Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-blind, randomised, placebo-controlled, phase 3 trial in Turkey.

BACKGROUND: CoronaVac, an inactivated whole-virion SARS-CoV-2 vaccine, has been shown to be well tolerated with a good safety profile in individuals aged 18 years and older in phase 1/2 trials, and provided a good humoral response against SARS-CoV-2. We present the interim efficacy and safety results of a phase 3 clinical trial of CoronaVac in Turkey. METHODS: This was a double-blind, randomised, placebo-controlled phase 3 trial. Volunteers aged 18-59 years with no history of COVID-19 and with negative PCR and antibody test results for SARS-CoV-2 were enrolled at 24 centres in Turkey. Exclusion criteria included (but were not limited to) immunosuppressive therapy (including steroids) within the past 6 months, bleeding disorders, asplenia, and receipt of any blood products or immunoglobulins within the past 3 months. The K1 cohort consisted of health-care workers (randomised in a 1:1 ratio), and individuals other than health-care workers were also recruited into the K2 cohort (randomised in a 2:1 ratio) using an interactive web response system. The study vaccine was 3 µg inactivated SARS-CoV-2 virion adsorbed to aluminium hydroxide in a 0·5 mL aqueous suspension. Participants received either vaccine or placebo (consisting of all vaccine components except inactivated virus) intramuscularly on days 0 and 14. The primary efficacy outcome was the prevention of PCR-confirmed symptomatic COVID-19 at least 14 days after the second dose in the per protocol population. Safety analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov (NCT04582344) and is active but no longer recruiting. FINDINGS: Among 11 303 volunteers screened between Sept 14, 2020, and Jan 5, 2021, 10 218 were randomly allocated. After exclusion of four participants from the vaccine group because of protocol deviations, the intention-to-treat group consisted of 10 214 participants (6646 [65·1%] in the vaccine group and 3568 [34·9%] in the placebo group) and the per protocol group consisted of 10 029 participants (6559 [65·4%] and 3470 [34·6%]) who received two doses of vaccine or placebo. During a median follow-up period of 43 days (IQR 36-48), nine cases of PCR-confirmed symptomatic COVID-19 were reported in the vaccine group (31·7 cases [14·6-59·3] per 1000 person-years) and 32 cases were reported in the placebo group (192·3 cases [135·7-261·1] per 1000 person-years) 14 days or more after the second dose, yielding a vaccine efficacy of 83·5% (95% CI 65·4-92·1; p<0·0001). The frequencies of any adverse events were 1259 (18·9%) in the vaccine group and 603 (16·9%) in the placebo group (p=0·0108) with no fatalities or grade 4 adverse events. The most common systemic adverse event was fatigue (546 [8·2%] participants in the vaccine group and 248 [7·0%] the placebo group, p=0·0228). Injection-site pain was the most frequent local adverse event (157 [2·4%] in the vaccine group and 40 [1·1%] in the placebo group, p<0·0001). INTERPRETATION: CoronaVac has high efficacy against PCR-confirmed symptomatic COVID-19 with a good safety and tolerability profile. FUNDING: Turkish Health Institutes Association.

Occult hepatitis B infection in Turkish HIV-infected patients: A multicentre, retrospective, cross-sectional study, Schindler study.

