Pharmacogenetics of tenofovir drug transporters in the context of HBV: Is there an impact?

BACKGROUND: Current treatments for chronic hepatitis B management include orally administered nucleos(t)ide analogues, such as tenofovir (TDF), which is an acyclic adenine nucleotide analogue used both in HBV and human immune deficiency virus (HIV). The course of HBV infection is mainly dependent on viral factors, such as HBV genotypes, immunological features and host genetic variables, but a few data are available in the context of HBV, in particular for polymorphisms of genes encoding proteins involved in drug metabolism and elimination. Consequently, the aim of this study was to evaluate the potential impact of genetic variants on TDF plasma and urine concentrations in patients with HBV, considering the role of HBV genotypes. METHODS: A retrospective cohort study at the Infectious Disease Unit of Amedeo di Savoia Hospital, Torino, Italy, was performed. Pharmacokinetic analyses were performed through liquidi chromatography, whereas pharmacogenetic analyses through real-time PCR. FINDINGS: Sixty - eight patients were analyzed: ABCC4 4976 C>T genetic variant showed an impact on urine TDF drug concentrations (p = 0.014). In addition, SLC22A6 453 AA was retained in the final regression multivariate model considering factors predicting plasma concentrations, while ABCC4 4976 TC/CC was the only predictor of urine concentrations in the univariate model. INTERPRETATION: In conclusion, this is the first study showing a potential impact of genetic variants on TDF plasma and urine concentrations in the HBV context, but further studies in different and larger cohorts of patients are required.

Presumptive pulmonary toxocariasis in a patient affected by acute myeloid leukemia and Hodgkin lymphoma: case report and review of the literature in immunocompromised hosts.

Toxocariasis is a zoonosis transmitted by the nematode Toxocara spp. Immunocompromised hosts are more susceptible than general population to bacterial, viral, fungal and parasitic infections. In this population toxocariasis may present as exacerbation or reactivation and could have severe or atypical manifestations being a diagnostic challenge for healthcare providers. We report a case of a presumptive pulmonary toxocariasis during chemotherapy in a patient affected by acute myeloid leukaemia (AML) and Hodgkin lymphoma and we summarize current evidence of pulmonary involvement in immunocompromised population with Toxocara spp infection in a narrative review. The aim of this work is also to revise the current literature on pulmonary involvement during Toxocara spp infection in immunocompromised hosts to improve knowledge on clinical presentation, treatment and outcome. A 66 years old man who had undergone to a cytarabine and idarubicin chemotherapy induction scheme for AML, complained of febrile neutropenia and dry cought. At the chest computed tomography (CT) there were multiple nodular pulmonary lesions with subpleural consolidations. The lung biopsy revealed inflammatory infiltration with diffuse small granulomas with minor eosinophil component. The laboratory analysis showed high immunoglobulin E (IgE) count with normal peripherical eosinophils, among the extended parasitological analysis, Toxocara immunoblot assay resulted positive. In the most accepted hypothesis of a polmunary toxocariasis infection, the patient was treated with a combination of albendazole plus corticosteroids for four weeks, with a positive outcome. Infection complications during chemotherapy are not uncommon, however, this is the first reported case of pulmonary toxocariasis during cytarabine and idarubicin treatment in AML. The revised literature shows male gender and younger age as possible risk factors, nevertheless the majority of cases of seropositivity for Toxocara was reported in solid organ malignancies. In this case, the suspect was mainly based on laboratory total elevated IgE, confirmed by serological, anatomo-pathological and radiological findings. Hypereosinophilia is often not present in chronic infection. In conclusion, pulmonary toxocariasis should be ruled out in patients with pulmonary involvement and high IgE titre, with or without peripheral eosinophilia, especially in those with known immunocompromised status.

HBsAg kinetics after 7 years of therapy with tenofovir disoproxil fumarate in a cohort of naïve patients affected by chronic hepatitis B with different genotypes.

