Elisabetta Teti

Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies

Despite the excellent efficacy of direct‐acting antivirals (DAA) reported in clinical trials, virological failures can occur, often associated with the development of resistance‐associated substitutions (RASs). This study aimed to characterize the presence of clinically relevant RASs to all classes in real‐life DAA failures.

Cortical sources of resting-state EEG rhythms are abnormal in naïve HIV subjects.

OBJECTIVE The aim of the study was to test the hypothesis that cortical sources of resting-state electroencephalographic (EEG) rhythms show peculiar frequency/spatial features in naïve human subjects with human immunodeficiency virus (HIV) compared to healthy control subjects. METHODS Resting-state eyes-closed EEG data were recorded in 18 naïve HIV subjects (15 males; mean age 39 years±2.0 standard error of mean, SEM) and in 18 age-matched cognitively normal subjects (15 males; 38.7years±2.2 SEM). EEG rhythms of interest were delta (2-4Hz), theta (4-8Hz), alpha1 (8-10Hz), alpha2 (10-12Hz), beta1 (13-20Hz) and beta2 (20-30Hz). Cortical EEG sources were estimated by normalised, low-resolution electromagnetic tomography (LORETA). RESULTS Mini Mental State Evaluation (MMSE) score was lower in HIV (26.5 ± 0.7 SEM) than in healthy (29.2 ± 0.5 SEM) subjects (p<0.05). Central and parietal delta sources showed higher amplitude in the HIV than in control subjects. Furthermore, topographically widespread, cortical sources of resting-state alpha rhythms were lower in amplitude in HIV subjects than in control subjects. CONCLUSIONS The present results suggest that topography and frequency of the cortical sources of resting-state EEG rhythms can distinguish groups of HIV and control subjects. SIGNIFICANCE These results encourage future studies in an enlarged cohort of HIV subjects to test the hypothesis that the present methodological approach provides clinically useful information for an early detection of the effect of HIV infection on brain and cognitive functions.

Depression and affective temperaments are associated with poor health-related quality of life in patients with HIV infection

Introduction. Human immunodeficiency virus (HIV) represents one of the most chronic and debilitating infections worldwide. Hopelessness and affective temperaments (mood that is characteristic of an individual’s habitual functioning) may play important roles in the health-related quality of life (HRQoL) of patients with HIV. The purpose of this study was to examine affective temperaments in a sample of patients with HIV, the impact of hopelessness on HRQoL, and associations among HRQoL, hopelessness, and affective temperaments. Methods. The study involved 88 participants who were administered the Short- Form Health Survey (SF-36), the Beck Hopelessness Scale (BHS), the Suicidal History Self-Rating Screening scale (SHSS), the Gotland Male Depression Scale (GMDS), and the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A). Results. Patients with a poorer HRQoL reported more severe depression and hopelessness than patients with a higher HRQoL. Patients with a poorer HRQoL also had higher scores on all dimensions of the TEMPS-A with a depressive component compared to patients with a higher HRQoL. The small sample size in this study limits the generalizability of the findings. Conclusion. Patients with a poorer HRQoL were more depressed and also at an increased risk of suicide as indicated by the more severe hopelessness they reported compared to patients with higher HRQoL. These patients were also more likely to have depressive affective temperaments than those with a higher HRQoL. (Journal of Psychiatric Practice 2013;19:109–117)

Pharmacogenetics as a tool to tailor antiretroviral therapy: A review.

Highly active antiretroviral therapy (HAART) has substantially changed human immunodeficiency virus (HIV) infection from an inexorably fatal condition into a chronic disease with a longer life expectancy. This means that HIV patients should receive antiretroviral drugs lifelong, and the problems concerning with a chronic treatment (tolerability, side effects, adherence to treatment) have now become dominant. In this context, strategies for the treatment personalization have taken a central role in optimizing the therapeutic response and prevention of adverse drug reactions. In this setting, the study of pharmacogenetics features could be a very useful tool in clinical practice; moreover, nowadays the study of genetic profiles allows optimizations in the therapeutic management of People Living With HIV (PLWH) through the use of test introduced into clinical practice and approved by international guidelines for the adverse effects prevention such as the genetic test HLA-B*5701 to detect hypersensitivity to Abacavir. For other tests further studies are needed: CYP2B6 516 G > T testing may be able to identify patients at higher risk of Central Nervous System side effects following standard dosing of Efavirenz, UGT1A1*28 testing before initiation of antiretroviral therapy containing Atazanavir may aid in identifying individuals at risk of hyperbilirubinaemia. Pharmacogenetics represents a ​​research area with great growth potential which may be useful to guide the rational use of antiretrovirals.

