[Assessment of body mass index in patients with chronic hepatitis C who received an effective antiviral therapy].

AIM: To evaluate the body mass index (BMI) in patients with chronic hepatitis C (CHC) with different stages of liver fibrosis and steatosis who received effective antiviral therapy (AVT). MATERIALS AND METHODS: The study included 278 CHC patients with a sustained virologic response (SVR) at the end of treatment. In addition to assessing the investigational data to determine the clinical status of the patient, we calculated BMI (following the World Health Organization guidelines) and determined the severity of liver fibrosis (F) and steatosis (S) using transient elastography. The patients were assessed at the start of antiviral therapy, after ≥6 months from the moment SVR was confirmed, and then every 12 to 24 months. RESULTS: By the end of the study, the mean patient age was 49 years, 53% of them were men, and 34% of the patients were obese. Excessive weight gain was registered in 17% (n=48) of the cases, with 60% newly diagnosed with Class 1 to 2 obesity. Both before the start of AVT and years after reaching SVR, the mean BMI corresponded to the reference pre-obesity values, the liver steatosis was significantly more often absent in normal BMI; on the contrary, fatty liver (predominantly S2 to S3) was registered in individuals with elevated BMI (p<0.0001). After the long-term period following a successful therapy, Stage F4 liver fibrosis patients were mainly diagnosed with obesity (80% versus 44% before AVT; p=0.0010). CONCLUSION: The high proportion of patients with elevated BMI and liver steatosis seen years after a successful CHC therapy indicates a continued risk of progression of chronic liver disease. Such patients should be advised on how important it is to change their lifestyle to reduce overweight and prevent weight gain. We also need long-term assessments of how liver steatosis changes over time and what are the outcomes associated with post-SVR increase in BMI.

[Efficacy and safety of narlaprevir/ritonavir and daclatasvir non interferon combination in population of Russian patients with chronic hepatitis C].

AIM: Evaluate efficacy and safety of a combination of direct - acting antivirals narlaprevir/ritonavir with daclatasvir in patients with viral hepatitis C. MATERIALS AND METHODS: The study enrolled adult patients with HCV genotype 1b infection without demonstrated NS5A resistance - associated substitutions Y93C/H/N/S and/or L31F/M/V/I. Patients were treated with narlaprevir 200 mg QD, ritonavir 100 mg QD and daclatasvir 60 mg QD. Treatment duration was 12 weeks. Proportion of patients achieving sustained virological response 12 weeks after treatment (SVR12) was the primary efficacy endpoint. RESULTS AND DISCUSSION: In total, 105 (75.0%) patients were treatment with the study combination. Patients' age varied from 21 to 69 years, the mean age being 43.2±10.9 years. There were slightly more women (55.2%), and 69 patients (65.7%) had comorbidities. SVR 12 was 89.5% (95% CI 82.0-94.7%). In 10 of 11 patients with treatment failures NS5A resistance - associated substitutions in residues 31 and/or 93 were found, as well as less clinically relevant substitutions L28M, P58S, R30Q, Q62K. Adverse events (AEs) were found in less than one half of patients (45 patients, or 42.9% in the safety population). Almost all recorded AEs were mild to moderate. CONCLUSION: Efficacy of treatment with a combination of narlaprevir/ritonavir and daclatasvir in treatment - naïve patients with HCV genotype 1b was close to 90%. This combination was found to be safe and well - tolerated.

Inhibitory effect of streptococci on the growth of M. catarrhalis strains and the diversity of putative bacteriocin-like gene loci in the genomes of S. pneumoniae and its relatives.

S. pneumoniae is a facultative human pathogen causing a wide range of infections including the life-threatening pneumoniae or meningitis. It colonizes nasopharynx as well as its closest phylogenetic relatives S. pseudopneumoniae and S. mitis. Both the latter, despite the considerable morphological and phenotypic similarity with the pneumococcus, are considerably less pathogenic for humans and cause infections mainly in the immunocompromized hosts. In this work, we compared the inhibitory effect of S. pneumoniae and its relatives on the growth of Moraxella catarrhalis strains using the culture-based antagonistic test. We observed that the inhibitory effect of S. mitis strains is kept when a hydrogen peroxide produced by cells is inactivated by catalase, and even when the live cells are killed in chloroform vapors, in contrast to the pneumococcus whose inhibiting ability disappeared when the cells die. It was suggested that this effect may be due to the production of bacterial antimicrobial peptides by S. mitis, so we examined the genomes of our strains for the presence of bacteriocin-like peptides encoding genes. We observed that a set of bacteriocin-like genes in the genome of S. mitis is greatly poorer in comparison with S. pneumoniae one; moreover, in one S. mitis strain we found no bacteriocin-like genes. It could mean that there are probably some additional opportunities of S. mitis to inhibit the growth of competing neighbors which are still have to be discovered.

