Mattia Trunfio

Clinical and viro-immunological correlates of HIV associated neurocognitive disorders (HAND) in a cohort of antiretroviral-naïve HIV-infected patients

The multifactorial pathogenesis of HIV-associated neurocognitive disorders may explain the inconsistent association between neurocognitive impairment and cerebrospinal fluid (CSF) HIV RNA. Clinical and viro-immunological (CSF and plasma HIV RNA, CSF/plasma HIV RNA ratio, circulating T-cell phenotypes) parameters were investigated in 155 HIV-infected, antiretroviral-naïve, asymptomatic study participants undergoing a neuropsychological evaluation. HIV associated neurocognitive disorders (HAND) was independently associated with AIDS events and a CSF/plasma ratio of at least one, after adjustment for CD4+ nadir of less than 200 cells/mmc, suggesting a role for active central nervous system (CNS) viral replication in the pathogenesis of neurocognitive impairment.

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

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.

Lower dolutegravir plasma concentrations in HIV-positive patients receiving valproic acid

Sir, Among the large spectrum of neurological disorders that can affect people living with HIV, seizures have been commonly reported. Before introducing new anticonvulsants, possible drug– drug interactions (DDIs) with antiretrovirals (ARVs) should be ruled out. DDIs may result in altered concentrations of both classes of drugs, leading to uncontrolled epilepsy, toxicity or emergence of drug-associated resistance mutations and ART failure. In HIV-positive patients, valproic acid is often used due to its mood-modulating properties and its favourable pharmacokinetic profile. Although concurrent use of valproic acid with older ARVs has been described, to date, no study has ruled out potential DDIs between valproic acid and the newest integrase inhibitor, dolutegravir. Both drugs are highly protein-bound and share secondary metabolizing pathways. Valproic acid is metabolized through glucuronidation by several uridine 50-diphospho-glucuronosyltransferase (UGT) enzymes, through b-oxidation in mitochondria and, to a lesser extent, through cytochrome P450. Dolutegravir is mainly metabolized by UGT1A1, but it is also a substrate of UGT1A3, UGT1A9 and CYP3A4. To better understand the determinants of dolutegravir plasma concentration in the clinical setting, we performed a registry analysis on data collected from Torino Therapeutic Drug Monitoring (TDM) laboratory. Plasma concentrations were measured at steady-state through a validated UPLC-MS/MS method with a limit of detection of 0.0117 lg/mL. Three hundred and sixty-three trough samples were withdrawn 21–27 h after drug intake in 149 patients. In seven patients on valproic acid (11 samples) lower dolutegravir trough concentrations were observed (median 0.068 lg/mL, IQR 0.037–0.148 lg/mL, minimum–maximum non-detectable–0.829 lg/mL) versus those not on valproic acid (median 0.557 lg/mL, IQR 0.290–1.135 lg/mL, minimum–maximum non-detectable–6.726 lg/mL). The highest dolutegravir concentration with valproic acid (0.829 lg/mL) was observed in a patient concomitantly receiving atazanavir, which is known to decrease dolutegravir metabolism through UGT1A1 inhibition. One patient had several trough levels measured and, despite other concomitant detectable ARVs, dolutegravir plasma concentrations were persistently low (Figure S1, available as Supplementary data at JAC Online). Following this preliminary observation, we performed detailed pharmacokinetic evaluations in two hospitalized patients requiring valproic acid while on dolutegravir-based regimens. Both signed written informed consent for sample withdrawal and data publication. The first patient was a woman admitted with progressive multifocal leucoencephalopathy and seizures. While on dolutegravir twice daily, she started valproic acid and lacosamide. Valproic acid was first administered intravenously (500 mg q8h) and then as oral modified-release tablets (500 mg q8h); 3 months later the oral dose was reduced to 250 mg q8h. Dolutegravir and valproic acid were measured at steady-state at five timepoints (pre-dose and 1, 3, 5 and 12 h after dose). Dolutegravir AUC, Cmin and Cmax showed variable profiles (Figure 1), while valproic acid concentrations were in the therapeutic range, between 50 and 100 lg/mL. With intravenous valproic acid, dolutegravir AUC was 82% lower than the mean reference AUC value for dolutegravir q12h (75.1 lg h/mL), with oral valproic acid 500 mg q8h it was 87% lower and with oral valproic acid 250 mg q8h it was 90.5% lower. The second instance was a female patient with bipolar disorder taking oral valproic acid 500 mg q8h, admitted with primary HIV infection. Intensified ART was started on admission with darunavir/ritonavir 600/100 mg q12h, dolutegravir 50 mg q24h and emtricitabine/tenofovir 200/245 mg q24h. Dolutegravir and valproic acid were measured 10 days after treatment initiation at six timepoints (pre-dose and 1, 3, 5, 12 and 24 h after dose). AUC was 80% lower than the mean reference value for dolutegravir q24h (53.6 lg h/mL), whereas Cmin was reduced by 87% (mean reference value 1.11 lg/mL). Although this result could partially be explained by the known interaction between dolutegravir and darunavir, the reduction in dolutegravir plasma concentrations was so high that other mechanisms need to be considered. Despite the small number of cases, these data may suggest a possible interaction between valproic acid and dolutegravir; the size of this potential DDI was relevant although both patients had dolutegravir plasma concentrations above the protein-adjusted 90% inhibitory quotient (0.064 lg/mL). Nevertheless this may be important for integrase inhibitor-exposed patients with HIV carrying resistance-associated mutations; the virological outcome of the two patients is unfortunately unavailable (one died and the other one was lost to follow-up). The mechanisms leading to this possible DDI are unknown. Dolutegravir absorption may be limited from excipients contained in some valproic acid gastro-resistant oral formulations, such as magnesium stearate. Magnesium, being a divalent ion, can chelate dolutegravir, reducing its absorption. Dolutegravir plasma concentrations were lower with reduced valproic acid doses at

