Long-term symptoms after SARS-CoV-2 infection in a cohort of people living with HIV.

BACKGROUND: Our Hospital in Northern Italy assists 3817 people living with HIV (PLWH) and has faced the impact of COVID-19. Little is known about the impact of HIV infection on the risk of post-COVID-19 conditions (PCCs) onset. We aim to assess the incidence of PCC in PLWH and the factors associated with its occurrence. METHODS: We performed a retrospective, observational study including all PLWH > 18 years registered in the Brescia Health Protection Agency database, assessing SARS-CoV-2 burden, vaccination status, socio-demographic, and viro-immunological parameters from February 2020 until May 2022. Persistence of self-reported symptoms (clustered into gastrointestinal, respiratory, osteo-muscular, and neuro-behavioral symptoms) was evaluated after 3 months by a telephone-administered questionnaire. We estimated the associations between all variables and outcomes through univariate and multivariable logistic models. RESULTS: In the study period, 653 PLWH were diagnosed with SARS-CoV-2 infection (17.1%). We observed 19 (2.9%) reinfections, 71 (10.9%) hospitalizations, and 3 (0.5%) deaths. We interviewed 510/653 PLWH (78%), and 178 (PCCs prevalence 34.9%; CI 95% 30.7-39.2) reported persistent symptoms. Asthenia/fatigue was the most reported symptom (60/178), followed by muscular pain (54/178). In the multivariate regression model, there was a lower risk of PCCs in males respect to females (adjusted OR = 0.64; CI 95% 0.99-3.66), while hospitalization during acute infection was associated with an increased the risk of PCCs (adjusted OR = 1.9; CI 95% 0.99-3.66). Notably, no viro-immunological variable modified the PCCs risk onset. CONCLUSIONS: Our study highlights a substantial prevalence of PCCs among PLWH, three months post-SARS-CoV-2 infection, independent of viro-immunological features or vaccination status.

Immunogenicity and safety of live attenuated and recombinant/inactivated varicella zoster vaccines in people living with HIV: A systematic review.

Few papers focus their attention on VZV vaccination effectiveness among people living with HIV (PLWH). Flanking the live attenuated vaccine (VZL) available, a newly recombinant vaccine (RZV) was recently introduced and approved for HZ prevention among adults. PLWH represents a population on which a particular attention should be applied, in order to guarantee the vaccine efficacy and safety. We performed a literature search in USNLM, PubMed, PubMed Central, PMC and Cochrane Library. From all the publications found eligible, data were extracted and processed per population, vaccine type, immunogenicity and ADRs. The review of the 13 included studies shows that both RZV and VZL are immunogenic and have an acceptable safety profile in adults and children living with HIV. However, given the lack of research available about vaccine efficacy in preventing VZV and HZ in PLWH, additional studies need to be performed, in order to achieve a full completeness of data.

The impact of time since SARS-Cov-2 vaccination, age, sex and comorbidities on COVID-19 outcome in hospitalized patients with SARS-CoV-2 infection.

We evaluated the impact of COVID-19 vaccination on disease outcome in hospitalized patients with SARS-CoV-2 infection with a prospective study. 745 vaccinated and 451 unvaccinated patients consecutively admitted to a COVID-19 Hospital from 1st September 2021 to 1st September 2022 were included. Compared with unvaccinated cases, vaccinated patients were older, had more comorbidities, but had a lower risk of O2 need (odds ratio, OR, 0.46; 95 % CI 0.32-0.65) by logistic regression analysis adjusted for age, sex, comorbidity and WHO COVID-19 Clinical Progression Scale at admission. The ORs for O2 need were 0.38 (0.24-0.61), 0.50 (0.30-0.83) and 0.57 (0.34-0.96) in patients vaccinated 14-120, 121-180 and > 180 days prior to hospitalization, respectively. An anti-spike Ig titer higher than 5000 U/ml was associated with a reduced risk of O2 need (OR 0.52; 95 % CI 0.30-0.92). This study shows that COVID-19 vaccination has a significant impact on COVID-19 outcomes in hospitalized patients.

Cohort profile: PRESTIGIO, an Italian prospective registry-based cohort of people with HIV-1 resistant to reverse transcriptase, protease and integrase inhibitors.