Abnormal cortical sources of resting state electroencephalographic rhythms in single treatment-naïve HIV individuals: A statistical z-score index

OBJECTIVE This study tested a simple statistical procedure to recognize single treatment-naïve HIV individuals having abnormal cortical sources of resting state delta (<4 Hz) and alpha (8-13 Hz) electroencephalographic (EEG) rhythms with reference to a control group of sex-, age-, and education-matched healthy individuals. Compared to the HIV individuals with a statistically normal EEG marker, those with abnormal values were expected to show worse cognitive status. METHODS Resting state eyes-closed EEG data were recorded in 82 treatment-naïve HIV (39.8 ys.±1.2 standard error mean, SE) and 59 age-matched cognitively healthy subjects (39 ys.±2.2 SE). Low-resolution brain electromagnetic tomography (LORETA) estimated delta and alpha sources in frontal, central, temporal, parietal, and occipital cortical regions. RESULTS Ratio of the activity of parietal delta and high-frequency alpha sources (EEG marker) showed the maximum difference between the healthy and the treatment-naïve HIV group. Z-score of the EEG marker was statistically abnormal in 47.6% of treatment-naïve HIV individuals with reference to the healthy group (p<0.05). Compared to the HIV individuals with a statistically normal EEG marker, those with abnormal values exhibited lower mini mental state evaluation (MMSE) score, higher CD4 count, and lower viral load (p<0.05). CONCLUSIONS This statistical procedure permitted for the first time to identify single treatment-naïve HIV individuals having abnormal EEG activity. SIGNIFICANCE This procedure might enrich the detection and monitoring of effects of HIV on brain function in single treatment-naïve HIV individuals.

Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir Combination Treatment in Patients with HIV/HCV Co-Infection: Results of an Italian Compassionate Use Program.

Patients co-infected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are at high risk of liver disease progression. We report a favorable safety profile and SVR12 rates of 96.7% among HIV/HCV co-infected patients participating in an Italian compassionate-use program of ombitasvir/paritaprevir/ritonavir + dasabuvir (OBV/PTV/r + DSV) ± ribavirin (RBV).

Antiretroviral therapy effects on sources of cortical rhythms in HIV subjects: Responders vs. Mild Responders

OBJECTIVE We tested the hypothesis that 5months of combined anti-retroviral therapy (cART) affect cortical sources of resting state cortical electroencephalographic (EEG) rhythms in naïve HIV subjects. METHODS Eyes-closed resting state EEG data were recorded at baseline (i.e. pre-treatment; T0), T1 (after 4weeks of cART), T2 (after 8weeks of cART), and T5 (after 5months of cART) in 38 naïve HIV subjects. EEG data were also recorded in 40 age-matched cognitively normal subjects for control purposes. EEG rhythms of interest were delta (2-4Hz), theta (4-8Hz), alpha 1 (8-10.5Hz), alpha 2 (10.5-13Hz), beta 1 (13-20Hz), and beta 2 (20-30Hz). Cortical EEG sources were estimated by LORETA software. RESULTS Compared to the control group, the HIV group at T0 showed greater delta sources and lower widespread alpha sources. cART induced a global improvement of biological (viral load, CD4 count) and EEG (delta, alpha) markers, remarkable even after 4weeks. Compared to HIV Responders (>100cells/μl at 5-month follow up), the HIV Mild Responders (<100cells/μl) showed greater parietal delta sources at baseline and lower occipital alpha sources at 5-month follow up. CONCLUSIONS In naïve HIV subjects, 5months of successful cART affect brain synchronization mechanisms at the basis of the generation of delta and alpha rhythms. SIGNIFICANCE The present EEG markers may be useful secondary neurophysiological end points for pharmacological clinical trials in naïve HIV subjects.

