The significance of glial cell line-derived neurotrophic factor analysis in Progressive Supranuclear Palsy.

Progressive Supranuclear Palsy (PSP) is an atypical parkinsonism. Major subtypes of the disease: PSP-Richardson's Syndrome (PSP-RS) and PSP Parkinsonism Predominant (PSP-P) vary in clinical features, the pathomechanism remains unexplored. The aim of this work is to analyze the relevance of glial cell line-derived neurotrophic factor (GDNF) evaluation in the serum and cerebrospinal fluid (CSF) in PSP subtypes and to verify its significance as a possible factor in the in vivo examination. Authors assessed the concentration of GDNF in the serum and CSF of 12 patients with PSP-RS, 12 with PSP-P and 12 controls. Additionally authors evaluated patients using Unified Parkinson's Disease Rating Scale-III part (UPDRS-III), Frontal Assessment Battery (FAB) and Magnetic Resonance Imaging (MRI). The evaluation revealed significantly increased concentrations of GDNF in the CSF among PSP-RS patients and substantially increased concentrations of GDNF in the serum in PSP-P. Though the GDNF concentrations differentiated PSP subtypes, no correlations between with clinical factors were observed however certain correlations with atrophic changes in MRI were detected. GDNF is a factor which may impact the pathogenesis of PSP. Possible implementation of GDNF as a therapeutic factor could be a perspective in the search for therapy in this currently incurable disease.

Human Immunodeficiency Virus as a Risk Factor for Cardiovascular Disease.

The developments in HIV treatments have increased the life expectancy of people living with HIV (PLWH), a situation that makes cardiovascular disease (CVD) in that population as relevant as ever. PLWH are at increased risk of CVD, and our understanding of the underlying mechanisms is continually increasing. HIV infection is associated with elevated levels of multiple proinflammatory molecules, including IL-6, IL-1ß, VCAM-1, ICAM-1, TNF-α, TGF-ß, osteopontin, sCD14, hs-CRP, and D-dimer. Other currently examined mechanisms include CD4 + lymphocyte depletion, increased intestinal permeability, microbial translocation, and altered cholesterol metabolism. Antiretroviral therapy (ART) leads to decreases in the concentrations of the majority of proinflammatory molecules, although most remain higher than in the general population. Moreover, adverse effects of ART also play an important role in increased CVD risk, especially in the era of rapid advancement of new therapeutical options. Nevertheless, it is currently believed that HIV plays a more significant role in the development of metabolic syndromes than treatment-associated factors. PLWH being more prone to develop CVD is also due to the higher prevalence of smoking and chronic coinfections with viruses such as HCV and HBV. For these reasons, it is crucial to consider HIV a possible causal factor in CVD occurrence, especially among young patients or individuals without common CVD risk factors.

Comparison between patients who interrupted ART and those with late HIV diagnosis.

Early diagnosis of human immunodeficiency virus (HIV) and retention in care are cornerstones of better prognosis of people living with HIV (PLWH). The purpose of this study was to compare patients who discontinued antiretroviral treatment (ART) with those who were diagnosed late with HIV. In this retrospective analysis of PLWH under the care of one of the Infectious Diseases Clinics in Poland between 2020 and 2021, two sub-analyses were carried out. One comparing patients who relinked to care after treatment interruption ("Group A") with those who had late HIV diagnosis ("Group B"), another comparing group A to those who were adherent to ART ("Group C"). 215 patients were included in this study (Group A = 47, Group B = 53, Group C = 115). Those who discontinued ART more often used actively drugs (p = 0.001) in comparison to those with late HIV diagnosis. In both bivariate and multivariable analysis migrants were more often diagnosed late with HIV than interrupted ART (p = 0.004 and 0.015, respectively). In the second analysis, in the multivariable analysis female sex was not associated with treatment interruption, whereas active drug usage was. People using drugs have a higher risk of ART interruption. Migrants are more at risk of late HIV diagnosis. Adequate interventions should be made towards both groups.

Changes in Primary HIV-1 Drug Resistance Due to War Migration from Eastern Europe.

