NSAIDs for early management of acute respiratory infections.

PURPOSE OF REVIEW: To review the rationale for and the potential clinical benefits of an early approach to viral acute respiratory infections with NSAIDs to switch off the inflammatory cascade before the inflammatory process becomes complicated. RECENT FINDINGS: It has been shown that in COVID-19 as in other viral respiratory infections proinflammatory cytokines are produced, which are responsible of respiratory and systemic symptoms. There have been concerns that NSAIDs could increase susceptibility to SARS-CoV-2 infection or aggravate COVID-19. However, recent articles reviewing experimental research, observational clinical studies, randomized clinical trials, and meta-analyses conclude that there is no basis to limit the use of NSAIDs, which may instead represent effective self-care measures to control symptoms. SUMMARY: The inflammatory response plays a pivotal role in the early phase of acute respiratory tract infections (ARTIs); a correct diagnosis of the cause and a prompt therapeutic approach with NSAIDs may have the potential to control the pathophysiological mechanisms that can complicate the condition, while reducing symptoms to the benefit of the patient. A timely treatment with NSAIDs may limit the inappropriate use of other categories of drugs, such as antibiotics, which are useless when viral cause is confirmed and whose inappropriate use is responsible for the development of resistance.

Association between markers of hepatitis B virus infection and risk of virological rebound in people with HIV receiving antiretroviral therapy.

OBJECTIVES: The aim of this analysis was to investigate the impact of hepatitis B virus (HBV) coinfection on the risk of HIV viral rebound (VR) after achieving suppression for the first time following initiation of antiretroviral therapy (ART) in the real-world setting. DESIGN: Patients living with HIV (PLWH) who were enrolled in the ICONA Foundation Study cohort and achieved viral suppression ≤50 copies/mL for the first time after starting ART were prospectively evaluated and divided in three exposure groups according to serology test results: (a) HIV-monoinfected; (b) HIV-positive/HBcAb-positive/HBsAg-negative; (c) HIV-positive/HBsAg-positive. The occurrence of VR, defined as two consecutive HIV-RNA values >50 copies/mL after achieving viral suppression for the first time (baseline), was investigated. METHODS: Standard survival analysis by means of Kaplan-Meier curves and Cox regression analysis with the serology exposure fitted as a time-fixed covariate measured at baseline was employed after controlling for key confounding factors. RESULTS: Of a total of 5657 patients included, 4090 (72%) were HIV-monoinfected, 1342 (23.7%)were HBcAb-positive, and 225 (3.9%) were HbsAg-positive coinfected. Overall, 654 (11.5%) PLWH experienced VR > 50 copies/mL during follow-up. After controlling for all sources of measured confounding, coinfected PLWH showed an increased risk of experiencing VR compared with those who were HIV-monoinfected. In particular, the strongest associations were seen for the HIV/HBsAg-positive participants [adjusted hazard ratio (aHR) = 1.56, 95% confidence interval (CI): 1.03-2.38, p = 0.037] but an excess of risk was also seen in those who were HIV-positive/HBcAb-positive/HBsAg-negative (aHR = 1.25, 95% CI: 1.00-1.55, p = 0.047). CONCLUSIONS: Coinfection with HBV seems to have an impact on the probability of maintaining HIV viral suppression achieved for the first time after ART initiation. Of note, even PLWH positive for HBcAb, a marker of inactive HBV infection, appeared to be at higher risk of VR compared with those who were HIV-monoinfected and their HIV-RNA should be carefully monitored.

Management of low-level HIV viremia during antiretroviral therapy: Delphi consensus statement and appraisal of the evidence.