The role of different genotypes in nucleos(t)ide analogs (NAs) treatment is still debated. Previous studies conducted on special populations evidenced that the E genotype had the lower virological and serological response. This descriptive study aims to recognize the hepatitis B "s" antigen (HBsAg) decline during tenofovir disoproxil fumarate (TDF) treatment in a cohort of patient affected by chronic hepatitis B (CHB). We retrospectively included all patients with CHB treated with TDF between April 2007 and March 2012 with a duration of treatment of 7 years. Kinetics of HBsAg was determined as serological response in this cohort. We include 110 subjects; virological response was observed in all subjects with genotypes A, B, and D; in 17 patients with C genotype (94.4%) and 24 with E genotype (96%). HBeAg loss was observed in 2 patients with genotype A (50%), 3 with B (100%), 0 with C (0%), 1 with D (20%), and 1 with E genotype (25%). In multivariate analysis we observed as predictive factors of HBsAg decline the baseline level of HBsAg (OR = 1.467; 95%CI: 1.221-5.113; p = 0.017) and viral genotypes (OR = 11.218; 95%CI: 5.441-41.138; p < 0.001). This study confirmed higher HBsAg decline after 7 years of treatment in A and B genotypes, and lower in C, E, and D genotypes. However, no evidence is enough to choose a single NAs, but in special populations, as well as in genotype E, the use of TDF should be preferred to entecavir.

Transjugular intrahepatic portosystemic shunt followed by splenectomy for complicated hepatosplenic schistosomiasis: a case report and review of the literature.

Hepatosplenic schistosomiasis is a complex clinical condition caused by the complications of chronic infection with Schistosoma species that cause intestinal schistosomiasis. Hepatosplenic schistosomiasis derives from the fibrotic reaction stimulated around parasite eggs that are transported by the mesenteric circulation to the liver, causing periportal fibrosis. Portal hypertension and variceal gastrointestinal bleeding are major complications of hepatosplenic schistosomiasis. The clinical management of hepatosplenic schistosomiasis is not standardised and a parameter that could guide clinical decision making has not yet been identified. Transjugular intrahepatic portosystemic shunt (TIPS) appears promising for use in hepatosplenic schistosomiasis but is still reported in very few patients. In this Grand Round, we report one patient with hepatosplenic schistosomiasis treated with TIPS, which resulted in regression of oesophageal varices but had to be followed by splenectomy due to persisting severe splenomegaly and thrombocytopenia. We summarise the main challenges in the clinical management of this patient with hepatosplenic schistosomiasis, highlight results of a scoping review of the literature, and evaluate the use of of TIPS in patients with early hepatosplenic schistosomiasis, to improve the prognosis.

Vaccination Campaign against Hepatitis B Virus in Italy: A History of Successful Achievements.

In Italy, the vaccination campaign against hepatitis B virus has been characterized by two phases. In the first phase (1984-1991), vaccination with plasma-derived vaccines was first recommended for the high-risk group. In the second phase (1991-nowadays), recombinant vaccine targeted, by law, infants 2 months old and teenagers 12 years old (limited to the first 12 years of campaign); screening for HBsAg became compulsory for all pregnant women during the third trimester of pregnancy. Successful achievements have been attained: No acute HBV case has been observed in the age group targeted by vaccination, the pool of chronic HBsAg carriers is strongly reduced, perinatal HBV transmission is under control, and acute delta virus hepatitis cases are nearly eliminated. The key point of this success has been the peculiar vaccination policy adopted. The combined vaccination of teenagers has generated an early immune cohort of youths, who are no longer at risk of acquiring HBV infection by sources of exposure (i.e., drug use and unsafe sex practices) typical of the young adults. Vaccination of household contacts with HBsAg-positive subjects represents an area of improvement; providing migrants and refugees access to healthcare services is also a focal point. In 2020, Italy became the first country in Europe to achieve the WHO's regional hepatitis targets.

Changes in Cerebrospinal Fluid, Liver and Intima-media-thickness Biomarkers in Patients with HIV-associated Neurocognitive Disorders Randomized to a Less Neurotoxic Treatment Regimen.