PURPOSE: The PRESTIGIO Registry was established in 2017 to collect clinical, virological and immunological monitoring data from people living with HIV (PLWH) with documented four-class drug resistance (4DR). Key research purposes include the evaluation of residual susceptibility to specific antiretrovirals and the validation of treatment and monitoring strategies in this population. PARTICIPANTS: The PRESTIGIO Registry collects annual plasma and peripheral blood mononuclear cell samples and demographic, clinical, virological, treatment and laboratory data from PLWH followed at 39 Italian clinical centres and characterised by intermediate-to-high genotypic resistance to ≥1 nucleoside reverse transcriptase inhibitors, ≥1 non-nucleoside reverse transcriptase inhibitors, ≥1 protease inhibitors, plus either intermediate-to-high genotypic resistance to ≥1 integrase strand transfer inhibitors (INSTIs) or history of virological failure to an INSTI-containing regimen. To date, 229 people have been recorded in the cohort. Most of the data are collected from the date of the first evidence of 4DR (baseline), with some prebaseline information obtained retrospectively. Samples are collected from the date of enrollment in the registry. FINDINGS TO DATE: The open-ended cohort has been used to assess (1) prognosis in terms of survival or development of AIDS-related or non-AIDS-related clinical events; (2) long-term efficacy and safety of different antiretroviral regimens and (3) virological and immunological factors predictive of clinical outcome and treatment efficacy, especially through analysis of plasma and cell samples. FUTURE PLANS: The registry can provide new knowledge on how to implement an integrated approach to study PLWH with documented resistance to the four main antiretroviral classes, a population with a limited number of individuals characterised by a high degree of frailty and complexity in therapeutic management. Given the scheduled annual updates of PLWH data, the researchers who collaborate in the registry can send study proposals at any time to the steering committee of the registry, which evaluates every 3 months whether the research studies can be conducted on data and biosamples from the registry and whether they are aimed at a better understanding of a specific health condition, the emergence of comorbidities or the effect of potential treatments or experimental drugs that may have an impact on disease progression and quality of life. Finally, the research studies should aim to be inclusive, innovative and in touch with the communities and society as a whole. TRIAL REGISTRATION NUMBER: NCT04098315.

Chronic Hepatitis C Cascade of Care in Prisoners-Is There Still Some Work to Do? Analysis of Two Large Penitentiaries in Northern Italy.

Penitentiaries have a higher burden of communicable diseases compared to the general population. Prisoners should be tested for hepatitis C virus (HCV) and have direct access to treatment. We analysed the HCV cascade of care in two penitentiaries in Brescia, Northern Italy. At admission, prisoners are offered a voluntary screening for HCV, while patients with known infections are tested with an HCVRNA measurement. We performed an observational retrospective study including all the subjects admitted to the penitentiaries from 1 January 2015 to 31 October 2021. We conducted a descriptive analysis. During the study period, 5378 admissions were registered, and 2932 (54.5%) screenings were performed. Hepatitis C virus antibody positivity was found in 269 tests (9.2%). Hepatitis C virus RNA was detectable in 169 people. During the study period, 77 treatments with direct-acting antivirals (DAAs) were administered. Follow-up was available in 45 patients, and sustained virological response (SVR) was documented in 44 of them. Retention in care occurred in less than half of the prisoners after release. Our data demonstrate poor screening adherence that could benefit from educational programs. Treatment rates could be improved with test-and-treat programs. More efforts are needed to eliminate HCV as a public threat by 2030. Dedicated local networks, including infectious diseases (ID) departments, substance abuse services and prisons, could mitigate these issues.

PRESTIGIO RING: "An 80-year-old man living with HIV resistant to all four antiretroviral classes and desiring treatment simplification".

People aging with 4 antiretroviral class resistant HIV are a very challenging population. It is difficult to build up a fully suppressive regimen, and the high prevalence of comorbidities and polypharmacy may cause drug-drug interactions and put adherence at risk. We herein present the case of an 80-year-old man, participating in the PRESTIGIO registry, asking for a reduction in his antiretroviral burden while on polypharmacy for his comorbidities.

Influence of efavirenz and 8-hydroxy-efavirenz plasma levels on cognition and central nervous system side effects.