In recent years, especially as a result of war in Ukraine, enormous movements of migration to Poland from eastern European countries have been reported, including people living with Human Immunodeficiency Virus (HIV). We have conducted multi-center, prospective study, which aimed to establish HIV-1 subtype and assess the presence of primary drug resistance mutations to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors in antiretroviral treatment naïve patients. The clinical trial recruited 117 individuals during 2 years period (2020-2022). The prevalence of HIV-1 subtype A was statistically significantly more frequent in Ukrainian, and HIV-1 subtype B in Polish patients (p < 0.05). Drug resistance mutations were detected in 44% of all cases and the comparison of presence of mutations in the analyzed groups, as well as in the subgroups of subtype A and B HIV-1 has not revealed any significant differences (p > 0.05), nevertheless Polish patients had multidrug resistance mutations more frequent (p < 0.05). The results from our trial show no increased risk of transmission of multidrug resistant HIV strains in our cohort of Ukrainian migrants.Clinical trials. Gov number NCT04636736; date of registration: November 19, 2020.

Clinical Phenotypes of Progressive Supranuclear Palsy-The Differences in Interleukin Patterns.

Progressive supranuclear palsy (PSP) is an atypical parkinsonian syndrome based on tau pathology; its clinical phenotype differs, but PSP with Richardson's syndrome (PSP-RS) and the PSP parkinsonism predominant (PSP-P) variant remain the two most common manifestations. Neuroinflammation is involved in the course of the disease and may cause neurodegeneration. However, an up-to-date cytokine profile has not been assessed in different PSP phenotypes. This study aimed to evaluate possible differences in neuroinflammatory patterns between the two most common PSP phenotypes. Serum and cerebrospinal fluid (CSF) concentrations of interleukin-1 beta (IL-1ß) and IL-6 were analyzed using enzyme-linked immunosorbent assay (ELISA) kits in 36 study participants-12 healthy controls and 24 patients with a clinical diagnosis of PSP-12 PSP-RS and 12 PSP-P. Disease duration among PSP patients ranged from three to six years. All participants underwent basic biochemical testing, and neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) values were calculated. Due to a lack of neuropathological examinations, as all patients remain alive, total tau levels were assessed in the CSF. Tau levels were significantly higher in the PSP-P and PSP-RS groups compared to the healthy controls. The lowest concentrations of serum and CSF interleukins were observed in PSP-RS patients, whereas PSP-P patients and healthy controls had significantly higher interleukin concentrations. Furthermore, there was a significant correlation between serum IL-6 levels and PLR in PSP-RS patients. The results indicate the existence of distinct neuroinflammatory patterns or a neuroprotective role of increased inflammatory activity, which could cause the differences between PSPS phenotypes and clinical course. The causality of the correlations described requires further studies to be confirmed.

Central nervous system disorders after use of dolutegravir: evidence from preclinical and clinical studies.

The evaluation of dolutegravir based on available preclinical and clinical studies reveals a risk of central nervous system (CNS) disorders associated with long-term use of the drug. The available literature on the pharmacokinetics of the drug, including its penetration of the blood-brain barrier, was reviewed, as well as clinical trials assessing the incidence of adverse effects in the CNS and the frequency of its discontinuation. This paper also summarizes the impact of factors affecting the occurrence of CNS disorders and indicates the key role of pharmacovigilance in the process of supplementing knowledge on the safety of drugs, especially those that are newly registered.

The prevalence of smoking cigarettes among HIV-infected patients after a decade. Single-center analysis.

OBJECTIVES: Smoking habit is known to be a risk factor for the development of multiple diseases and conditions, premature death, and worse quality of life. The prevalence of smoking in PLWH is 2-3 times higher than in the general population. The study aimed to evaluate how the prevalence of smoking has changed among PLWH over the past decade. METHODS: The data of n=204 PLWH hospitalized from November 2018 to November 2019 was analyzed. All patients filled out the survey including age, gender, the number of cigarettes smoked, the number of years as a smoker, and the impact of HIV diagnosis on the number of cigarettes smoked. The data was compared to a similar analysis performed in our department in 2009. RESULTS: The study showed a decrease in the prevalence of smoking among PLWH over the past decade. In comparison to 2009, a statistically significant (p<0.05) reduction in the number of smoking individuals among ever and never smokers was observed both in males and in females. CONCLUSIONS: The prevalence of smoking cigarettes among PLWH in our department has significantly decreased since 2009 but remains much higher than in the general population. Smoking cessation interventions provided by HIV care professionals are necessary and should be continued among PLWH.