Mediators and Biomarkers of Inflammation in Meningitis: Cytokine and Peptidome Profiling of Cerebrospinal Fluid.

Differential diagnosis of bacterial and viral meningitis is an urgent problem of the modern clinical medicine. Early and accurate detection of meningitis etiology largely determines the strategy of its treatment and significantly increases the likelihood of a favorable outcome for the patient. In the present work, we analyzed the peptidome and cytokine profiles of cerebrospinal fluid (CSF) of 17 patients with meningitis of bacterial and viral etiology and of 20 neurologically healthy controls. In addition to the identified peptides (potential biomarkers), we found significant differences in the cytokine status of the CSF of the patients. We found that cut-off of 100 pg/ml of IL-1ß, TNF, and GM-CSF levels discriminates bacterial and viral meningitis with 100% specificity and selectivity. We demonstrated for the first time the reduction in the level of two cytokines, IL-13 and GM-CSF, in the CSF of patients with viral meningitis in comparison with the controls. The decrease in GM-CSF level in the CSF of patients with viral meningitis can be explained by a disproportionate increase in the levels of cytokines IL-10, IFN-γ, and IL-4, which inhibit the GM-CSF expression, whereas IL-1, IL-6, and TNF activate it. These observations suggest an additional approach for differential diagnosis of bacterial and viral meningitis based on the normalized ratio IL-10/IL-1ß and IL-10/TNF > 1, as well as on the ratio IFN-γ/IL-1ß and IFN-γ/TNF < 0.1. Our findings extend the panel of promising clinical and diagnostic biomarkers of viral and bacterial meningitis and reveal opposite changes in the cytokine expression in meningitis due to compensatory action of pro- and antiinflammatory factors.

[Possibilities of using cepeginterferon alpha-2b in double (cepeginterferon alfa-2b and ribavirin) and triple (simeprevir, cepeginterferon alpha-2b, and ribavirin) antiviral therapy regimens for chronic hepatitis C. A review of clinical trials and experience of everyday clinical practice]. / Vozmozhnosti primeneniia tsepeginterferona al'fa-2b v sostave dvukh- (tsepeginterferon al'fa-2b i ribavirin) i trekhkomponentnoi (simeprevir, tsepeginterferon al'fa-2b i ribavirin) skhem protivovirusnoi terapii khronicheskogo gepatita S. Obzor klinicheskikh issledovanii i opyta povsednevnoi klinicheskoi praktiki.

Since the incidence of chronic hepatitis C (CHC) increases steadily, the priority of national health care is to provide antiviral therapy (AVT) for the maximum number of patients infected with hepatitis C virus (HCV). The regimens including pegylated interferons (PEG-IFN) are still in demand in the Russian Federation. A number of clinical trials have been conducted to evaluate the efficacy and safety of cepeginterferon alpha-2b (cePEG-IFN alpha-2b), an original PEG-IFN-α developed in the Russian Federation. Their results have shown that cePEG-IFN alpha-2b in the two-component AVT regimen has at least no less clinical efficacy than PEG-IFN alpha-2b and PEG-INF alpha-2a in HCV monoinfected and HCV/HIV co-infected patients. The pooled analysis of data has indicated that the use of cePEG-IFN alpha-b in combination with ribavirin allows an average of 80% of the patients with HCV genotypes 2 and 3 and 62% of those with HCV genotype 1 to achieve a sustained virological response (SVR). In clinical practice when the two-component AVT regimen (cePEG-IFN alpha-b and ribavirin) was used in patients with early-stage CHC and mild fibrosis, SVR was recorded in 90.7% of the patients with HCV genotype 2/3 and in 75% of those with HCV genotype 1. The experience in using cePEG-IFN alpha-2b as a component of the three-component AVT regimen (simeprevir, cePEG IFN alfa-2b, and ribavirin) has been published. The observational program manly covered young patients with mild or moderate fibrosis. SVR was observed in 94% of the patients. Another paper describes the experience with the triple AVT therapy (simeprevir, cePEG-IFN alfa-2b, and ribavirin) in 22 patients, the majority of whom had advanced fibrosis. SVR was recorded in 71.4% of those who had completed treatment. Thus, an individual approach and assessment of predictive response factors to two- or three-component AVT regimens including cePEG-IFN alpha 2b can achieve successful treatment outcomes in most patients with CHC, which is, in some cases, more economically sound than interferon-free regimens used as first-line therapy.