Symptomatic cerebrospinal fluid HIV-1 escape with no resistance-associated mutations following low-level plasma viremia

The majority of neurologically symptomatic cerebrospinal fluid HIV-1 escape cases are connected with resistance-associated mutations and potentially explained by low cerebrospinal fluid antiretroviral concentrations. However, there are still significant knowledge gaps regarding the physiopathology and long-term management of neurosymptomatic viral escape. We report a case of Parkinson-like syndrome following cerebrospinal fluid HIV-1 escape in a 40-year-old female patient with an history of persistent low-level plasma viremia under treatment. No resistance-associated mutations, high viral diversity (env deep sequencing), adequate pharmacokinetics, atypical CD3-CD14-CD4+CD5-CD2-/+CD7-/+ lymphocytes, low-level Epstein-Barr virus replication, and white matter autoimmune reactivity were observed in the cerebrospinal fluid. Antiretroviral regimen modification led to rapid clinical and radiological improvements. This case may increase the current uncertain knowledge on the origin of cerebrospinal fluid HIV-1 and illustrates the consequences of uncontrolled compartmental viral replication; it also highlights the relevance and persistence of immune activation and the possibility of various detrimental mechanisms underlying neurosymptomatic viral escape.

Ultrasonography of an Oral Cavity Onchocercidae Nodule

A 51-year-old caucasian woman, living in Italy since her birth, presented with a 6-month history of a left swollen cheek and intraoral nodule, unresponsive to antibiotics. Her previous medical history was positive for seasonal allergies and left jowl reconstructive surgery with filling for a car accident 5 years before. Blood tests were unremarkable; physical examination showed an asymptomatic left cheek bulge and a 1 × 0.5 cm nontender noninflammatory submucosal firm nodule located in the left maxillary vestibule. An intraoral ultrasound examination was performed (Figure 1). Differential diagnoses of benign and malignant lesions were likely ruled out and preliminary diagnoses of probable filariasis or foreign body reaction were made. Filariasis serology and microfilaremia were negative. The patient refused antiparasitic treatment, and an excisional biopsy was performed; the healing was complicated by a surgical site infection. Microscopy revealed a cystic cavity containing a cross section of an onchocercidae worm (Figure 2). Considering the clinical picture, histology, and epidemiology, an ultimate presumable diagnosis of dirofilariasis was made. Dirofilaria are mosquito-borne nematodes infecting canines. Man is a dead-end host rarely infected by bites of vector mosquitoes. Endemic areas include tropical and subtropical regions, the United States, Australia, and the Mediterranean area. Recently, dirofilariasis spread to previously free countries because of climate changes and emerging vectors. Most of the cases involve the head, neck, or periocular region; oral dirofilariasis is rare. Themost commonpresentation is a single symptomless subcutaneous/submucosal nodule. As in our case, dirofilarias usually affect adult females, and microfilaremia, eosinophilia, and immunoglobulin E elevation are absent. Serology is not helpful; polymerase chain reaction has been suggested, but it is resource consuming and not widely available. Because of the wide variety of the differential diagnoses, surgical excision is the most used technique to reach the diagnosis. However, histopathology has limitations because the nematode morphology may be altered by inflammatory responses or surgical manipulations, as in our case. To date, scarce data are available about ultrasonography of dirofilarial nodules; doppler imaging may also be helpful in the differential diagnosis. Older lesions present calcification and fibrosis, whereas younger nodules may show a weakly moving filiform worm (see Supplemental Video 1). In cases

Cognitive Neuro-Rehabilitation of HIV-Associated Neurocognitive Disorders : Case Reports of A New Computer-Based Restorative Approach In 3 Hiv-Positive Cart-Treated Patients

Cognitive Neuro-Rehabilitation of HIV-Associated Neurocognitive Disorders: Case Reports of A New Computer-Based Restorative Approach In 3 Hiv-Positive Cart-Treated Patients Francesca Iannuzzi1,*, Francesca Bai1, Lidia Borghi2, Mattia Trunfio1, Elena Anna Maria Vegni2, Antonella d’Arminio Monforte1 and Giulia Marchetti1 1Clinic of Infectious and Tropical Diseases, Department of Health Sciences, University of Milan, San Paolo Hospital, Milan, Italy 2Unit of Clinical Psychology, Department of Health Sciences, University of Milan, San Paolo Hospital, Milan, Italy Casereport Open Access Journal of Neurophysiology and Neurological Disorders

Viro-immunological characterization of naïve patients with high cerebrospinal fluid (CSF) HIV RNA.

HIV can spread into the central nervous system (CNS) early in the course of infection and this turns into intrathecal inflammation and neuronal damage. We aimed to investigate clinical and immunological parameters associated with elevated CSF VL in HIV‐infected ART‐naïve patients.