The prevalence of neurocognitive impairment in people living with HIV is estimated between 30 and 50%. The pathogenesis of HIV-associated neurocognitive disorders is complex and multifactorial. Aim of the study was to measure the change in CSF biomarkers, Fibroscan and IMT measurements in PLWH with HAND randomized to a less neurotoxic regimen, or continuing their treatment. Adult patients with HAND were screened and enrolled if presenting no major resistance associated mutations, no HIV viral replication, not on efavirenz or darunavir, with R5-tropic HIV and without major confounding conditions. Lumbar puncture, IMT and Fibroscan measurements were performed. After 1:1 randomization to a less neurotoxic regimen consisting of darunavir/cobicistat plus emtricitabine plus maraviroc, or mantaining actual care, tests were repeated after 24 weeks: CSF biomarkes (HIV RNA, tau, p-tau, Beta-amyloid1-42, S100Beta and neopterin) were included. Non-parametric tests (Mann-Whitney and Wilcoxon's) were used. 28 participants completed the study. Male and European ancestry were prevalent; median age was 55 years (51-60). All patients were virally suppressed; median CD4 + count was 626 cell/uL (469-772). Baseline characteristics were similar between the study arms. A significant decrease in CSF p-tau and an increase in CSF neopterin and NFL were observed. We observed a significant reduction in liver stiffness at W24. Despite a small sample size we observed changes in neuromarkers and in hepatic stiffness in patients randomized to the experimental arm. We observed changes in CSF biomarkers (lower phosphorylated-tau and higher neopterin and NFL) that need to be replicated in large cohorts. Subclinical neurotoxicity may be observed in patients with HAND and warrants prospective studies.

Five Decades of HBV Infection in Italy: A Continuous Challenge.

In Italy, Hepatitis B virus (HBV) infection has been characterized by several changes over the last five decades. In 2019, the incidence of acute HBV among subjects targeted by the vaccination campaign was 0 cases in the age group 0-14 years and 0.1/100,000 in the age group 15-24. Nowadays, the burden of different stages of HBV-related chronic liver diseases is minimal. Intravenous drug use is no longer a risk factor (O.R. 0.7; 95% C.I. 0.5-1.02) for acquiring acute HBV; the proportion of cases reporting this exposure fell from 29.8% to 3.3% over the last two decades. The key public health intervention has been the compulsory vaccination campaign started in 1991 for infants 3 months old and 1-2 years old (the latter group for the first 12 years of the campaign). Moreover, non-immunogenic factors and the availability of effective oral antiviral drugs have played and continue to play a prominent role. The potential availability of new oral antiviral drugs with the inherent ability to eliminate the genomic HBV reservoirs may represent a further crucial step in the elimination of the virus in people that are already infected.

Real-Life Experience of Continuously Infused Ceftolozane/Tazobactam in Patients with Bronchiectasis and Multidrug-Resistant Pseudomonas aeruginosa Infection in the Outpatient Setting.

(1) Background: Ceftolozane/tazobactam (C/T) is a novel ß-lactam/ß-lactamase inhibitor with excellent activity against the multidrug-resistant (MDR) P. aeruginosa. Continuous infusion (CI) dosing allows the optimization of pharmacokinetic and pharmacodynamic (PK/PD) properties of ß-lactam antibiotics and may support patients' treatment as outpatients. (2) Methods: Adult patients receiving their entire course of C/T as a CI in the outpatient setting were retrospectively included in the study. The primary outcome evaluated was clinical resolution. The secondary outcomes evaluated were PK/PD target attainment (ƒT > 4 × MIC) and microbiologic clearance at the end of treatment. Therapeutic drug monitoring to assess C/T concentration was performed. (3) Results: Three patients were enrolled in the study and received 9 g of C/T in CI every 24 h. One patient received an additional course of antimicrobial therapy due to disease exacerbation six months after initial treatment, accounting for four evaluated treatments. The primary outcome was achieved in 3/4 treatments and the secondary outcome was achieved in 4/4 and 3/3, respectively. In all patients, free ceftolozane concentrations were >10 times higher than the EUCAST breakpoint (4 mg/L). (4) Conclusions: Elastomeric infusion of C/T delivered in CI can be an effective and convenient way to treat acute diseases caused by MDR-P. aeruginosa, avoid hospital admission, and contribute to infection control strategies. Despite the small number of enrolled patients, clinical and microbiological results support this strategy.