[Immunogenetic predictors of a rapid virologic response to antiviral therapy in patients with chronic hepatitis C].

AIM: To determine the correlation between interleukin 28B (IL28B) gene polymorphism in patients with chronic hepatitis C (CHC), the presence or absence a rapid virologic response to antiviral therapy, and a number of immunological characteristics as a basis for a personalized approach to treating the patients. SUBJECTS AND METHODS: Seventeen CHC patients infected with hepatitis C virus genotype 1b were examined and underwent genetic testing for IL28B gene polymorphism for rs12979860 (CC, CT or TT genotypes) and rs8099917 (TT, TG or GG genotypes) using the modified method of adjacent samples, which revealed single nucleotide substitutions in the genes. Their immunological parameters were identified by a flow cytometry technique by taking into account whether a rapid virologic response had been achieved. RESULTS: The key phenomena of a rapid virologic response in the representatives of different IL28B genotypes are the nonspecific proliferative activity of blood natural killer cells before treatment, as well as the count of regulatory T cells before and 4 weeks after therapy start. CONCLUSION: To predict the efficiency of antiviral therapy for CHC, it is desirable to supplement genetic studies with immunological data.

[Outcomes of severe pandemic influenza A/H1N1/2009].

AIM: To study the outcomes of severe pandemic influenza A/H1N1/2009. SUBJECTS AND METHODS: The study enrolled 24 patients, including 8 males and 16 females (10 of whom were pregnant), aged 17 to 58 years, with a laboratorily verified diagnosis of pandemic influenza A/H1N1/2009, treated at the intensive care unit for the significant symptoms of acute respiratory failure (RF). Real-time RT-PCR was used to verify the diagnosis. Organs and tissues from deceased patients were histologically studied; chest computed tomography, body plethysmography, fibrobronchoscopy, breath test, and 6-minute walk test were performed in the late period. RESULTS: Within the first 30 days, a fatal outcome caused by therapy-resistant progressive RF was observed in 33% of the patients with pandemic influenza treated at the intensive care unit. Diffuse alveolar damage caused by influenza virus, which gives rise to hyaline membranes, underlies RF. Lung tissue fibrosis formed in recovered patients. CONCLUSION: The severity of pandemic influenza A/H1N1/2009 was determined by massive bilateral pneumonia, interstitial (alveolar) pulmonary edema, formation of diffuse bilateral lung fibrosis at the outcome of severe virus pneumonia (acute respiratory distress syndrome) with a decrease in vital and diffusing capacities, thereby generating a need to follow up this patient category and, possibly, to elaborate special rehabilitation programs.

Hepatitis B virus genetic typing using mass-spectrometry.

Mini-sequencing with subsequent result registration using MALDI-ToF mass-spectrometry was employed for hepatitis B virus genetic typing in Russian population. This approach was employed for hepatitis B virus genetic typing in HBsAg-positive patients with chronic hepatitis B, hepatitis of combined etiology and hepatic cirrhosis and allowed to show the prevalence of D genotype (83.3%) in all groups of patients. Other hepatitis B virus genotypes: genotype A (5.9%), genotype C (3.6%), and mixed infection with D and C (7.2%) were also found in patients with chronic hepatitis B and hepatic cirrhosis. All genotypes were found in patients with chronic hepatitis B and hepatic cirrhosis. Chronic hepatitis of combined etiology was noted only in patients with genotype D. Possibility of detection of mixed infection with hepatitis B viruses of various genotypes is a distinct advantage of mini-sequencing approach over direct nucleotide sequence evaluation for hepatitis B virus genetic typing.

[HCV genome variability in acute and chronic viral hepatitis C].

AIM: To evaluate HCV genome variability in acute and chronic phases of viral hepatitis C. MATERIAL AND METHODS: The study of heterogeneity of HCV in acute hepatitis C has detected genetic heterogeneity and variability of individual HCV population circulating in the blood. Significant genetic heterogeneity of HCV was observed in 1b, 2a and 3a genotypes. Variability of HCV did not depend on virus load. Genetic HCV structure changed significantly both in patients with manifest ALT deviations and in normal ALT, mean number of HCV genetic variants in these groups being the same. No significant correlations were found between virus concentration in the patient's blood, its variability and ALT values. Genetic heterogeneity of interferon-sensitive region of gene NS5A subtype 1b HCV was studied in blood of 16 patients with chronic hepatitis C resistant to interferon therapy. RESULTS: It is shown that genetic heterogeneity and variability of an individual HCV population circulating in blood serum can not be a prognostic criterion in assessment of variants of acute hepatitis C course. No mutations in ISDR region were found in 25% of 16 patients studied. 75% cases had 1-3 replacements of amino acid sequences, most frequent mutation was replacements in position 2218 (histidin/arginin). The above results are close to those obtained in Japanese and European populations. Results of ISDR sequence-analysis conducted before treatment may predict efficacy of interferon-alpha2 treatment in an individual patient in future. Large-scale trials are necessary for detection of mutations responsible for resistance to interferon-alpha2 in patients living in Russia.