OBJECTIVES: To investigate whether efavirenz (EFV) or 8-hydroxy-EFV (8-OH-EFV) plasma levels are associated with neurocognitive impairment and central nervous system (CNS) side effects. METHODS: We conducted a cross-sectional analysis to explore the potential links between EFV/8-OH-EFV levels and cognitive performance or CNS-related side effects in patients screened within a randomized trial involving a switch from EFV to rilpivirine. The Mann-Whitney test was employed to compare drug levels in patients with or without cognitive impairment, depression, anxiety, sleep disorder or CNS symptoms. Additionally, Spearman's test was used to assess correlations between drug levels and test scores. RESULTS: Among 104 patients, neither EFV nor 8-OH-EFV levels were linked to cognitive impairment, although trends towards higher EFV levels were observed in those with impaired executive function (p = 0.055) and language performances (p = 0.021). On the other hand, elevated 8-OH-EFV levels, but not EFV levels, were associated with more CNS side effects (222 vs. 151 ng/mL, p = 0.027), depressive symptoms (247 vs. 164 ng/mL, p = 0.067) and sleep impairment (247 vs. 164 ng/mL, p = 0.078). Consistently, a trend towards a correlation between EFV levels and lower z-scores in executive function and motor function was observed, while 8-OH-EFV levels, but not EFV levels, were directly correlated with symptom scores. CONCLUSIONS: Higher levels of 8-OH-EFV were associated with CNS side effects, while EFV levels were only marginally associated with cognitive performance, thus suggesting that EFV and its metabolite may act differently in determining detrimental neurological effects.

Knowledge and Attitudes towards HIV and HCV among the Population Attending the Fast-Track Cities Mobile Unit in Brescia, Italy.

The Infectious and Tropical Diseases Department of the University of Brescia organized free rapid screening tests for HIV and HCV as part of the Fast-Track City commitment. A cross-sectional study was conducted, consisting of an anonymous multiple-choice questionnaire that was administered to individuals who underwent the screening or consultation. The study aimed to compare knowledge and attitudes towards HIV and HCV between age groups (18-40 vs. >40) and sexual orientations (heterosexual vs. LGBTQ+). Overall, 333 questionnaires were completed. Overall, only 107 (32%) of respondents knew how HIV is transmitted. Major differences were shown between different age groups, where people under the age of 40 had a significantly higher correct response rate than people over 40 (n = 101; 39% versus n = 6; 7.8%, p < 0.00001). Similarly, almost half of LGBTQI+ people (n = 28; 44.4%) gave the correct answer, versus 30% (n = 79) of heterosexuals (p = 0.0359). Only 9.6% of the population demonstrated high levels of knowledge for both HIV and HCV. Our study highlights that misconceptions about HIV and HCV should be addressed in prevention and education programs, whose target should also be specific populations.

Pillars of long-term antiretroviral therapy success.

BACKGROUND: Meeting the challenge of antiretroviral therapy (ART) whose efficacy can last a lifetime requires continuous updating of the virological, pharmacological, and quality of life outcomes to be pursued and a continuous review of literature data on the efficacy and tolerability of new drugs and therapeutic strategies. METHODS: With the aim of identifying open questions and answers about the current controversies in modern ART, we adapted the Design Thinking methodology to the needs of the design phase of a scientific article, involving a team of experts in HIV care. RESULTS: Five main pillars of treatment success were discussed: sustained virologic suppression over time; immunological recovery; pharmacological attributes; long-term tolerability and safety of ART; and people's satisfaction and quality of life. The definition of the outcomes to be achieved in each thematic area and the tools to achieve them were reviewed and discussed. CONCLUSIONS: Long-term treatment success should be intended as a combination of HIV-RNA suppression, immune recovery, and high quality of life. To achieve this, the regimen should be well-tolerated, with high potency, genetic barrier, and forgiveness, and should be tailored by a person-centered perspective, based on individual needs, preferences, and therapeutic history.

Early Onset Delirium During Hospitalization Increases In-Hospital and Postdischarge Mortality in COVID-19 Patients: A Multicenter Prospective Study.