OBJECTIVE: While antiretroviral therapy (ART) is highly effective, detection of low levels of HIV-1 RNA in plasma is common in treated individuals. Given the uncertainties on the topic, we convened a panel of experts to consider different clinical scenarios, producing a Delphi consensus to help guide clinical practice. METHODS: A panel of 17 experts in infectious diseases, virology and immunology rated 32 statements related to four distinct scenarios: (1) low-level viremia during stable (≥6 months) first-line ART (≥2 consecutive HIV-1 RNA measurements 50-500 copies/mL); (2) a viral blip during otherwise suppressive ART (a HIV-1 RNA measurement 50-1000 copies/mL with adjacent measurements <50 copies/mL); (3) low-level viral rebound during previously suppressive ART (≥2 consecutive HIV-1 RNA measurements 50-500 copies/mL); (4) residual viremia during suppressive ART (persistent HIV-1 RNA quantification below 50 copies/mL). A systematic review, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement, informed the 32 statements. The Delphi procedure was modified to include two voting rounds separated by a moderated group discussion. Grading of Recommendations, Assessment, Development, and Evaluations-based recommendations were developed. RESULTS: Overall, 18/32 statements (56.2%) achieved a strong consensus, 3/32 (9.4%) achieved a moderate consensus and 11/32 (34.4%) did not achieve a consensus. Across the four scenarios, the panel unanimously emphasised the importance of implementing specific interventions prior to considering therapy changes, including assessing adherence, testing for genotypic drug resistance and scheduling more frequent follow-up visits. Strategies indicated in selected circumstances included therapeutic drug monitoring, quantifying total HIV-1 DNA and evaluating concomitant chronic infections. CONCLUSIONS: While acknowledging the many uncertainties about source, significance and optimal management of low-level viremia during ART, the findings provide insights to help harmonise clinical practice. There is a need for well-designed randomised studies assessing different interventions to manage low-level viremia and future research regarding its definition.

Managing low-level HIV viraemia in antiretroviral therapy: a systematic review and meta-analysis.

OBJECTIVE: HIV-1 management has advanced significantly with antiretroviral therapy (ART), yet challenges persist, including low-level HIV-1 viraemia (LLV). LLV presents a complex scenario, with varied definitions in the literature, reflecting uncertainties in its clinical interpretation. Questions arise regarding the underlying mechanisms of LLV, whether it signifies ongoing viral replication or stems from other factors. This study aimed to systematically review strategies for LLV management, providing insights into optimal clinical approaches. METHODS: MEDLINE, EMBASE, Cochrane Library, Web of Science and Canadian Agency for Drugs and Technologies in Health were searched for relevant literature on LLV management. We included studies published between 2004 and 2024, assessing interventions such as ART modification, genotypic resistance testing, adherence assessment, performing therapeutic drug monitoring, testing for chronic coinfections and assessing the viral reservoir via HIV DNA quantification. Meta-analyses were conducted where feasible. RESULTS: The systematic review identified 48 eligible records. Findings indicated limited evidence supporting the effectiveness of ART regimen modification in achieving virological suppression among individuals with LLV. However, studies assessing genotypic resistance testing revealed a significant association between resistance-associated mutations and virological suppression during LLV. Adherence to ART emerged as a critical determinant of treatment efficacy, with interventions showing promise in achieving viral suppression. The clinical utility of therapeutic drug monitoring in managing LLV remained inconclusive. Gaps in the literature were identified regarding follow-up scheduling, managing concurrent chronic infections and assessing inflammatory markers in LLV management. CONCLUSIONS: While ART modification may not consistently achieve virological suppression, genotypic resistance testing may offer insights into treatment outcomes. Adherence to ART emerged as a crucial factor, necessitating tailored interventions. However, further research is needed to elucidate the clinical utility of therapeutic drug monitoring and other management strategies. The study highlights the importance of ongoing research to refine therapeutic approaches and improve patient outcomes in LLV management. PROSPERO REGISTRATION NUMBER: CRD42024511492.

Brain abscess caused by Actinomyces turicensis in a non-immunocompromised adult patient: a case report and systematic review of the literature.