Rapid-progressing progressive multifocal leukoencephalopathy in two patients newly diagnosed with HIV: case series and review of literature.

The JC Polyomavirus (JCPyV) is a virus of global distribution and is usually kept under control by the immune system. In patients with AIDS, a latent JCPyV infection can reactivate and develop into progressive multifocal leukoencephalopathy (PML). Around half of the patients with PML die within 2 years since the diagnosis, yet in rare cases, the disease advances significantly quicker and seems to be insusceptible to any medical actions. In our clinic, we observed two cases of such course in HIV-positive patients in the AIDS stage. On admission, both patients had mild neurological symptoms such as dizziness, vision disturbances, and muscle weakness. Both had extremely low CD4 lymphocyte count (7 cells/µL, 40 cells/µL) and high HIV-1 viral load (VL) (50,324 copies/ml, 78,334 copies/ml). PML was confirmed by PCR for JCPyV DNA in cerebrospinal fluid (CSF) coupled with clinical and radiological features. Despite receiving though antiretroviral (ARV) treatment paired with intra-venous (IV) steroids, the disease progressed rapidly with neurological manifestations exacerbating throughout the few weeks following the admission. Eventually, both patients developed respiratory failure and died within less than 3 months after the onset of the neurological symptoms. Even though such curse of the disease is not common, it should be a warning to all how deadly both PML and AIDS can be and remind doctors to offer testing even to asymptomatic patients.

Long-term Administration of 3-Di-O-Tolylguanidine Modulates Spatial Learning and Memory in Rats and Causes Transition in the Concentration of Neurotransmitters in the Hippocampus, Prefrontal Cortex and Striatum.

The sigma-1 and sigma-2 (σ1 and σ2) receptors are found in high concentrations in the brain, and their altered expression leads to a variety of neuropsychiatric disorders. 3-di-tolylguanidine (DTG) stimulates the activity of both of these receptors. We assessed the effects of administering DTG to adult male Sprague Dawley rats on learning and memory consolidation processes and on the levels of neurotransmitters in selected brain structures. Spatial learning and memory were evaluated in the water maze test. The DTG was administered orally at daily doses of 3 mg/kg (DTG3), 10 mg/kg (DTG10) or 30 mg/kg (DTG30) for 10 weeks before and during the water-maze test. After completion of the experiment, the concentration of monoamines and their metabolites as well as amino acids in structures involved in cognitive performance - the hippocampus, prefrontal cortex, and striatum - were determined using high performance liquid chromatography (HPLC). The DTG10 group showed an improvement in memory processes related to the "new" platform location, whereas the DTG30 group was worse at finding the "old" platform location. Since the administration of DTG led to differences in dopaminergic transmission, it was assumed to influence memory processes in this way. Changes in histidine, serine, alanine, taurine, and glutamic acid levels in selected structures of the brains of rats with memory impairment were also observed. We conclude that long-term administration of DTG modulates spatial learning and memory in rats and changes the concentrations of neurotransmitters in the hippocampus, prefrontal cortex, and striatum..

Delayed HIV diagnosis during the COVID-19 pandemic in Poland: A call for targeted HIV testing for those under suspicion of SARS-CoV-2.

OBJECTIVES: The aim of this study was to analyse patients newly diagnosed with HIV who were originally admitted to hospitals with suspicion of COVID-19. METHODS: This was a retrospective case series undertaken at four sites. Only adults with new HIV diagnosis and COVID-19 exclusion hospitalized in 2020-2021 were included. Demographic, clinical and laboratory data were collected from medical records. RESULTS: Twenty-five patients were included in the analysis: 19 men (76%), 11 of Ukrainian origin (44%). The median age was 38.5 years (range 25-59). The mode of HIV transmission was heterosexual for 11 (44%) patients, eight (32%) were men who have sex with men and three (12%) were people who inject drugs. The median duration of symptoms prior to hospital presentation was 20.6 days (range 3-90). The median number of SARS-CoV-2 tests per patient was 2.62 (range 1-7). All SARS-CoV-2 tests were negative. Screening for HIV was performed on average on the 18th day of hospitalization (range 1-36 days). Twenty-three patients (92%) were late presenters, 22 (88%) had advanced disease, and 19 (76%) were in the AIDS stage. The median CD4 T-cell count was 72 cells/µL (range 3-382). The rate of positive HIV testing at the two sites where it was available for people with suspected COVID-19 was 0.13% (7/5458 during the study period). CONCLUSIONS: We strongly recommend introducing the HIV screening test in the diagnostic algorithm for every patient suspected of having COVID-19, presenting with clinical and/or radiological pulmonary symptoms.

