Effectiveness of Paritaprevir/Ritonavir/Ombitasvir/Dasabuvir in Hemodialysis Patients With Hepatitis C Virus Infection and Advanced Liver Fibrosis: Case Reports.

Hepatitis C virus infection is common among patients on hemodialysis therapy and is an important cause of morbidity and mortality. We investigated the safety and effectiveness of a paritaprevir/ritonavir/ombitasvir/dasabuvir regimen in a group of 10 patients on hemodialysis therapy with genotype 1a, 1b, or 4 hepatitis C virus infection who had predictors of unfavorable response, such as compensated cirrhosis (7 patients) or advanced fibrosis and failure of previous therapy (3 patients). The treatment, with or without ribavirin, was administered daily for 12 or 24 weeks. Clinical and virologic assessment was performed every 4 weeks during the treatment and at posttreatment weeks 4 and 12. All patients achieved a sustained virologic response at posttreatment week 12. 80% of patients reported at least one adverse event: fatigue and anemia of mild intensity were the most common; a single episode of moderate liver decompensation was observed. The paritaprevir/ritonavir/ombitasvir/dasabuvir antiviral regimen is effective and well tolerated in genotype 1 or 4 hepatitis C virus-infected patients on hemodialysis therapy with compensated cirrhosis and/or failure of previous treatments.

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

BACKGROUND & AIMS: 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. METHODS: Of the 200 virological failures that were analyzed in 197 DAA-treated patients, 89 with pegylated-interferon+ribavirin (PegIFN+RBV) and 111 without (HCV-1a/1b/1g/2/3/4=58/83/1/6/24/25; 56.8% treatment experienced; 65.5% cirrhotic) were observed. Sanger sequencing of NS3/NS5A/NS5B was performed by home-made protocols, at failure (N=200) and whenever possible at baseline (N=70). RESULTS: The majority of the virological failures were relapsers (57.0%), 22.5% breakthroughs, 20.5% non-responders. RAS prevalence varied according to IFN/RBV use, DAA class, failure type and HCV genotype/subtype. It was 73.0% in IFN group vs 49.5% in IFN free, with the highest prevalence of NS5A-RASs (96.1%), compared to NS3-RASs (75.9% with IFN, 70.5% without) and NS5B-RASs (66.6% with IFN, 20.4% without, in sofosbuvir failures). In the IFN-free group, RASs were higher in breakthrough/non-responders than in relapsers (90.5% vs 40.0%, P<.001). Interestingly, 57.1% of DAA IFN-free non-responders had a misclassified genotype, and 3/4 sofosbuvir breakthroughs showed the major-RAS-S282T, while RAS-L159F was frequently found in sofosbuvir relapsers (18.2%). Notably, 9.0% of patients showed also extra target RASs, and 47.4% of patients treated with ≥2 DAA classes showed multiclass resistance, including 11/11 NS3+NS5A failures. Furthermore, 20.0% of patients had baseline-RASs, which were always confirmed at failure. CONCLUSIONS: In our failure setting, RAS prevalence was remarkably high in all genes, with a partial exception for NS5B, whose limited resistance is still higher than previously reported. This multiclass resistance advocates for HCV resistance testing at failure, in all three genes for the best second-line therapeutic tailoring.

Effectiveness and safety of risankizumab in HIV patients with psoriasis: A case series.

Biological therapies represent the gold-standard treatment of severe forms of plaque psoriasis. However, people living with HIV are often under-treated for psoriasis because very limited data are available on the use of biologics in this population. We report four cases of patients affected by HIV and moderate-to-severe plaque psoriasis, all treated with risankizumab, a monoclonal antibody that selectively targets interleukin-23. After 16 weeks, all patients experienced complete or almost complete skin clearance without any adverse events. Data on the effectiveness and safety of biological therapies in people living with HIV are limited to case reports or small case series, especially for the most recently approved inhibitors of interleukin-23. Our experienced, although limited, supports the role of risankizumab as a safe and effective therapy for psoriasis amongst patients living with HIV.

Immunogenicity and Safety of BNT162b2 Homologous Booster Vaccination in People Living with HIV under Effective cART.

Data on COVID-19 boosting vaccination in people living with HIV (PLWH) are scant. We investigated the immunogenicity and safety of the BNT162b2 homologous boosting vaccination. Anti-SARS-CoV-2 spike antibodies (LIAISON® SARS-CoV-2 S1/S2 IgG test, DiaSorin®), CD4+, CD8+ and viraemia were monitored at T0 (pre-vaccination), T1 (4 weeks after the second dose), T2 (pre-booster) and T3 (4 weeks after the booster dose). Humoral responses were evaluated according to sex, age, BMI, nadir and baseline CD4+ counts, as well as type of cART regimen. Forty-two subjects were included: the median age was 53 years (IQR: 48−61); the median time since HIV was 12.4 years (IQR: 6.5−18.3); the median nadir and baseline CD4+ counts were 165 (IQR: 104−291) and 687 cells/mm3 (IQR: 488−929), respectively. The booster dose was administered at a median of 5.5 months after the second dose. Median anti-SARS-CoV-2 IgG concentration had significantly decreased at T2 compared to T1 (107 vs. 377, p < 0.0001). Antibody levels elicited by the booster dose (median: 1580 AU/mL) were significantly higher compared with those of all the other time points (p < 0.0001). None of the investigated variables significantly affected antibody response induced by the booster dose. Local and systemic side-effects were referred by 23.8% and 14.3% of the subjects, respectively. One patient developed sensorineural hearing loss (SNHL) 24 h after boosting. He recovered auditory function upon endothympanic administration of corticosteroids. The BNT162b2 boosting vaccination in PLWH is safe and greatly increased the immune response with respect to the primary vaccination.