BACKGROUND: Actinomyces turicensis is rarely responsible of clinically relevant infections in human. Infection is often misdiagnosed as malignancy, tuberculosis, or nocardiosis, therefore delaying the correct identification and treatment. Here we report a case of a 55-year-old immunocompetent adult with brain abscess caused by A. turicensis. A systematic review of A. turicensis infections was performed. METHODS: A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The databases MEDLINE, Embase, Web of Science, CINAHL, Clinicaltrials.gov and Canadian Agency for Drugs and Technology in Health (CADTH) were searched for all relevant literature. RESULTS: Search identified 47 eligible records, for a total of 67 patients. A. turicensis infection was most frequently reported in the anogenital area (n = 21), causing acute bacterial skin and skin structure infections (ABSSSI) including Fournier's gangrene (n = 12), pulmonary infections (n = 8), gynecological infections (n = 6), cervicofacial district infections (n = 5), intrabdominal or breast infections (n = 8), urinary tract infections (n = 3), vertebral column infections (n = 2) central nervous system infections (n = 2), endocarditis (n = 1). Infections were mostly presenting as abscesses (n = 36), with or without concomitant bacteremia (n = 7). Fever and local signs of inflammation were present in over 60% of the cases. Treatment usually involved surgical drainage followed by antibiotic therapy (n = 51). Antimicrobial treatments most frequently included amoxicillin (+clavulanate), ampicillin/sulbactam, metronidazole or cephalosporins. Eighty-nine percent of the patients underwent a full recovery. Two fatal cases were reported. CONCLUSIONS: To the best of our knowledge, we hereby present the first case of a brain abscess caused by A. turicensis and P. mirabilis. Brain involvement by A. turicensis is rare and may result from hematogenous spread or by dissemination of a contiguous infection. The infection might be difficult to diagnose and therefore treatment may be delayed. Nevertheless, the pathogen is often readily treatable. Diagnosis of actinomycosis is challenging and requires prompt microbiological identification. Surgical excision and drainage and antibiotic treatment usually allow for full recovery.

From Prioritization to Universal Treatment: Successes and Challenges of Hepatitis C Virus Elimination in Italy.

Italy has had the highest prevalence of hepatitis C virus (HCV) infection and mortality from HCV-related liver cancer in Europe. Although direct-acting antivirals (DAA) were initially restricted to persons with advanced fibrosis, their use has since been extended to all infected individuals; more than 244 000 persons have been treated to date. HCV liver-related mortality is expected to decline by 75% by 2030, achieving the World Health Organization target for mortality. However, Italy risks failing to meet the overall goal of eliminating HCV infection by 2030. In this light, €71.5 million have been allocated for screening initially specific target populations (persons who inject drugs, prison inmates, and the 1969-1989 birth cohort). Herein, we outline the challenges and recommendations for how to move Italy toward HCV elimination, including expanding screening programs in other populations, increasing awareness through strategic communication, sustaining DAA access, and tailoring care models to meet the needs of key populations.

Multishell diffusion MRI reveals whole-brain white matter changes in HIV.

Diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) have been previously used to explore white matter related to human immunodeficiency virus (HIV) infection. While DTI and DKI suffer from low specificity, the Combined Hindered and Restricted Model of Diffusion (CHARMED) provides additional microstructural specificity. We used these three models to evaluate microstructural differences between 35 HIV-positive patients without neurological impairment and 20 healthy controls who underwent diffusion-weighted imaging using three b-values. While significant group effects were found in all diffusion metrics, CHARMED and DKI analyses uncovered wider involvement (80% vs. 20%) of all white matter tracts in HIV infection compared with DTI. In restricted fraction (FR) analysis, we found significant differences in the left corticospinal tract, middle cerebellar peduncle, right inferior cerebellar peduncle, right corticospinal tract, splenium of the corpus callosum, left superior cerebellar peduncle, left superior cerebellar peduncle, pontine crossing tract, left posterior limb of the internal capsule, and left/right medial lemniscus. These are involved in language, motor, equilibrium, behavior, and proprioception, supporting the functional integration that is frequently impaired in HIV-positivity. Additionally, we employed a machine learning algorithm (XGBoost) to discriminate HIV-positive patients from healthy controls using DTI and CHARMED metrics on an ROIwise basis, and unique contributions to this discrimination were examined using Shapley Explanation values. The CHARMED and DKI estimates produced the best performance. Our results suggest that biophysical multishell imaging, combining additional sensitivity and built-in specificity, provides further information about the brain microstructural changes in multimodal areas involved in attentive, emotional and memory networks often impaired in HIV patients.