Evaluation of Clinical Biomarkers Related to CD4 Recovery in HIV-Infected Patients-5-Year Observation.

Human Immunodeficiency Virus infection leads to the impairment of immune system function. Even long-term antiretroviral therapy uncommonly leads to the normalization of CD4 count and CD4:CD8 ratio. The aim of this study was to evaluate possible clinical biomarkers which may be related to CD4 and CD4:CD8 ratio recovery among HIV-infected patients with long-term antiretroviral therapy. The study included 68 HIV-infected patients undergoing sustained antiretroviral treatment for a minimum of 5 years. Clinical biomarkers such as age, gender, advancement of HIV infection, coinfections, comorbidities and applied ART regimens were analyzed in relation to the rates of CD4 and CD4:CD8 increase and normalization rates. The results showed that higher rates of CD4 normalization are associated with younger age (p = 0.034), higher CD4 count (p = 0.034) and starting the therapy during acute HIV infection (p = 0.012). Higher rates of CD4:CD8 ratio normalization are correlated with higher CD4 cell count (p = 0.022), high HIV viral load (p = 0.006) and acute HIV infection (p = 0.013). We did not observe statistically significant differences in CD4 recovery depending on gender, HCV/HBV coinfections, comorbidities and opportunistic infections. The obtained results advocate for current recommendations of introducing antiretroviral therapy as soon as possible, preferably during acute HIV infection, since it increases the chances of sufficient immune reconstruction.

Frailty and prefrailty in people living with HIV, with focus on women living with HIV.

With the increasing lifespan of people living with HIV (PLWH), frailty and prefrailty are becoming topics which require more attention. The reciprocal interactions between chronic inflammation, comorbidities and frailty demonstrate the complex pathophysiology of frailty and its consequences. Female sex, HIV infection without antiretroviral treatment, reduced CD4 cell count, depression and cardiovascular disease are some of the risk factors for frailty among PLWH. Frailty predisposes to falls and can therefore lead to more frequent fractures, hospitalization and death, especially in women with osteoporosis. Continuous antiretroviral treatment, prevention of comorbidities such as depression and diagnosis of prefrailty are crucial interventions to slow the development of frailty. This review summarizes the literature on frailty in people living with HIV and discusses frailty management strategies in order to improve the health outcomes in women living with HIV.

Inflammatory Bowel Disease in Adult HIV-Infected Patients-Is Sexually Transmitted Infections Misdiagnosis Possible?

BACKGROUND: The aim of our study was to describe 50 cases of inflammatory bowel disease (IBD) and HIV co-existence that are under medical supervision in Warsaw. METHODS: This was a retrospective descriptive study. Fifty HIV-infected patients, diagnosed with IBD during the years 2001-2019, were identified. IBD was diagnosed endoscopically and then confirmed by biopsy. All data was obtained from medical records. RESULTS: All studied patients were male with a median age of 33 years old (range 20-58 years). All, except one, were men who have sex with men (MSM). The median CD4 cell count was 482 cells/µL (range 165-1073 cells/µL). Crohn's disease (CD) was diagnosed in 7 patients (14%), ulcerative colitis (UC) in 41 patients (82%), and 2 patients (4%) had indeterminate colitis. Forty-nine patients (98%) reported a history of unprotected receptive anal intercourse and different sexual transmitted infections (STIs). Only in 10 patients (20%) were one or more IBD relapses observed. CONCLUSIONS: We recommend HIV testing for every MSM with IBD suspicion. Moreover, STIs testing should be performed in every IBD patient with colorectal inflammation, using molecular and serological methods. Persons who reported unprotected receptive anal intercourse seem to have the biggest risk of STI-associated proctitis or proctocolitis mimicking IBD.

Adenovirus 36 Infection in People Living with HIV-An Epidemiological Study of Seroprevalence and Associations with Cardiovascular Risk Factors.