Objective: Delirium is a common feature in COVID-19 patients. Although its association with in-hospital mortality has previously been reported, data concerning postdischarge mortality and delirium subtypes are scarce. We evaluated the association between delirium and its subtypes and both in-hospital and postdischarge mortality.Methods: This multicenter longitudinal clinical-based study was conducted in Monza and Brescia, Italy. The study population included 1,324 patients (median age: 68 years) with COVID-19 admitted to 4 acute clinical wards in northern Italy during the first pandemic waves (February 2020 to January 2021). Delirium within 48 hours of hospital admission was assessed through validated scores and/or clinically according to DSM-5 criteria. The association of delirium-and its subtypes-with in-hospital and postdischarge mortality (over a median observation period of 257 [interquartile range: 189-410] days) was evaluated through Cox proportional hazards models.Results: The 223 patients (16.8%) presenting delirium had around 2-fold increased in-hospital (hazard ratio [HR] = 1.94; 95% CI, 1.38-2.73) and postdischarge (HR = 2.01; 95% CI, 1.48-2.73) mortality than those without delirium. All delirium subtypes were associated with greater risk of death compared to the absence of delirium, but hypoactive delirium revealed the strongest associations with both in-hospital (HR = 2.03; 95% CI, 1.32-3.13) and postdischarge (HR = 2.22; 95% CI, 1.52-3.26) mortality.Conclusions: In patients with COVID-19, early onset delirium is associated not only with in-hospital mortality but also with shorter postdischarge survival. This suggests that delirium detection and management are crucial to improving the prognosis of COVID-19 patients.Trial Registration: ClinicalTrials.gov identifier: NCT04412265.

Timing and implications for immune response to vaccine in SARS-CoV-2 breakthrough infections.

COVID-19 vaccines elicit a strong anti-S antibodies response. We aim to describe antibody titers in peri-vaccination SARS-CoV-2 infections. This is a retrospective longitudinal single-cohort study. Serological tests were performed at the time of the first SARS-CoV-2 vaccine dose (T0) and 60 (T1), 120 (T2), and 240 (T3) days after. The study included 4,682 subjects. Group A had the infection without an anti-S Ig response. Group B and C seroconverted for anti-N Ig between T0 and T1 and between T1 and T2, respectively. Group D was persistently anti-N Ig negative. Group B showed an initial sub-optimal response, reaching the highest titer at T3. Those who received the second dose 120 days after the infection had higher titers compared to those who received it 21 days after the first dose. The immune response depends on the number and the timing of vaccine doses, highlighting the need for a more personalized approach to vaccination.

Development and validation of an electronic database-based frailty index to predict mortality and hospitalization in a population-based study of adults with SARS-CoV-2.

Background: Electronic health databases are used to identify people at risk of poor outcomes. Using electronic regional health databases (e-RHD), we aimed to develop and validate a frailty index (FI), compare it with a clinically based FI, and assess its association with health outcomes in community-dwellers with SARS-CoV-2. Methods: Data retrieved from the Lombardy e-RHD were used to develop a 40-item FI (e-RHD-FI) in adults (i.e., aged ≥18 years) with a positive nasopharyngeal swab polymerase chain reaction test for SARS-CoV-2 by May 20, 2021. The considered deficits referred to the health status before SARS-CoV-2. The e-RHD-FI was validated against a clinically based FI (c-FI) obtained from a cohort of people hospitalized with COVID-19 and in-hospital mortality was evaluated. e-RHD-FI performance was evaluated to predict 30-day mortality, hospitalization, and 60-day COVID-19 WHO clinical progression scale, in Regional Health System beneficiaries with SARS-CoV-2. Results: We calculated the e-RHD-FI in 689,197 adults (51.9% females, median age 52 years). On the clinical cohort, e-RHD-FI correlated with c-FI and was significantly associated with in-hospital mortality. In a multivariable Cox model, adjusted for confounders, each 0.1-point increment of e-RHD-FI was associated with increased 30-day mortality (Hazard Ratio, HR 1.45, 99% Confidence Intervals, CI: 1.42-1.47), 30-day hospitalization (HR per 0.1-point increment = 1.47, 99%CI: 1.46-1.49), and WHO clinical progression scale (Odds Ratio = 1.84 of deteriorating by one category, 99%CI 1.80-1.87). Conclusion: The e-RHD-FI can predict 30-day mortality, 30-day hospitalization, and WHO clinical progression scale in a large population of community-dwellers with SARS-CoV-2 test positivity. Our findings support the need to assess frailty with e-RHD.