Differential plasmacytoid dendritic cell phenotype and type I Interferon response in asymptomatic and severe COVID-19 infection.

SARS-CoV-2 fine-tunes the interferon (IFN)-induced antiviral responses, which play a key role in preventing coronavirus disease 2019 (COVID-19) progression. Indeed, critically ill patients show an impaired type I IFN response accompanied by elevated inflammatory cytokine and chemokine levels, responsible for cell and tissue damage and associated multi-organ failure. Here, the early interaction between SARS-CoV-2 and immune cells was investigated by interrogating an in vitro human peripheral blood mononuclear cell (PBMC)-based experimental model. We found that, even in absence of a productive viral replication, the virus mediates a vigorous TLR7/8-dependent production of both type I and III IFNs and inflammatory cytokines and chemokines, known to contribute to the cytokine storm observed in COVID-19. Interestingly, we observed how virus-induced type I IFN secreted by PBMC enhances anti-viral response in infected lung epithelial cells, thus, inhibiting viral replication. This type I IFN was released by plasmacytoid dendritic cells (pDC) via an ACE-2-indipendent but Neuropilin-1-dependent mechanism. Viral sensing regulates pDC phenotype by inducing cell surface expression of PD-L1 marker, a feature of type I IFN producing cells. Coherently to what observed in vitro, asymptomatic SARS-CoV-2 infected subjects displayed a similar pDC phenotype associated to a very high serum type I IFN level and induction of anti-viral IFN-stimulated genes in PBMC. Conversely, hospitalized patients with severe COVID-19 display very low frequency of circulating pDC with an inflammatory phenotype and high levels of chemokines and pro-inflammatory cytokines in serum. This study further shed light on the early events resulting from the interaction between SARS-CoV-2 and immune cells occurring in vitro and confirmed ex vivo. These observations can improve our understanding on the contribution of pDC/type I IFN axis in the regulation of the anti-viral state in asymptomatic and severe COVID-19 patients.

Forecasting the long-term impact of COVID-19 on hepatitis C elimination plans in Italy: A mathematical modelling approach.

BACKGROUND: Italy has a high HCV prevalence, and despite the approval of a dedicated fund for 'Experimental screening' for 2 years, screening has not been fully implemented. We aimed to evaluate the long-term impact of the persisting delay in HCV elimination after the Coronavirus disease 2019 (COVID-19) pandemic in Italy. METHODS: We used a mathematical, probabilistic modelling approach evaluating three hypothetical 'Inefficient', 'Efficient experimental' and 'WHO Target' screening scenarios differing by treatment rates over time. A Markov chain for liver disease progression evaluated the number of active infections, decompensated cirrhosis (DC), hepatocellular carcinoma (HCC) and HCV liver-related deaths up to the years 2030 and 2050. RESULTS: The 'WHO Target' scenario estimated 3900 patients with DC and 600 with HCC versus 4400 and 600 cases, respectively, similar for both 'Inefficient' and 'Efficient experimental' screening up to 2030. A sharp (10-fold) decrease in DC and HCC was estimated by the 'WHO Target' scenario compared with the other two scenarios in 2050; the forecasted number of DC was 420 cases versus 4200 and 3800 and of HCC <10 versus 600 and 400 HCC cases by 'WHO Target,' 'Inefficient' and 'Efficient experimental' scenarios, respectively. A significant decrease of the cumulative estimated number of liver-related deaths was observed up to 2050 by the 'WHO Target' scenario (52000) versus 'Inefficient' or 'Efficient experimental' scenarios (79 000 and 74 000 liver-related deaths, respectively). CONCLUSIONS: Our estimates highlight the need to extensively and efficiently address HCV screening and cure of HCV infection in order to avoid the forecasted long-term HCV adverse outcomes in Italy.

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.

Droplet digital PCR assay as an innovative and promising highly sensitive assay to unveil residual and cryptic HBV replication in peripheral compartment.