Background. With the life expectancy of people living with HIV (PLHIV) rapidly approaching that of the general population, cardiovascular health in this group is as relevant as ever. Adenovirus 36 (Adv36) is one of the few viruses suspected to be a causative factor in promoting obesity in humans, yet there is a lack of data on this infection in PLHIV. Methods. PLHIV on stable suppressive antiretroviral therapy were included in the study, with assessment of anthropometric measures, blood pressure, serum lipid levels, fasting serum glucose and insulin, non-classical serum cardiovascular risk markers related to inflammation (hsCRP, resistin, calprotectin), and anti-Adv36 antibodies during a routine check-up. Results. 91 participants were recruited, of which 26.4% were Adv36-seropositive (Adv36(+)). Compared to Adv36-seronegative (Adv36(−)) controls, Adv36(+) individuals had a lower waist circumference (Adv36(+) 89.6 ± 7.7 cm, Adv36(−) 95.5 ± 11.7 cm, p = 0.024) and a lower waist-to-hip ratio (Adv36(+) 0.88 ± 0.06, Adv36(−) 0.92 ± 0.09, p = 0.014), but this did not reach statistical significance in the multivariate analysis (p > 0.05). Adv36(+) participants were less likely to be on lipid-lowering treatment (Adv36(+) 12.5%, Adv36(−) 34.3%, p = 0.042), even after adjustment for relevant baseline characteristics (OR = 0.23, 95%CI = 0.04−0.91), but no differences in cholesterol or triglyceride levels were found. No other statistically significant associations were observed. Conclusions. We found no evidence to support the claim that past Adv36-infection is associated with an increased prevalence of cardiovascular risk factors or with elevated inflammatory markers in PLHIV. More research is needed to replicate these findings in other samples of PLHIV and to compare them with the HIV-negative population.

VCAM-1 as a Biomarker of Endothelial Function among HIV-Infected Patients Receiving and Not Receiving Antiretroviral Therapy.

The Human Immunodeficiency Virus and retroviral therapy are both known risk factors for cardiovascular disease. It remains an open question whether HIV or ARV leads to increased arterial inflammation. The objective of this study was to investigate the changes in endothelial activation by measuring VCAM-1 levels among HIV-infected patients who were and were not treated with antiretroviral therapy. It is a retrospective study that included 68 HIV-infected patients, 23 of whom were never antiretroviral-treated, 15 who were ART-treated for no longer than a year, and 30 who were ART-treated for longer than a year. Blood samples were collected for biochemical analysis of the concentration of VCAM-1. The results show a statistically lower VCAM-1 level (p = 0.007) in patients treated with ART longer than a year (1442 ng/mL) in comparison to treatment-naïve patients (2392 ng/mL). The average VCAM-1 level in patients treated no longer than a year (1552 ng/mL) was also lower than in treatment-naïve patients, but with no statistical significance (p = 0.096). Long-term antiretroviral therapy was associated with the decline of VCAM-1 concentration. That may suggest the lowering of endothelial activation and the decreased risk of the development of cardiovascular disease among ARV-treated patients. However, VCAM-1 may not be a sufficient factor itself to assess this, since simultaneously there are a lot of well-known cardiovascular-adverse effects of ART.

Significance of Vascular Cell Adhesion Molecule-1 and Tumor Necrosis Factor-Alpha in HIV-Infected Patients.

BACKGROUND: The aim of this study was the evaluation of the correlation between VCAM-1 and TNF-alpha serum concentrations and various clinical and laboratory parameters in HIV-infected patients. METHODS: All included subjects were patients of the Department of Infectious and Tropical Diseases and Hepatology of the Medical University of Warsaw in Poland in the years 2014-2016. The inclusion criteria were: confirmed HIV infection, Caucasian origin, and age > 18 years old. PCT, CRP, serum HIV-1 RNA, CD4/CD8 T cell count, PCR HCV RNA, HBsAg, VCAM-1, and TNF-alpha were measured. The VCAM-1 and TNF-alpha serum levels were evaluated by ELISA. RESULTS: Seventy-two HIV-infected patients were included (16 women and 56 men: mean age 38.7 years, 66.6% cigarette smokers, 34.7% HCV co-infected HCV, and 27.8% ART-naïve). VCAM-1 concentrations were significantly higher in HIV/HCV co-infected patients than in HIV mono-infected patients (125.6 ± 85.4 vs. 78.4 ± 58.6 ng/mL, p = 0.011) and ART-naïve in comparison to patients on cART (121.9 ± 76.5 vs. 69.4 ± 57.1 ng/mL, p = 0.003). The significant positive correlation between HCV-infection and VCAM-1 and negative correlation between cART use and VCAM-1 was confirmed in multivariate analyses. The only variable associated significantly with TNF-alpha concentration was lymphocytes T CD8+ cell count (p = 0.026, estimate = 0.033). CONCLUSIONS: Successful cART and HCV eradication seemed to play an important role in the reduction of endothelial dysfunction and persistent inflammation in HIV-infected patients. CD8 T cell count seemed to be one of the markers of the pro-inflammatory state in HIV-infection patients.