[Blood levels of HbsAg in patients with different variants of chronic HBV-infection].

AIM: To estimate HbsAg in patients with different variants of chronic HBV infection. MATERIAL AND METHODS: Assay of HbsAg (IU/ml) in blood serum was made in 156 patients with chronic HBV infection (70 males and 86 females, age 19 to 78 years) using the test-system HbsAg Architect Lot 59665LF00 (Abbott) on the automatic analyzer Architect with construction of 4-parameter logistic curve. RESULTS: There are significant differences in the levels of HbsAg depending on the course of chronic HBV-infection: inactive carriers of HBV (12,884.14 +/- 5,512.26 IU/ml) had much lower blood levels of HbsAg than patients with HbeAg-negative (66,992.28 +/- 25,908.74 IU/ml) and HbeAg-positive chronic VHB (135,039.3 +/- 48,127.06 IU/ml) patients with chronic mixed hepatitis (82,783.12 +/- 21,001.34 IU/ml) and cirrhosis of HBV-etiology (67,477.86 +/- 24,081.9 IU/ml). No significant differences were found between two subgroups of pregnant women with or without viremia by HbsAg concentration in the blood. Maximal mean content of blood HbsAg was registered in patients with HbeAg-positive chronic hepatitis B. CONCLUSION: Significant differences in blood serum levels of HbsAg exist between patients with chronic viral hepatitis B and inactive carriers of HBV.

[Detection of the circulation of Crimean-Congo hemorrhagic fever virus in the piedmont steppes of the North Caucasus].

The laboratory verified cases of Crimean-Congo hemorrhagic fever (CCHF) in the piedmont steppes of the North Caucasus (Malgobeksky District, Republic of Ingushetia) are first described. The source of the first infection was Ixodidae ticks; three subsequent sources were contacts with the bloody discharges from patients. CCHF virus genome was detected in the blood of the cattle from an epidemic focus and in the pools of the Ixodes ticks Haemaphysalis parva Neum., 1897 and Boophilus annulatus Say, 1821, taken from cattle. The problem of including the piedmont steppes of the North Caucasus into the CCHF nosological area is discussed.

[Diagnostic significance of type IV collagen and hyaluronic acid in the serum of patients with chronic hepatitis C for staging hepatic fibrosis].

AIM: To evaluate diagnostic value of serologic fibrosis markers (hyaluronic acid--HA and type IV collagen C-IV) in patients with chronic hepatitis C (CHC) and hepatic cirrhosis (HC). MATERIAL AND METHODS: HA and C-IV were measured in 88 CHC patients with fibrosis stage 1 (n = 63) and 3 (n = 25), 13 patients with acute hepatitis C (AHC), 28 patients with hepatic cirrhosis (HC), 19 patients with pulmonary fibrosis (PF). The control group consisted of 32 healthy subjects. RESULTS: HA concentrations in the serum of CHC patients with mild to severe inflammation and fibrosis (F1 and F3) were normal (100 ng/ml). For HC diagnosis, HA test proved highly sensitive and specific (in HA 100 ng/ml sensitivity was 100%, specificity 84.6%), but this method cannot stage hepatic fibrosis. HA test was inferior to C-IV test. A mean C-IV concentration in the serum of CHC patients at the stage of marked fibrosis (F3) is significantly higher than in F1, in HC (A) patients higher than in patients with CHC F3. CONCLUSION: It is shown than concentration of C-IV above 196 ng/ml can differentiate fibrosis stage 1 from stage 3 with specificity 58.7 and sensitivity 88%.

[What surgeon must know about rabies and its treatment]. / Chto dolzhen znat' khirurg o beshenstve i ego lechenii.

From 1991 to 2002 10 patients with rabies were treated, all the patients died. Epidemiology, clinical picture, specific symptoms are described, rarity of this severe disease is noted. The necessity of urgent preventive vaccination immediately after bites is emphasized.