Droplet digital PCR is an innovative and promising approach for highly sensitive quantification of nucleic acids that is being increasingly used in the field of clinical virology, including the setting of hepatitis B virus (HBV). Here, we comprehensively report a robust and reproducible ddPCR assay for the highly sensitive quantification of serum HBV-DNA. The assay showed a limit of detection of 4 copies/ml (<1IU/ml) by Probit analysis, showed a good linearity (R2 = 0.94) and a high intra- and inter-run reproducibility with differences between the values obtained in the same run or in two independent runs never exceeding 0.14logcopies/mL and 0.21logcopies/mL, respectively. By analysing serum samples from chronically HBV infected patients (mostly under antiviral treatment), ddPCR successfully quantified serum HBV-DNA in 89.8% of patients with detectable serum HBV-DNA < 20 IU/mL [equivalent to <112copies/ml] by classical Real-Time PCR assay, with a median (IQR) of 8(5-14)IU/mL [45(28-78)copies/ml], and in 66.7% of patients with undetectable serum HBV-DNA, with a median (IQR) of 5(4-9)IU/mL [28(20-50)copies/ml]. Similarly, by analysing serum samples from patients with a serological profile compatible with occult HBV infection (anti-HBc+/HBsAg-), ddPCR successfully quantified serum HBV-DNA in 40% of patients with a median (IQR) value of 1(1-2)IU/mL [5(5-11)copies/ml], in line with the extremely limited viral replication typically observed in occult HBV infection. Overall, the availability of assays for the highly sensitive quantification of serum HBV-DNA can provide an added value in optimizing the diagnosis of occult hepatitis B infection, improving the therapeutic management of chronically HBV infected patients, also in the light of innovative drugs (upcoming in clinical practise) aimed at achieving HBV functional cure.

Daptomycin-induced eosinophilic pneumonia: a case report and systematic review.

Introduction Acute eosinophilic pneumonia (AEP) is a rare respiratory condition caused by eosinophil accumulation in the pulmonary tissue that can be related to drug administration. Daptomycin, an antibiotic active against gram-positive bacteria, is one of the leading causes of AEP among drugs. In order to raise awareness of this rare syndrome, in our work we have described a case of an 82 years-old male with Enterococcus faecalis endocarditis treated with daptomycin, who developed a daptomycin-induced AEP. We have performed a systematic review of the literature for all similar reported cases. Methods The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. To conduct the analysis, the terms "daptomycin AND eosinoph* AND pneum*", were entered the databases Medline, Cinahl and Embase on April 13th, 2023. We considered relevant all records documenting AEP after daptomycin use. No restrictions in terms of year or language were made. A formal appraisal of observational studies was performed by Newcastle-Ottawa Scale. All results and data were reported by means of tables. Results Our search identified 93 relevant records, published between 2007 and 2023. A total of 120 patients were considered. Patients who experienced AEP were mostly males (n=88, 73.3%) with a mean age of 68.28 years (SD11.54). Daptomycin was most frequently prescribed for osteoarticular infections (n=75, 62.5%) and to treat gram-positive cocci infections. The most frequently isolated pathogen was Methicillin-resistant Staphylococcus aureus (MRSA). Daptomycin was mostly used with off-label indications (n=89, 74%). Symptoms of AEP were usually reported after a mean of 21.75 days of treatment (range 3-84) and typically included fever, dyspnea, dry cough and acute respiratory failure. Reported treatment strategies invariably included daptomycin withdrawal, respiratory support, and corticosteroid treatment. One hundred and sixteen patients fully recovered. A fatal outcome was described in 4 patients. Suggestive symptoms and imaging raised suspicion for AEP, confirmed with bronchoalveolar lavage in 57.5% of the cases. Discussion and Conclusions Daptomycin-induced AEP is a rare but potentially fatal complication, mostly reported after long treatment with daptomycin. Clinicians should be aware of this syndrome, as it could be initially misdiagnosed for an acute infectious respiratory syndrome, resulting in a delay in its diagnosis and treatment. Furthermore, since the risk of developing AEP is increased by longer drug exposure, caution should be used when discussing the use of daptomycin in longer treatment regimens.

Optimizing Antiretroviral Therapy with Bictegravir/Emtricitabine/Tenofovir Alafenamide in virologically suppressed PLWH.