Impact of preventive chemotherapy on Strongyloides stercoralis: A systematic review and meta-analysis.

BACKGROUND: Strongyloides stercoralis is a neglected soil-transmitted helminth (STH) that leads to significant morbidity in endemic populations. Infection with this helminth has recently been recognised by the World Health Organization (WHO) as a major global health problem to be addressed with ivermectin preventive chemotherapy, and therefore, there is now, the need to develop guidelines for strongyloidiasis control that can be implemented by endemic countries. This study aimed to evaluate the impact of ivermectin preventive chemotherapy (PC) on S. stercoralis prevalence in endemic areas to generate evidence that can inform global health policy. METHODOLOGY/PRINCIPAL FINDINGS: This study was a systematic review and meta-analysis. We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and LILACS for literature published between 1990 and 2022 and reporting prevalence of S. stercoralis before and after PC with ivermectin, administered either at school or at community level. The search strategy identified 933 records, eight of which were included in the meta-analysis. Data extraction and quality assessment were carried out by two authors. Meta-analysis of studies based on fecal testing demonstrated a significant reduction of S. stercoralis prevalence after PC: prevalence Risk Ratio (RR) 0.18 (95% CI 0.14-0.23), I2 = 0. A similar trend was observed in studies that used serology for diagnosis: RR 0.35 (95% CI 0.26-0.48), I2 = 4.25%. A sensitivity analysis was carried out for fecal tests where low quality studies were removed, confirming a post-intervention reduction in prevalence. The impact of PC could not be evaluated at different time points or comparing annual vs biannual administration due to insufficient data. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate a significant decrease of S. stercoralis prevalence in areas where ivermectin PC has taken place, supporting the use of ivermectin PC in endemic areas.

A Historical Overview on the Role of Hepatitis B and C Viruses as Aetiological Factors for Hepatocellular Carcinoma.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the leading cause of hepatocellular carcinoma (HCC) worldwide. Currently, HBV-related HCC predominates in Sub-Saharan Africa and South-East-Asia, while HCV-related HCC predominates in northern Africa and in the western world. Liver cirrhosis is the underlying condition in most HBV cases and in nearly all HCV cases. Several cofactors, viral and non-viral, play a role in the progression toward HCC: dual HBV/HCV infection, HDV, HIV, alcohol intake, smoking, diabetes mellitus, obesity, and NAFLD/NASH. HBV vaccine is effective in preventing both infection and HCC; antiviral drugs may suppress HBV replication and eradicate HCV infection, halting progression to HCC. Inequalities exist between high- and low-income countries with respect to vaccine availability and access to antivirals. These factors represent barriers to the control of HCC incidence. Lack of an effective vaccine against HCV is also a serious barrier to HCV elimination and HCC prevention. The most crucial steps and knowledge that have arisen over time on the association between the two major hepatotropic viruses and HCC are discussed in this historical review.

Case Report: Role of Point-of-Care Ultrasound in the Diagnosis of Bacillary Angiomatosis.

Clinical skin manifestations are commonly seen in resource-limited settings, but they are frequently misdiagnosed due to the lack of microbiological tests with ensuing stigma and long-term disability. The adoption of portable ultrasound devices, which extend physical examination in the hands of trained clinicians, has partially improved the situation. Specific protocols, such as focused assessment with sonography for HIV-associated tuberculosis (FASH), have led to simplified diagnostic pathways. Here we describe a case of bacillary angiomatosis in a patient with advanced HIV disease presenting with subacute unusual cutaneous lesions. The patient also presented with significant weight loss, anemia, and prostration. Highly sensitive rapid tests for tuberculosis and cryptococcosis were negative, and CD4 count was very low. Ultrasound scanning (US) and biopsy of the cutaneous lesions finally led to diagnosis and treatment. This report illustrates the benefits of integrating ultrasound-based protocols with clinical skills, as the diagnosis was suspected based on clinical presentation and US and confirmed by pathology. The importance of adoption of US protocols by infectious diseases clinicians is discussed.