COVID-19 Pneumonia with Migratory Pattern in Agammaglobulinemic Patients: A Report of Two Cases and Review of Literature.

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in serum immunoglobulins and early-onset infections. Coronavirus Disease-2019 (COVID-19) pneumonia in immunocompromised patients presents clinical and radiological peculiarities which have not yet been completely understood. Very few cases of agammaglobulinemic patients with COVID-19 have been reported since the beginning of the pandemic in February 2020. We report two cases of migrant COVID-19 pneumonia in XLA patients.

The presence of resistance-associated mutations in reverse transcriptase gene is associated with cerebrospinal fluid HIV-1 escape: A multicentric retrospective analysis.

Higher risk of cerebrospinal fluid escape (CVE) has been associated with the use of specific antiretroviral (ARV) classes, such as protease inhibitors. We assessed whether archived resistance-associated mutations (RAMs) can mediate this relationship by identifying patients treated with incompletely active antiretroviral regimens. A retrospective multicentric study on 282 adult people with HIV on antiretroviral therapy (ART) and available historical plasma genotype resistance testing (HGRT) for reverse transcriptase (RT) and protease genes between 2001 and 2021. The odds ratio for demographic, clinic-, and ART-related variables and CVE was estimated by multivariable modeling. HGRT-adjusted central nervous system effectiveness penetration (CPE) score was computed in modeling the risk. Median age, plasma VL, and CD4 count were 49 years, <50 copies/mL, and 310 cells/µL. CVE was detected in 51 participants (17.0%). No difference in CVE prevalence was observed according to ART type, number of ARVs or ARV classes. Participants with CVE had more frequently plasma (52.9% vs. 32.1%, p = 0.005) and CSF RAMs in RT (n = 63, 57.1% vs. 28.6%, p = 0.029), but not in protease gene. The presence of plasma RAMs in RT associated with increased odds of CVE in adjusted analyses (aOR 3.9, p < 0.001) and in models restricted to plasma viral load ≤50 copies/mL (n = 202; aOR 4.3, p = 0.003). CVE risk decreased by 40% per each point increase in HGRT-adjusted CPE score in multivariable models (p < 0.001). Rather than the type of ARV classes or of ART regimens, functional mono or dual regimens caused by the presence of RAMs affecting ART components may explain the majority of cases of CVE.

Does the rapid initiation of antiretroviral therapy at HIV diagnosis impact virological response in a real-life setting? A single-centre experience in Northern Italy.

Rapid initiation of antiretroviral therapy (ART) has been proven efficacious and safe, but more investigations are needed to define feasibility of rapid ART approach in real-life settings.We conducted a retrospective, observational study on newly HIVdiagnosed patients referred to our Infectious Diseases Department from September 1st, 2015, to July 31st, 2019. According to the timing of ART initiation, we distinguished 3 groups of patients (rapid, intermediate and late group) and represented the trend of virological response during a 400-days-period. The hazard ratios of each predictor on viral suppression were estimated through the Cox proportional hazard model.The median time from HIV diagnosis to the first medical referral was 15 days and the median time from the first care access to therapy start was 24 days. Among patients, 37.6% started ART within 7 days, 20.6% between 8 and 30 days, and 41.8% after 30 days. Longer time to ART start and higher baseline viral load were associated with a lower probability of viral suppression. After one year, all groups showed a high viral suppression rate (99%). In a high-income setting the rapid ART approach seems useful to accelerate viral suppression which is great over time regardless of ART initiation timing.

Reduced probability of improving viro-immunological state in subjects with vertical transmission of HIV reaching adult age: A multicenter retrospective cohort study.