The pillar of treatment success, defined as viral suppression and immune restoration, should be integrated into a modern vision of therapeutic success with pharmacological attributes of ART, such as potency, forgiveness, and genetic barrier of single drugs and regimens, as well as their longterm tolerability and safety. Moreover, the longterm success of lifelong treatment cannot be separated from the opinions and preferences of PLWH. Regimen Optimization in the setting of HIV suppression may reduce pill burden, and/or dosing frequency, enhance tolerability and/or decrease toxicity, prevent or mitigate DDIs, eliminate food/fluid requirements, relieve pill fatigue, decrease stigma or concerns associated with taking oral med, allow pregnancy, reduce costs (DHHS 2023). Regimen Optimization should be tailored by a person-centered perspective, based on the individual therapeutic history, past toxicities and comorbidities. The treatment strategy should be based on the perceived tolerability and quality of life, considering the preferences of people on treatment along with the virological and pharmacological factors. The health care system should facilitate universal and rapid access to personalized, robust, and effective therapies. The BIC/FTC/TAF association ensures all these characteristics and therefore represents a valid strategy for optimizing treatment in PLWH virologically suppressed.

Expression analysis of miRNA hsa-let7b-5p in naso-oropharyngeal swabs of COVID-19 patients supports its role in regulating ACE2 and DPP4 receptors.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the novel coronavirus responsible for worldwide coronavirus disease (COVID-19). We previously observed that Angiotensin-converting enzyme 2 (ACE2) and Dipeptidyl peptidase-4 (DPP4) are significantly overexpressed in naso-oropharyngeal swabs (NPS) of COVID-19 patients, suggesting their putative functional role in the disease progression. ACE2 and DPP4 overexpression in COVID-19 patients may be associated to epigenetic mechanism, such as miRNA differential expression. We investigated if hsa-let7b-5p, reported to target both ACE2 and DPP4 transcripts, could be involved in the regulation of these genes. We verified that the inhibition and overexpression of hsa-let7b-5p matched to a modulation of both ACE2 and DPP4 levels. Then, we observed a statistically significant downregulation (FC = -1.5; p < 0.05) of hsa-let7b-5p in the same COVID-19 and control samples of our previous study. This is the first study that shows hsa-let7b-5p low expression in naso-oropharyngeal swabs of COVID-19 patients and demonstrates a functional role of this miR in regulating ACE2 and DPP4 levels. These data suggest the involvement of hsa-let7b-5p in the regulation of genes necessary for SARS-CoV-2 infections and its putative role as a therapeutic target for COVID-19.

Optimizing diagnostic algorithms to advance Hepatitis C elimination in Italy: A cost effectiveness evaluation.

OBJECTIVES: Optimized diagnostic algorithms to detect active infections are crucial to achieving HCV elimination. We evaluated the cost effectiveness and sustainability of different algorithms for HCV active infection diagnosis, in a context of a high endemic country for HCV infection. METHODS: A Markov disease progression model, simulating six diagnostic algorithms in the birth cohort 1969-1989 over a 10-year horizon from a healthcare perspective was used. Conventionally diagnosis of active HCV infection is through detection of antibodies (HCV-Ab) detection followed by HCV-RNA or HCV core antigen (HCV-Ag) confirmatory testing either on a second sample or by same sample reflex testing. The undiagnosed and unconfirmed rates were evaluated by assays false negative estimates and each algorithm patients' drop-off. Age, liver disease stages distribution, liver disease stage costs, treatment effectiveness and costs were used to evaluate the quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratios (ICER). RESULTS: The reference option was Rapid HCV-Ab followed by second sample HCV-Ag testing which produced the lowest QALYs (866,835 QALYs). The highest gains in health (QALYs=974,458) was obtained by HCV-RNA reflex testing which produced a high cost-effective ICER (€891/QALY). Reflex testing (same sample-single visit) vs two patients' visits algorithms, yielded the highest QALYs and high cost-effective ICERs (€566 and €635/QALY for HCV-Ag and HCV-RNA, respectively), confirmed in 99.9% of the 5,000 probabilistic simulations. CONCLUSIONS: Our data confirm, by a cost effectiveness point of view, the EASL and WHO clinical practice guidelines recommending HCV reflex testing as most cost effective diagnostic option vs other diagnostic pathways.