Impact of Combined Antiretroviral Therapy on Metabolic Syndrome Components in Adult People Living with HIV: A Literature Review.

The development of metabolic derangements as a result of HIV treatment has been an important area of research since the introduction of zidovudine in the 1980's. Antiretroviral therapy has intensely evolved in the last three decades, with new drugs gradually incorporated into everyday clinical practice. With the life expectancy of people living with HIV rapidly approaching that of their HIV-negative counterparts, the influence of these antiretrovirals on the development of the components of the metabolic syndrome remains of major interest to clinicians and their patients. In this review, we aimed to discuss the impact of cART on components of the metabolic syndrome, i.e., weight, plasma lipid levels, plasma glucose levels, and blood pressure, describing the influence of cART classes and of individual antiretrovirals. We also aimed to outline the limitations of the research conducted to date and the remaining knowledge gaps in this area.

Challenges in diagnosing fever in traveler returning from tropical ares - is it dengue or chikungunya? Case report.

Arthropod-borne viral infections caused by dengue virus (DENV) and chikungunya virus (CHIKV) are prevalent in the same regions and are spread by the same mosquito type (Aedes) and have similar clinical manifestations. This study emphasized the challenges of diagnosing fever in a patient returning from a tropical area. We report a case of a 52-year-old patient who presented with fever, myalgia, and headache after travelling to Laos and Thailand. After ten days of the disease, the diagnosis of chikungunya was made. Recent travel history should be a standard part of assessment when consulting febrile patients and is essential for further diagnosis. Malaria should permanently be excluded from travellers returning from tropical regions with fever. In the differential diagnosis, dengue, chikungunya, and other mosquito-borne infections should be considered. Patients wishing to travel to such areas need to be educated beforehand on the necessary preventative measures.

Change in γ-glutamyl transpeptidase activity as a useful tool in identifying a group of patients with elevated risk of hepatocellular carcinoma development after DAA treatment of chronic hepatitis C.

AIM OF THE STUDY: Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) incidence will be diminishing due to use of direct acting antiviral agents (DAA), but there is still constant risk for HCC development. Elevated serum g-glutamyl transpeptidase (GGT) activity is associated with increased risk of liver cancer. In our study we tried to determine whether change in GGT activity may be useful in identifying patients with elevated risk of HCC development after DAA treatment. MATERIAL AND METHODS: The study population consisted of 111 patients with chronic hepatitis C (CHC) treated with DAA. Laboratory tests [alanine aminotransferase (ALT), GGT, a-fetoprotein (AFP)] and liver stiffness measurement (using FibroScan) were performed at the beginning and at the end of therapy. RESULTS: Pre-treatment ALT activity, GGT activity and AFP concentration in patients with CHC were directly associated with the stage of liver fibrosis. Elimination of HCV after DAA treatment caused significant reduction in serum GGT activity and was not associated with pre-treatment liver fibrosis. AFP concentration was significantly lower after treatment. It was observed regardless of pre-treatment AFP concentration, but the largest reduction was demonstrated in the group of patients with advanced fibrosis. In multivariate analysis there was no significant difference in GGT activity after treatment only in patients with pre-treatment normal AFP concentration and advanced liver fibrosis. CONCLUSIONS: Patients who after achieving a sustained virological response (SVR) did not lower both AFP concentration and GGT activity may have higher risk of HCC development. Special monitoring may be required in patients with advanced liver fibrosis and normal AFP concentration before treatment.