[Detection of type specific antibodies to hepatitis C virus NS4 protein in hepatitis C patients by enzyme immunoassay]. / Vyiavlenie tipospetsificheskikh anti-HCNS4-antitel u bol'nykh gepatitom C metodom immunofermentnogo analiza.

A multi-enzyme immmune-assay test system was designed for serotyping of genotypes hepatitis C virus (HCV) and a method of such typing of the serum of patients with hepatitis C was worked out. The above test-system was worked out on the basis of a study of 10 type-specific peptides modeling different fragments from NS4-protein variable region of HCV. The designed test system was evaluated by using a set of 42 serum samples obtained at random from patients with chronic hepatitis C, which had been preliminarily genotyped by polymerase chain reaction. The serotyping makes it possible to identify the type-specific antibodies in the blood sera of patients, including those cases when viremia was absent. Differences in the circulation of HCV in Moscow (Russia) and Vitebsk (Byelorussia) were established by using the designed test-system.

[Acute fatty gestational hepatosis in infectious and obstetrical clinic]. / Ostryi zhirovoi gepatoz beremennykh v infektsionnoi i akusherskoi klinike.

Moscow infection hospital N 1 admitted in 1970-2000 fifty seven pregnant women with acute fatty gestational hepatosis (AFGH). 10 women died. AFGH is a severe complication of pregnancy. It occurs rather rarely, has clinical variants, can be mistaken for infectious diseases, primarily for viral hepatitides. When AFGH diagnosis is verified, the patient must immediately deliver otherwise the prognosis is poor.

A multicentre, randomized study to evaluate the safety and efficacy of histamine dihydrochloride and interferon-alpha-2b for the treatment of chronic hepatitis C.

Interferon- (IFN-)alpha is currently the standard of care treatment for patients with chronic hepatitis C virus (HCV) infection. A significant part of the benefit of IFN-alpha in chronic hepatitis C is believed to be related to the activation of lymphocytes such as T cells and natural killer (NK) cells, which participate in the elimination of infected cells. Histamine dihydrochloride (HDC) has been shown to potentiate the IFN-alpha-induced activation of T cells and NK cells by a mechanism that involves the protection of these lymphocytes against oxygen radical-induced functional inhibition and apoptosis. This study was designed to examine the efficacy and safety of HDC in combination with IFN-alpha-2b in treatment-naïve patients with chronic HCV infection. All patients received IFN-alpha-2b, 3 MIU, three times weekly via subcutaneous injection, and were randomized to one of four HDC regimens (1 mg of either: once a day, three times a week; once a day, five times a week; twice a day, three times a week or; twice a day, five times a week). The doses of HDC in combination with IFN-alpha-2b resulted in sustained viral response rates ranging from 31% to 38%. Sustained biochemical response rates ranged from 28% to 41% across the four treatment groups. Patients infected with HCV genotype 1, and those with high baseline viral levels, which are characteristics associated with poor prognosis, had sustained virologic response rates ranging from 18% to 42% and 15% to 39%, respectively. Combination treatment was generally well tolerated. We propose that the potential benefit of HDC + IFN therapy for chronic HCV infection should be the focus of further investigation.

[Use of PCR for detection of positive (genomic) and negative (replicative) RNA chains of hepatitis C virus in the serum, lymphocytes, and liver of patients with chronic hepatitis C]. / Vyiavlenie pozitivnykh (genomnykh) i negativnykh (replikativnykh) tsepei RNK virusa gepatita C v syvorotke krovi, limfotsitakh i tkani pecheni bol'nykh khronicheskim gepatitom C s pomoshch'iu polimeraznoi tsepnoi reaktsii.

The presence of viral RNA in liver tissue and peripheral blood serum and lymphocytes of patients with chronic hepatitis C (CHC) was studied by polymerase chain reaction with nested primers on the 5'-untranslated region of hepatitis C virus (HCV) genome. Positive (genome) RNA was more often detected in the liver (81% cases) than in the peripheral blood serum (55%) or lymphocytes (64%). Active replication of HCV (presence of negative RNA chains) was observed only in the liver (in 37% cases). Correlation between the frequency of HCV RNA detection in the liver, blood cells and sera and parameters of the inflammatory process activity (SGPT level, histologic activity index and sclerosis index) was investigated. No relationship between the studied parameters was revealed. Positive correlation between the presence of HCV genome RNA in lymphocytes and serum was detected. A tendency to a decrease in the incidence of replicative RNA of the virus in liver tissue with increase in the activity of chronic hepatitis C was observed.