Meet-Test-Treat for HCV management: patients' and clinicians' preferences in hospital and drug addiction services in Italy.

BACKGROUND: It has been estimated that the incidence of chronic hepatitis C virus (HCV) will not decline over the next 10 years despite the improved efficacy of antiviral therapy because most patients remain undiagnosed and/or untreated. This study aimed to investigate the opinion of relevant target populations on the practicability, effectiveness and best modalities of the test-and-treat approach in the fight against HCV in Italy. METHODS: A survey was delivered to patients with HCV from the general population, patients from drug addiction services, hospital physicians and healthcare providers for drug addiction services. RESULTS: For both hospital clinicians and SerD HCPs, tolerability is shown as the most important feature of a suitable treatment. Time to treatment (the time from first contact to initiation of treatment) is deemed important to the success of the strategy by all actors. While a tolerable treatment was the main characteristic in a preferred care pathway for general patients, subjects from drug addiction services indicated that a complete Meet-Test-Treat pathway is delivered within the habitual care center as a main preference. This is also important for SerD HCPs who are a strong reference for their patients; hospital clinicians were less aware of the importance of the patient-HCP relationship in this process. CONCLUSION: The health system is bound to implement suitable pathways to facilitate HCV eradication. A Meet-Test-Treat program within the drug addiction services may provide good compliance from subjects mainly concerned with virus transmission.

A mathematical model by route of transmission and fibrosis progression to estimate undiagnosed individuals with HCV in different Italian regions.

BACKGROUND: Although an increase in hepatitis C virus (HCV) prevalence from Northern to Southern Italy has been reported, the burden of asymptomatic individuals in different Italian regions is currently unknown. METHODS: A probabilistic approach, including a Markov chain for liver disease progression, was applied to estimate current HCV viraemic burden. The model defined prevalence by geographic area using an estimated annual historical HCV incidence by age, treatment rate, and migration rate from the Italian National database. Viraemic infection by age group was estimated for each region by main HCV transmission routes of individuals for stage F0-F3 (i.e. patients without liver cirrhosis and thus potentially asymptomatic) and F4 (patients with liver cirrhosis, thus potentially symptomatic). RESULTS: By January 2020, it was estimated that there were 409,184 Italian individuals with HCV (prevalence of 0.68%; 95% CI: 0.54-0.82%), of which 300,171 (0.50%; 95% CI: 0.4-0.6%) were stage F0-F3. Considering all individuals with HCV in stage F0-F3, the geographical distributions (expressed as the proportion of HCV infected individuals by macroarea within the overall estimated number of F0-F3 individuals and prevalence values, expressed as the percentage of individuals with HCV versus the overall number of individuals for each macroarea) were as follows: North 42.1% (0.45%; 95% CI: 0.36-0.55%), Central 24.1% (0.61%; 95% CI: 0.48-0.74%), South 23.2% (0.50%; 95% CI: 0.4-0.61%), and the Isles 10.6% (0.49%; 95% CI: 0.39-0.59%). The population of people who inject drugs accounted for 50.4% of all individuals infected (F0-F3). Undiagnosed individuals (F0-F3) were ~ 15 years younger (⁓ 50 years) compared with patients with stage F4 (⁓ 65 years), with similar age distributions across macroareas. In contrast to what has been reported on HCV epidemiology in Italy, an increasing trend in the proportion of potentially undiagnosed individuals with HCV (absolute number within the F0-F3) from South (23.2%) to North (42.1%) emerged, independent of similar regional prevalence values. CONCLUSION: This targeted approach, which addresses the specific profile of undiagnosed individuals, is helpful in planning effective elimination strategies by region in Italy and could be a useful methodology for other countries in implementing their elimination plans.

Prevalence of hepatitis C virus estimates of undiagnosed individuals in different Italian regions: a mathematical modelling approach by route of transmission and fibrosis progression with results up to January 2021.

