PNPLA3 and TLL-1 Polymorphisms as Potential Predictors of Disease Severity in Patients With COVID-19

Albeit the pathogenesis of COVID-19 remains unclear, host’s genetic polymorphisms in genes involved in infection and reinfection, inflammation, or immune stimulation could play a role in determining the course and outcome. We studied in the early phase of pandemic consecutive patients (N = 383) with SARS-CoV-2 infection, whose subsequent clinical course was classified as mild or severe, the latter being characterized by admission to intensive therapy unit or death. Five host gene polymorphisms (MERTK rs4374383, PNPLA3 rs738409, TLL-1 rs17047200, IFNL3 rs1297860, and INFL4 rs368234815) were assessed by using whole nucleic acids extracted from nasopharyngeal swabs. Specific protease cleavage sites of TLL-1 on the SARS-CoV-2 Spike protein were predicted in silico. Male subjects and older patients were significantly at higher risk for a severe outcome (p = 0.02 and p < 0.001, respectively). By considering patients ≤65 years, after adjusting for potential confounding due to sex, an increased risk of severe outcome was found in subjects with the GG genotype of PNPLA3 (adj-OR: 4.69; 95% CI = 1.01–22.04) or TT genotype of TLL-1 (adj-OR=9.1; 95% CI = 1.45–57.3). In silico evaluation showed that TLL-1 is potentially involved in the Spike protein cleavage which is essential for viral binding and entry into the host cells using the host receptor angiotensin-converting enzyme 2 (ACE2). Subjects carrying a GG genotype in PNPLA3 gene might have a constitutive upregulation of the NLRP3 inflammasome and be more prone to tissue damage when infected by SARS-CoV-2. The TT genotype in TLL-1 gene might affect its protease activity on the SARS-CoV-2 Spike protein, enhancing the ability to infect or re-infect host’s cells. The untoward effect of these variants on disease course is evident in younger patients due to the relative absence of comorbidities as determinants of prognosis. In the unresolved pathogenetic scenery of COVID-19, the identification of genetic variants associates with more prolonged course or with a severe outcome of infection would support the development of predictive tools useful to stratify subjects by risk class at presentation. Moreover, the individuation of key genes could contribute to a better understanding of the pathways involved in the pathogenesis, giving the basis for rational therapeutic approaches

Fast relapse and high drop out rate of 48 weeks daily interferon monotherapy in HIV-infected patients with chronic hepatitis C

BACKGROUND: The standard of care for HCV Hepatitis is the combination of interferon (IFN) plus Ribavirin. In HIV patients the use of this combination therapy may induce drug interactions, and reduces the adherence to HAART. The aim of this study is to evaluate safety and efficacy of a 48 weeks daily dose IFN schedule. METHODS: We evaluated 50 coinfected patients; alpha IFN 2a was administered at a dose of 3 MU daily. The baseline values were the following : CD4+ 515 cells/mmc (mean); HIV-RNA <50 copies/ml in all patients; HCV-RNA 28, 3 × 106 copies/ml. RESULTS: At 48 weeks, 10 patients (20%) achieved a biochemical and virological response according to an intention to treat analysis. Twenty four patients (48%) underwent a drop-out mainly by side effects related to overlapping toxicity of interferon and antiretroviral therapy. All the patients, who responded to the treatment, showed a fast relapse one month after the end of treatment. CONCLUSION: Although our results demonstrated a very poor outcome and a bad tolerance to interferon monotherapy, this approach should not be dropped out, mainly in patients at high risk for side effects and in those with cirrhosis who do not tolerate or are at increased risk for the use of ribavirin

HIV testing history and access to treatment among migrants living with HIV in Europe.

Migrants are overrepresented in the European HIV epidemic. We aimed to understand the barriers and facilitators to HIV testing and current treatment and healthcare needs of migrants living with HIV in Europe. A cross-sectional study was conducted in 57 HIV clinics in nine countries (Belgium, Germany, Greece, Italy, The Netherlands, Portugal, Spain, Switzerland and United Kingdom), July 2013 to July 2015. HIV-positive patients were eligible for inclusion if they were as follows: 18 years or older; foreign-born residents and diagnosed within five years of recruitment. Questionnaires were completed electronically in one of 15 languages and linked to clinical records. Primary outcomes were access to primary care and previous negative HIV test. Data were analysed using random effects logistic regression. Outcomes of interest are presented for women, heterosexual men and gay/bisexual men. A total of 2093 respondents (658 women, 446 heterosexual men and 989 gay/bisexual men) were included. The prevalence of a previous negative HIV test was 46.7%, 43.4% and 82.0% for women, heterosexual and gay/bisexual men respectively. In multivariable analysis previous testing was positively associated with: receipt of post-migration antenatal care among women, permanent residency among heterosexual men and identifying as gay rather than bisexual among gay/bisexual men. Access to primary care was found to be high (&gt;83%) in all groups and was strongly associated with country of residence. Late diagnosis was common for women and heterosexual men (60.8% and 67.1%, respectively) despite utilization of health services prior to diagnosis. Across all groups almost three-quarters of people on antiretrovirals had an HIV viral load &lt;50 copies/mL. Migrants access healthcare in Europe and while many migrants had previously tested for HIV, that they went on to test positive at a later date suggests that opportunities for HIV prevention are being missed. Expansion of testing beyond sexual health and antenatal settings is still required and testing opportunities should be linked with combination prevention measures such as access to PrEP and treatment as prevention