Clinical Effectiveness and Pharmacokinetics of Dalbavancin in Treatment-Experienced Patients with Skin, Osteoarticular, or Vascular Infections.

Dalbavancin (DBV) is a lipoglycopeptide approved for the treatment of Gram-positive infections of the skin and skin-associated structures (ABSSSIs). Currently, its off-label use at different dosages for other infections deserves attention. This work aimed to study the clinical effectiveness and tolerability of DBV in outpatients with ABSSSIs, osteoarticular (OA), or other infections, treated with either one or two 1500 mg doses of dalbavancin, for different scheduled periods. A liquid chromatography-tandem mass spectrometry method was used to measure total DBV concentrations. PK/PD parameters and the clinical and microbiological features of this cohort were evaluated in order to investigate the best predictors of treatment success in real-life settings. Of the 76 screened patients, 41 completed the PK study. Long-term PK was comparable to previous studies and showed significant differences between genders and dosing schedules. Few adverse events were observed, and treatment success was achieved in the vast majority of patients. Failure was associated with lower PK parameters, particularly Cmax. Concluding, we were able to describe DBV PK and predictors of treatment success in selected infections in this cohort, finding DBV Cmax as a possible candidate for therapeutic drug-monitoring purposes, as well as highlighting the dual-dose one-week-apart treatment as the optimal choice for OA infections.

Autochthonous West Nile Virus Infection Outbreak in Humans (Asti, Piedmont, Italy, August-October 2018) and Long-Term Sequelae Follow-Up.

West Nile virus (WNV) infection is a reemerging zoonosis recently provoking significant outbreaks throughout Europe. During the summer of 2018, the number of WNV infections rose with a peak of new diagnoses of West Nile neuro-invasive disease (WNND). Most of the Italian cases were clustered in the Po River Valley. We present a case series of nine patients with WNV infection admitted to the Cardinal Massaia Hospital from 30 August 2018 to 1 October 2018. Demographic, immunovirological, clinical and therapeutic data are shown, and a report on clinical sequelae from the subsequent follow-up in patients with WNV and WNND. We showed the clinical, radiological and biochemical characteristics of WNV-infected patients. The risk factors and the clinical presentation of WNV in most patients in our case series were typical of that described in the literature, although, despite the high morbidity and mortality of WNND, we showed survival of 100% and long-term sequelae in only three patients. Environmental conditions may be essential in WNV outbreaks, and WNND can be clinically neurological multiform. Our long-lasting follow-up with clinical or radiological monitoring confirmed the morbidity of long-term neurological sequelae after WNND. Further studies are needed to investigate the epidemiology and physiopathology of bacterial superinfections after WNV infection.

Temocillin: Applications in Antimicrobial Stewardship as a Potential Carbapenem-Sparing Antibiotic.

Temocillin is an old antibiotic, but given its particular characteristics, it may be a suitable alternative to carbapenems for treating infections due to ESBL-producing Enterobacterales and uncomplicated UTI due to KPC-producers. In this narrative review, the main research question was to summarize current evidence on temocillin and its uses in infectious diseases. A search was run on PubMed using the terms ('Temocillin' [Mesh]) AND ('Infection' [Mesh]). Current knowledge regarding temocillin in urinary tract infection, blood-stream infections, pneumonia, intra-abdominal infections, central nervous system infections, skin and soft tissues infections, surgical sites infections and osteoarticular Infections were summarized. Temocillin retain a favourable profile on microbiota and risk of Clostridioides difficile infections and could be an option for treating outpatients. Temocillin may be a valuable tool to treat susceptible pathogens and for which a carbapenem could be spared. Other advantages in temocillin use are that it is well-tolerated; it is associated with a low rate of C. difficile infections; it is active against ESBL, AmpC, and KPC-producing Enterobacterales; and it can be used in the OPAT clinical setting.