INTRODUCTION: Young adults with vertical transmission (VT) of human immunodeficiency virus (HIV) represent a fragile population. This study evaluates factors associated with viro-immunological outcome of these patients. METHODS: We performed a multicenter study including HIV-infected subjects with VT ≥ 18 years old from six Italian clinics. Subjects were observed from birth to death, lost to follow-up, or last visit until December 31, 2019. Condition of "optimal viro-immunological status" (OS) was defined as the simultaneous presence of HIV ribonucleic acid (RNA) < 50 copies/mL, CD4+ > 500 cells/mm3 , and CD4+/CD8+ ratio ≥ 1. RESULTS: A total of 126 subjects were enrolled. At 18 years of age, 52/126 (44.4%) had HIV-RNA > 50 copies/mL, 47/126 (38.2%) had CD4+ < 500/mm3 , and 78/126 (67.2%) had CD4+/CD8+ < 1; 28 subjects (23.7%) presented in the condition of OS. Having a CD4+/CD8+ ratio ≥ 1 at 18 years of age was related with an increased probability of shift from suboptimal viro-immunological status (SOS) to OS (HR: 7.7, 95% confidence interval [CI]: 4.23-14.04), and a reduced risk of shift from the OS to the SOS (HR: 0.49, 95% CI: 0.26-0.92). Acquired immunodeficiency syndrome (AIDS) diagnosis significantly reduced the probability of shift from a viro-immunological SOS to OS (HR: 0.09, 95% CI: 0.03-0.30). Subjects who had not achieved an OS at 18 years of age had an increased risk of discontinuation of combination antiretroviral therapy (cART, p = .019). CONCLUSIONS: Only a small proportion of subjects with VT of HIV reached the adult age with "OS". Transition to the adult care with a compromised viro-immunological condition represents a negative driver for future optimal infection control, with a higher risk of discontinuation of cART and a reduced probability to improve the immunological status later in the years.

First Italian report of a liver abscess and metastatic endogenous endophthalmitis caused by ST-23 hypervirulent Klebsiella pneumoniae in an immunocompetent individual.

BACKGROUND: Klebsiella pneumoniae is a common species in the gut of mammals and is widely distributed in the environment. However, the environmental source of hvKp that precedes gut colonization is unclear, but once that it reaches the gut there is a possible generalized spread y fecal-oral transmission especially in endemic areas. Liver abscess might develop when the bacteria, using its virulence factors, cross the intestinal barrier and invade the liver by the portal circulation. This syndrome, prevalent mostly in Asian countries, is increasingly reported in Western Countries and leaves open questions about the source of infection. CASE: Here we describe for the first time in Italy, a case of pyogenic liver abscess caused by a hypervirulent Klebsiella pneumoniae (HvKp) complicated by endophthalmitis and other metastatic infections in lung and prostate in an immunocompetent Chinese healthy individual with no recent travel in Asia. CONCLUSION: This case underlines the need for increased awareness of hypervirulent K. pneumoniae, even in settings where it occurs infrequently and where there are not evident epidemiological links.

Non-B subtypes account for a large proportion of clustered primary HIV-1 infections in Italy.

OBJECTIVES AND DESIGN: Using pol sequences obtained for routine resistance testing, we characterised the molecular patterns of HIV-1 transmission and factors associated with being part of a transmission cluster among individuals who in 2008-2014 presented with primary HIV-1 infection (PHI) at 11 urban centres across Italy. METHODS: Pol sequences were obtained by Sanger sequencing. Transmission clusters were identified by phylogenetic analysis (maximum likelihood method, confirmed by Bayesian analysis). Multivariable logistic regression explored factors associated with a participant being part of a transmission cluster. RESULTS: The PHI cohort comprised 186 participants (159/186, 85.5% males) with median age 44 years, median CD4 count 464 cells/mm3 and median plasma HIV-1 RNA 5.6 log10 copies/mL. Drug resistance associated mutations were found in 16/186 (8.6%). A diversity of non-B subtypes accounted for 60/186 (32.3%) of all infections. A total of 17 transmission clusters were identified, including 44/186 (23.7%) participants. Each cluster comprised 2-6 sequences. Non-B subtypes accounted for seven clusters and 22/44 (50%) of clustered sequences. In multivariable logistic regression analysis, factors associated with being part of a transmission cluster comprised harbouring a non-B subtype (adjusted OR (adjOR) 2.28; 95% CI 1.03 to 5.05; p=0.04) and showing a lower plasma HIV-1 RNA (adjOR 0.80, 95% CI 0.64 to 0.99; p=0.04). CONCLUSIONS: There was a large contribution of diverse non-B subtypes to transmission clusters among people presenting with acute or recent HIV-1 infection in this cohort, illustrating the evolving dynamics of the HIV-1 epidemic in Italy, where subtype B previously dominated.