Decline of Prevalence of Resistance Associated Substitutions to NS3 and NS5A inhibitors at DAA-failure in Hepatitis C Virus in Italy over the years 2015 to 2018

Background: A minority of patients fail to eliminate HCV and resistance-associated substitutions (RASs) are commonly detected at failure of interferon-free DAA regimens. Material and methods: Within the Italian network VIRONET-C, the prevalence of NS3/NS5A/NS5B RASs was retrospectively evaluated in patients who failed an EASL recommended DAA-regimen in 2015-2018. NS3, NS5A and NS5B Sanger sequencing was performed using homemade protocols. The geno2pheno system was used to infer HCV-genotype/subtype and predict drug resistance. The changes in the prevalence of RASs over time were evaluated using the chi-square test for trend, predictors of RASs at failure were analysed by logistic regression. Results: We included 386 real-life HCV pts failed to recommended DAA regimens: 92% (271/294) Italians, 75% (286/384) males, median age was 56 years (IQR 52-61); 106 (28%) were treatment-experienced: 91 (86%) with IFN-based treatments, 26 (25%) with DAA-based regimens. Metavir fibrosis stage was F4 in 76% (245/322), 65% (240/369) had clinical cirrhosis. Patients with HIV and HBV coinfection were 10% (33/317) and 8% (6/72), respectively. HCV genotype (G) was G1b in 122 pts (32%), G3a 103 (27%), G1a 97 (25%), G4d 30 (8%), G2c 19 (5%), G3h 5 (1.3%), G4a 4 (1%) and 1 (0.3%) each for G3g, G4n/o/v. DAA regimens were: LDV/SOF in 115 (30%), DCV/SOF in 103 (27%), 3D in 83 (21%), EBR/GRZ in 32 (8%), VEL/SOF in 29 (7%), GLE/PIB in 18 (5%) and 2D in 6 (2%); ribavirin was administered in 123 (32%). Antiviral treatment was completed by 352 pts (91%), while 34 (9%) discontinued prematurely. The NS5A fasta-sequence was available for all pts, NS5B for 361 (94%), NS3 for 365 (95%). The prevalence of any RASs was 87%, namely 78/135 (58%) in NS3, 303/359 (85%) in NS5A, 114/286 (40%) in NS5B (Tab 1). The prevalence of any RASs significantly declined from 2015 to 2018 (100%, 13/13 vs 81%, 101/125, p=0.01): NS5A RASs from 100%, 13/13 to 76%, 76/100 (p&lt;0.001), NS3 RASs from 88%, 7/8 to 44%, 28/63 (p=0.02), while NS5B RASs remained stable. Independent predictors of any RASs included liver cirrhosis/advanced fibrosis (AOR 3.72, CI 95% 1.51-9.17, p=0.004) and genotype (G2 vs G1a AOR 0.01, CI 95% 0.0-0.3, p&lt;0.001; G3 vs G1a AOR 0.22, CI 95% 0.05-0.98, p&lt;0.047; G4 vs G1a AOR 0.13, CI 95% 0.03-0.63, p&lt;0.011), with a modest effect scored for past treatment (AOR 3.45, CI 95% 1.00-11.92, p=0.05), after adjusting for DAA regimen and year of genotype. Notably, full activity was predicted for GLE/PIB in 75.9% of cases and for at least two components of VEL/SOF/VOX in 59% of cases and no case with full-resistance to either regimen was found (Tab 2). Conclusions: Despite decreasing prevalence over the years, RASs remain a common signature at virological failure of DAA treatment, particularly in patients with the highest grade of liver fibrosis. Their distribution may vary according to genotype, so the identification of RASs after failure could play a crucial role in optimizing retreatment strategies

Test for CCR5 tropism and treatment with maraviroc in Sicily: an observational retrospective multicentre study