Microbiological, Clinical, and PK/PD Features of the New Anti-Gram-Negative Antibiotics: ß-Lactam/ß-Lactamase Inhibitors in Combination and Cefiderocol-An All-Inclusive Guide for Clinicians.

Bacterial resistance mechanisms are continuously and rapidly evolving. This is particularly true for Gram-negative bacteria. Over the last decade, the strategy to develop new ß-lactam/ß-lactamase inhibitors (BLs/BLIs) combinations has paid off and results from phase 3 and real-world studies are becoming available for several compounds. Cefiderocol warrants a separate discussion for its peculiar mechanism of action. Considering the complexity of summarizing and integrating the emerging literature data of clinical outcomes, microbiological mechanisms, and pharmacokinetic/pharmacodynamic properties of the new BL/BLI and cefiderocol, we aimed to provide an overview of data on the following compounds: aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, cefiderocol, ceftaroline/avibactam, ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/relebactam, meropenem/nacubactam and meropenem/vaborbactam. Each compound is described in a dedicated section by experts in infectious diseases, microbiology, and pharmacology, with tables providing at-a-glance information.

Trichinella britovi outbreak in Piedmont, North-West Italy, 2019-2020: Clinical and epidemiological insights in the one health perspective.

BACKGROUND: Trichinellosis, a foodborne zoonosis due to nematodes of the genus Trichinella, occurs in the form of outbreaks following meat consumption. North Italy has been rarely involved. We report here the most significant wildlife derived trichinellosis outbreak ever registered in the Piedmont region. METHOD: We retrospectively included 96 outpatients referred to our institution (December 20th, 2019-January 15th, 2020) 2020 after consuming raw sausages prepared from a single wild boar hunted in the Susa Valley, 59 km away from Torino, in November 2019. RESULTS: We confirmed 35 cases and found additional 10 probable/suspected cases. Our cohort found that 47% of patients were symptomatic, with a median time from symptoms to presentation at clinic and serology testing of 14 days. Peripheral blood eosinophilia >500/µl and CK alterations were common. Further qualitative and quantitative analysis at the International Trichinella Reference Center c/o ISS, Rome identified T. britovi as the causative agent. CONCLUSIONS: No autochthonous human case has ever been detected in Torino province, and a single wild boar has tested positive for Trichinella since active surveillance was implemented in 2013. This outbreak should raise attention on the preventive role of veterinary surveillance and the need to optimize sampling procedures and targeted health education.

Beta Lactams Plus Daptomycin Combination Therapy for Infective Endocarditis: An Italian National Survey (BADAS).

BACKGROUND: infective endocarditis (IE) remains a severe disease frequently encountered in clinical practice and often requiring interdisciplinary medical and surgical management. This national survey aims to describe the clinical prescribing habits of the use of daptomycin in the setting of IE and the possible role for combination therapy with beta-lactams. METHODS: The study was a cross-sectional internet-based questionnaire survey on therapy with daptomycin. The questionnaire was designed with closed-ended questions and distributed using the SurveyMonkey® platform between October 2019 to December 2020. RESULTS: 55 clinicians from twelve Italians regions joined the questionnaire. The survey reported use of daptomycin as first-line choice in 31.48% of cases and as the first-line anti-MRSA agent in 44.44%. The empiric use of daptomycin was stated in the high suspicion of MRSA rather than MSSA, enterococcal or streptococcal IE. The rationale of daptomycin for the empirical treatment of native and prosthetic valve IE was mostly the possibility of administering an aminoglycoside-sparing combination regimen, high bacterial killing rate and high clinical efficacy. CONCLUSIONS: In conclusion, in selected patients, daptomycin could be a feasible option for the treatment of infective endocarditis in line with data from the European registry of daptomycin.