Improvement of ALT decay kinetics by all-oral HCV treatment: Role of NS5A inhibitors and differences with IFN-based regimens

Background Intracellular HCV-RNA reduction is a proposed mechanism of action of direct-acting antivirals (DAAs), alternative to hepatocytes elimination by pegylated-interferon plus ribavirin (PR). We modeled ALT and HCV-RNA kinetics in cirrhotic patients treated with currently-used all-DAA combinations to evaluate their mode of action and cytotoxicity compared with telaprevir (TVR)+PR. Study design Mathematical modeling of ALT and HCV-RNA kinetics was performed in 111 HCV-1 cirrhotic patients, 81 treated with all-DAA regimens and 30 with TVR+PR. Kinetic-models and Cox-analysis were used to assess determinants of ALT-decay and normalization. Results HCV-RNA kinetics was biphasic, reflecting a mean effectiveness in blocking viral production >99.8%. The first-phase of viral-decline was faster in patients receiving NS5A-inhibitors compared to TVR+PR or sofosbuvir+simeprevir (p<0.001), reflecting higher efficacy in blocking assembly/secretion. The second-phase, noted δ and attributed to infected-cell loss, was faster in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.27 vs 0.21 d-1, respectively, p = 0.0012). In contrast the rate of ALT-normalization, noted λ, was slower in patients receiving TVR+PR or sofosbuvir+simeprevir compared to NS5A-inhibitors (0.17 vs 0.27 d-1, respectively, p<0.001). There was no significant association between the second-phase of viral-decline and ALT normalization rate and, for a given level of viral reduction, ALT-normalization was more profound in patients receiving DAA, and NS5A in particular, than TVR+PR. Conclusions Our data support a process of HCV-clearance by all-DAA regimens potentiated by NS5A-inhibitor, and less relying upon hepatocyte death than IFN-containing regimens. This may underline a process of “cell-cure” by DAAs, leading to a fast improvement of liver homeostasis.

Antiretroviral therapy affects the z-score index of deviant cortical EEG rhythms in naïve HIV individuals

Objective Here we tested the effect of combined antiretroviral therapy (cART) on deviant electroencephalographic (EEG) source activity in treatment-naïve HIV individuals. Methods Resting state eyes-closed EEG data were recorded before and after 5 months of cART in 48 male HIV subjects, who were naïve at the study start. The EEG data were also recorded in 59 age- and sex-matched healthy subjects as a control group. Frequency bands of interest included delta, theta, alpha1, alpha2 and alpha3, based on alpha frequency peak specific to each individual. They also included beta1 (13–20 Hz) and beta2 (20–30 Hz). Low-resolution brain electromagnetic tomography (LORETA) estimated EEG cortical source activity in frontal, central, temporal, parietal, and occipital regions. Results Before the therapy, the HIV group showed greater parietal delta source activity and lower spatially diffuse alpha source activity compared to the control group. Thus, the ratio of parietal delta and alpha3 source activity served as an EEG marker. The z-score showed a statistically deviant EEG marker (EEG +) in 50% of the HIV individuals before therapy (p < 0.05). After 5 months of cART, delta source activity decreased, and alpha3 source activity increased in the HIV subjects with EEG + (about 50% of them showed a normalized EEG marker). Conclusions This procedure detected a deviant EEG marker before therapy and its post-therapy normalization in naïve HIV single individuals. Significance The parietal delta/alpha3 EEG marker may be used to monitor cART effects on brain function in such individuals.

Brain and cognitive functions in two groups of naïve HIV patients selected for a different plan of antiretroviral therapy: A qEEG study.

OBJECTIVE Cortical sources of electroencephalographic (EEG) rhythms were investigated in two sub-populations of naïve HIV subjects, grouped based on clinical criteria to receive different combination anti-retroviral therapies (cARTs). These EEG sources were hypothesized to reflect beneficial effects of both regimes. METHODS Eyes-closed resting state EEG data were collected in 19 (Group A) and 39 (Group B) naïve HIV subjects at baseline (i.e. pre-treatment; T0) and after 5months of cART (T5). Compared with the Group A, the Group B was characterized by slightly worse serological parameters and higher cardiovascular risk. At T0, mean viral load (VL) and CD4 count were 87,694copies/ml and 435cells/μl in the Group A and 187,370copies/ml and 331cells/μl in the Group B. The EEG data were also collected in 50 matched control HIV-negative subjects. Cortical EEG sources were assessed by LORETA software. RESULTS Compared to the Control Group, the HIV Groups showed lower alpha (8-12Hz) source activity at T0 while the Group B also exhibited higher delta source activity. The treatment partially normalized alpha and delta source activity in the Group A and B, respectively, in association with improved VL, CD4, and cognitive functions. CONCLUSIONS Different cART regimens induced diverse beneficial effects in delta or alpha source activity in the two naïve HIV Groups. SIGNIFICANCE These sources might unveil different neurophysiological effects of diverse cART on brain function in naïve HIV Groups as a function of clinical status and/or therapeutic compounds.