Purpose of the study: Maraviroc (MVC) is the first CCR5 inhibitor licensed for clinical use. A pre-treatment test is mandatory to identify R5 tropic patients. Aim of this study is to detect indications and results of tropism test and to evaluate efficacy and tolerability of MVC-based regimen. Methods: An observational retrospective multicentre study was performed in Sicily in 15 Infectious Diseases Units. Clinical records of 213 screened for tropism HIV+ subjects were reviewed for age, sex, risk, clinical stage (CDC, CD4 cell count, HIV RNA viral load), therapeutic line, indication and result of test for tropism; within subjects treated with MVC, HIV RNA, CD4 cell count and metabolic parameters trend and adverse events were analysed. Summary of results: Median age 44 (IQR 30&#x2013;50) years, 67.1% males; 46.3% heterosexuals, 28.6% MSMs, 21.4% IVDUs; 23.7% CDC A, 32.1% CDC B, 44.2% CDC C; median CD4 was 217 (IQR 121&#x2013;374) cells/&#x00B5;l and mean of HIV RNA was 4.72 (Cl 95% 4.07&#x2013;4.67) log10 copies/ml; median therapeutic line was 4 (IQR 2&#x2013;7). 80.8% were submitted to Trofile&#x2122; test, 19.2% to genotypic test, 75.5% after a therapeutic failure. 56.8% of subjects screened were R5, 7.5% X4, 21.6% DM, 14% undefined. All X4 patients were tested after a therapeutic failure; patients screened for toxicity were more frequently R5 (75%) (p&#60;0.01). 76 (35.7%) multi-experienced (at baseline 8% HIV RNA&#60;50 copies/ml, median CD4 cell count 219 (IQR 124&#x2013;345) cells/&#x00B5;l) subjects were treated with MVC plus an optimized background treatment: MVC was associated in 74% of cases with a protease inhibitors (56% darunavir/ritonavir), in 42% with raltegravir, in 56% with a NUC-sparing regimen. After 12 months of treatment 56.8% (ITT analysis) and 61.7% (AT) of patients had HIV RNA&#60;50 copies/ml; median CD4 cell count was 387 (IQR 222&#x2013;455) cells/&#x00B5;l. After 24 months 64.8% (ITT) 80% (AT) had HIV-RNA&#60;50 copies/ml. Median CD4 cell count was 381 (IQR 218.515) cells/&#x00B5;l with a median increase of 168 (IQR 54&#x2013;274) cells/&#x00B5;l. At 24 months median value of total and HDL cholesterol and triglycerides were within the normal range. 7 patients stopped the treatment: 2 died, 1 adverse event, 4 virological failure. Conclusions: Although the test has been proposed to patients with long treatment history and failure, only 3/5 of R5 tropic patients were treated with MVC. An high number of multi-experienced subjects treated with a MVC-based regimen obtained HIV RNA&#60;50 copies/ml and a satisfactory increase of CD4 cell count

Barriers to health care services for migrants living with HIV in Spain

BACKGROUND: In Spain, migrants are disproportionately affected by HIV and experience high rates of late diagnosis. We investigated barriers to health care access among migrants living with HIV (MLWH) in Spain. METHODS: Cross sectional electronic survey of 765 adult HIV-positive migrants recruited within 18 health care settings between July 2013 and July 2015. We collected epidemiological, demographic, behavioral and clinical data. We estimated the prevalence and risk factors of self-reported barriers to health care using multivariable logistic regression. RESULTS: Of those surveyed, 672 (88%) had information on health care access barriers: 23% were women, 63% from Latin America and Caribbean, 14% from Sub-Saharan Africa and 15% had an irregular immigration status. Men were more likely to report barriers than women (24% vs. 14%, P = 0.009). The main barriers were: lengthy waiting times for an appointment (9%) or in the clinic (7%) and lack of a health card (7%). Having an irregular immigration status was a risk factor for experiencing barriers for both men (OR: (4.0 [95%CI: 2.2–7.2]) and women (OR: 10.5 [95%CI: 3.1–34.8]). Men who experienced racial stigma (OR: 3.1 [95%CI: 1.9–5.1]) or food insecurity (OR: 2.1 [95%CI: 1.2–3.4]) were more likely to report barriers. Women who delayed treatment due to medication costs (6.3 [95%CI: 1.3–30.8]) or had a university degree (OR: 5.8 [95%CI: 1.3–25.1]) were more likely to report barriers. CONCLUSION: Health care barriers were present in one in five5 MLWH, were more common in men and were associated to legal entitlement to access care, perceived stigma and financial constraints

Infectious diseases among foreign prisoners: results of a hospital-based management model in Palermo

Foreign prisoners have a high vulnerability in terms of morbidity and access to care in overcrowded Italian prisons. This paper presents and comments on the management model of infectious diseases in foreign prisoners at our outpatient clinic, in order to describe a model of management for these conditions. Overall, 133 subjects (mean age 35.5 years) from 29 countries were followed for a period of 15 years. The most commonly represented area of origin (54.1%) was the Maghreb region. HCV infection (40.6%), HIV (22.5%), HBV (9.8%) and co-infection (15%, HIV/HCV or HIV/HBV) were observed. Ten subjects had tuberculosis, and only 30% of them were compliant with the treatment. Only 46.3% of HCV mono-infected patients completed the entire diagnostic process and even a lower percentage (37%) of them took treatment regularly. 90% of HBV mono-infected patients and 84% of those HIV mono- and co-infected completed the diagnostic workout. 77% of patients in each group took therapy regularly. Overall, the results show limited effectiveness. Therefore, it would be necessary to improve communication between healthcare professionals and correctional systems. Moreover, it appears urgent to reduce overcrowding in prisons to limit morbidity in prisoners