RNA. Five patients who completed the 24-week follow-up after the end of treatment had a sustained viral response with ALT levels within normal range. Therapy was well tolerated in all patients. Even if our data are not definitive, our results show that once-weekly administration of Peg-interferon alfa-2b in patients with acute HCV infection may be an effective and convenient regimen.

Successful simplification of HAART in patients with acute primary HIV infection.

Aggressive treatment has been advocated for the management of primary HIV infection (PHI), but the composition and the optimal duration of therapy are still to be determined. In addition, time to undetectable viral load (VL), rate and duration of VL suppression as well as subsequent therapeutic choices remain issues widely debated. We evaluated the rate and duration of VL suppression in 12 consecutive patients with PHI given triple-drug treatment with zidovudine, lamivudine and indinavir (highly active antiretroviral therapy, HAART) at onset of the acute illness and subsequently switched to a simplified 2-NRTI-based regimen once VL suppression was maintained for at least 6 months. Throughout the study, no patient discontinued treatment because of symptoms attributed to the study medications. In the study population, undetectable VL was achieved after a median of 84 days (range: 67-135) on HAART and was maintained for a median of 194 days (range: 179-205) before simplification. After switching to simplified maintenace, undetectable VL was maintained in all patients for at least 6 months. Only one patient experienced virological failure, plasma HIV-RNA remaining suppressed for a median foliow-up of 33 months (15-54) and T-CD4+ being steadily higher than 500/mL in the remaining patients. Our results suggest that simplification of HAART in patients promptly treated during PHI and maintaining undetectable VL for at least 6 months before simplification may be a valid option capable of controlling viral replication and maintaining an optimal immunological profile for a prolonged time.