Cortical sources of resting state electroencephalographic rhythms probe brain function in naïve HIV individuals.

OBJECTIVE: Here we evaluated the hypothesis that resting state electroencephalographic (EEG) cortical sources correlated with cognitive functions and discriminated asymptomatic treatment-naïve HIV subjects (no AIDS). METHODS: EEG, clinical, and neuropsychological data were collected in 103 treatment-naïve HIV subjects (88 males; mean age 39.8 years ±â€¯1.1 standard error of the mean, SE). An age-matched group of 70 cognitively normal and HIV-negative (Healthy; 56 males; 39.0 years ±â€¯2.0 SE) subjects, selected from a local university archive, was used for control purposes. LORETA freeware was used for EEG source estimation in fronto-central, temporal, and parieto-occipital regions of interest. RESULTS: Widespread sources of delta (<4 Hz) and alpha (8-12 Hz) rhythms were abnormal in the treatment-naïve HIV group. Fronto-central delta source activity showed a slight but significant (p < 0.05, corrected) negative correlation with verbal and semantic test scores. So did parieto-occipital delta/alpha source ratio with memory and composite cognitive scores. These sources allowed a moderate classification accuracy between HIV and control individuals (area under the ROC curves of 70-75%). CONCLUSIONS: Regional EEG abnormalities in quiet wakefulness characterized treatment-naïve HIV subjects at the individual level. SIGNIFICANCE: This EEG approach may contribute to the management of treatment-naïve HIV subjects at risk of cognitive deficits.

Prevalence of Single and Multiple Natural NS3, NS5A and NS5B Resistance-Associated Substitutions in Hepatitis C Virus Genotypes 1-4 in Italy.

Natural resistance-associated substitutions (RASs) are reported with highly variable prevalence across different HCV genotypes (GTs). Frequency of natural RASs in a large Italian real-life cohort of patients infected with the 4 main HCV-GTs was investigated. NS3, NS5A and NS5B sequences were analysed in 1445 HCV-infected DAA-naïve patients. Sanger-sequencing was performed by home-made protocols on 464 GT1a, 585 GT1b, 92 GT2c, 199 GT3a, 16 GT4a and 99 GT4d samples. Overall, 20.7% (301/1455) of patients showed natural RASs, and the prevalence of multiclass-resistance was 7.3% (29/372 patients analysed). NS3-RASs were particularly common in GT1a and GT1b (45.2-10.8%, respectively), mainly due to 80K presence in GT1a (17%). Almost all GTs showed high prevalence of NS5A-RASs (range: 10.2-45.4%), and especially of 93H (5.1%). NS5A-RASs with fold-change >100x were detected in 6.8% GT1a (30H/R-31M-93C/H), 10.3% GT1b (31V-93H), 28.4% GT2c (28C-31M-93H), 8.5% GT3a (30K-93H), 45.5% GT4a (28M-30R-93H) and 3.8% GT4d (28V-30S-93H). Sofosbuvir RAS 282T was never detected, while the 159F and 316N RASs were found in GT1b (13.4-19.1%, respectively). Natural RASs are common in Italian patients infected with HCV-GTs 1-4. High prevalence of clinically-relevant RASs (such as Y93H) supports the appropriateness of HCV resistance-test to properly guide DAA-based therapy.

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.

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.

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.

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.

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.

Cortical sources of resting-state EEG rhythms in "experienced" HIV subjects under antiretroviral therapy.

OBJECTIVE: Treatment-naïve patients with human immunodeficiency virus (HIV) are characterized by diffuse abnormalities of resting-state cortical electroencephalographic (EEG) rhythms (Babiloni et al., 2012a). Here, we tested the hypothesis that these EEG rhythms vary as a function of the systemic immune activity and antiretroviral therapy (ART) in HIV patients. METHODS: Resting-state eyes-closed EEG data were recorded in 68 ART-HIV patients (mini mental state evaluation (MMSE) of 27.5 ± 0.3 SEM), in 60 treatment-naïve HIV subjects (MMSE of 27.5 ± 0.4 SEM) and in 75 age-matched cognitively normal subjects (MMSE of 29.3 ± 0.1 SEM). Based on the CD4 lymphocytes' count, we divided ART-HIV subjects into two subgroups: those with CD4>500 cells/µl (ART-HIV+) and those with CD4<500 cells/µl (ART-HIV-). EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-12 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). Cortical EEG sources were estimated by LORETA software. RESULTS: Widespread theta, alpha, and beta sources were lower in ART-HIV subjects than in control subjects. Furthermore, occipital and temporal alpha 1 sources were lower in treatment-naïve HIV than in ART-HIV subjects. Moreover, the opposite was true for widespread pathological delta sources. Finally, parietal, occipital, and temporal alpha 1 sources were lower in ART-HIV- than in ART-HIV+ subjects. CONCLUSIONS: In ART-HIV subjects, cortical sources of resting-state alpha rhythms are related to systemic immune activity and cART. SIGNIFICANCE: This EEG procedure may produce biomarkers of treatment response in patients' brain compartments for longitudinal clinical studies.

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.