This study provides an update on hepatitis C virus (HCV) estimates across Italy up to January 2021. A mathematical probabilistic modelling approach, including a Markov chain for liver disease progression, was used to estimate current HCV viraemic burden. Prevalence was defined by geographic area using an estimated annual historical HCV incidence by age, treatment, and migration rate from the Italian National database (ISTAT). Viraemic infection was estimated for the main HCV transmission routes by stages F0-F3 (patients without liver cirrhosis, i.e., potentially asymptomatic liver disease) and F4 (patients with liver cirrhosis, i.e., potentially symptomatic liver disease). By January 2021, we estimated that there were 398,610 individuals in Italy with active HCV infection (prevalence of 0.66%; 95% CI: 0.66-0.67), of which 287,730 (0.48%; 95% CI: 0.46-0.59%) were stage F0-F3. Prevalence values for all individuals with active HCV infection were: North 0.54% (95% CI: 0.53-0.54%), Central 0.88% (95% CI: 0.87-0.89%), South 0.72% (95% CI: 0.71-0.73%), and the Isles 0.67% (95% CI: 0.66-0.68%). The population at risk for previous/current drug injection accounted for 48.6% of all individuals with active HCV infection. A modelling approach such as this to estimate and update the prevalence of active HCV infection could be a useful methodology for the evaluation of healthcare policies related to HCV elimination plans.

Preferences of PLWH and of clinicians for HIV treatment aimed at long-term success.

This study aimed to develop a new approach to manage people living with HIV (PLWH), investigating preferences of clinicians and PLWH in order to improve linkage to care of PLWH. A survey was performed with the Discrete Choice Experiment (DCE) method to investigate the preferences of two categories, clinicians and PLWH, for attributes of HIV care pathways, therapy and quality of life. Our results suggest that the most important feature of a care pathway was the site of testing for both categories, followed by modality of counselling for clinicians and by pre-exposure prophylaxis for PLWH. Regarding therapy, choices were mostly oriented by modality of administration for both categories, and by CD4 cells increase for clinicians and side effects for PLWH. People living with HIV reported that, out of 13 candidates, the two most important factors related to good long-term quality of life would be reduction of viral transmissibility and good emotional life. A tailored approach could be the key to long-term treatment success, but this approach must necessarily be based on evaluation of the specific complexities of the patient.

Genotypic HIV-1 tropism determination might help to identify people with exhausted treatment options and advanced disease.

OBJECTIVES: To evaluate HIV-1 tropism in 1382 combined antiretroviral therapy (cART)-experienced patients failing therapy to characterize those with exhausted therapeutic options. METHODS: HIV-1 genotypic tropism was inferred through Geno2Pheno by estimating the false-positive-rate (FPR) values. Cumulative resistance and drug activity were evaluated by Stanford algorithm. RESULTS: Overall, median (IQR) CD4 count (cells/mm3) nadir and at last genotypic resistance test (GRT) available were 98 (33-211) and 312 (155-517), respectively. Considering HIV-1 tropism, 30.5% had X4/dual-mixed strains (FPR ≤5%: 22.2%; FPR 5%-10%: 8.3%). By stratifying according to tropism, by decreasing FPR, a significant decrease of CD4 nadir and at last GRT was observed. The proportion of individuals with CD4 count <200 cells/mm3, who were perinatally infected and with a long treatment history significantly increased as FPR levels decreased. Regarding resistance, 933 (67.5%) individuals accumulated at least one class resistance, with 52.7%, 48.2%, 23.5% and 13.2% of individuals showing resistance to NRTIs, NNRTIs, PIs and INIs; while 23.2%, 27.2%, 14.3% and 2.8% harboured resistance to 1, 2, 3 and 4 classes, respectively. Individuals with FPR ≤5% showed a significantly higher level of resistance to PIs, NRTIs and INIs compared with others. The proportion of individuals harbouring strains susceptible to ≤2 active drugs was only about 2%; nonetheless, this proportion doubled (4.6%) in patients infected with FPR ≤5%. CONCLUSIONS: Our findings showed that a small proportion of cART failing individuals have limited therapeutic options. However, tropism determination might help to identify people who have accumulated a high level of resistance and have a greater risk of advanced disease.