OBJECTIVE: Occult hepatitis B infection (OHBI) appears to have a higher prevalence in populations at high risk for hepatitis B virus (HBV) infection with concomitant liver disease. The aim was to assess the prevalence of OHBI in a sample of human immunodeficiency virus -1 positive and HBV surface antigen-negative (HIV-1+/HBsAg-) Turkish patients. METHODS: Ten centres in Turkey were included in the study. Patients were selected on the basis of a power calculation with a known population size of HIV-positive patients and a reported prevalence of OHBI. Gender, age, occupation, place of residence, treatment and clinical status, and laboratory results, including immunodeficiency panel, antibody tests, hemogram, biochemistry, and coagulation studies were evaluated retrospectively. RESULTS: The number of HIV-infected patients followed in these centres was 3172 and the sample population numbered 278. All 278 were HBsAg negative. The mean age of the sample was 37.2 ± 13.1 years and 235 (84.5%) were male. All but one patient (99.6%) had been treated with antiretroviral therapy. Of the 278 patients, 169 (60.6%) were positive for Anti-HBs and 125 (44.8%) were positive for Anti-HBc IgG. HIV RNA was detected in 203/278 (73%) of the patients. Four HBV DNA (1.4%) were diagnosed with OHBI. There was no significant difference in hemogram, hemoglobin or bilirubin concentrations in those with OHBI compared with the other patients. CONCLUSION: In a representative sample of HIV+ patients from 10 Turkish centres, the prevalence of OHBI was found to be 1.4%. In HIV positive patients, it is important to identify those with OHBI for optimal clinical management and prognosis.

Low recurrence rate of hepatocellular carcinoma following ledipasvir and sofosbuvir treatment in a real-world chronic hepatitis C patients cohort.

The aims of the present study were to evaluate the efficacy and tolerability of ledipasvir/sofosbuvir (LDV/SOF) with or without ribavirin in the treatment of chronic hepatitis C (CHC) in patients with advanced liver disease and to analyse whether the use of LDV/SOF treatment is associated with a new occurrence of hepatocellular carcinoma (HCC) during and after LDV/SOF treatment. The Turkish Early Access Program provided LDV/SOF treatment to a total of 200 eligible CHC patients with advanced liver disease. The median follow-up period was 22 months. All patients were Caucasian, 84% were infected with genotype 1b, and 24% had a liver transplantation before treatment. The sustained virological response (SVR12) was 86.0% with ITT analysis. SVR12 was similar among patients with Child-Pugh classes A, B and C disease and transplant recipients. From baseline to SVR12, serum ALT level and MELD score were significantly improved (P < 0.001). LDV/SOF treatment was generally well tolerated. Only one patient developed a new diagnosed HCC. Seventeen of the 35 patients, who had a history of previous HCC, developed HCC recurrence during the LDV/SOF treatment or by a median follow-up of 6 months after treatment. HCC recurrence was less commonly observed in patients who received curative treatment for HCC compared with those patients who received noncurative treatment (P = 0.007). In conclusion, LDV/SOF with or without ribavirin is an effective and tolerable treatment in CHC patients with advanced liver disease. Eradication is associated with improvements in liver function and a reduced risk of developing a new occurrence of HCC.

Daclatasvir plus asunaprevir dual therapy for chronic HCV genotype 1b infection: results of Turkish early access program.

 Background. Daclatasvir and asunaprevir dual therapy is approved for the treatment of HCV genotype 1b infection in several countries. AIM: To evaluate the efficacy and safety of daclatasvir and asunaprevir dual therapy in Turkish patients. MATERIAL AND METHODS: Sixty-one patients with HCV genotype 1b were enrolled in the Turkish early access program. Most of the patients were in difficult-to-treat category. Patients were visited at each 4 week throughout the follow-up period. Laboratory findings and adverse events were recorded at each visit. RESULTS: Fifty-seven of 61 enrolled patients completed 24 weeks of treatment. Two patients died as a result of underlying diseases at 12-14th weeks of treatment. Two patients stopped the treatment early as a consequence of virological breakthrough, and 2 patients had viral relapse at the post-treatment follow-up. Overall SVR12 rates were 90% (55/61) and 93.2% (55/59) according to intention-to-treat (ITT) and per protocol (PP) analysis respectively. In ITT analysis, SVR12 was achieved by 93% (13/14) in relapsers, 80% (12/15) in interferon-ineligible patients and 91% (20/22) in previous nonresponder patients. SVR12 rates were 86.5% and 91.4% in patients with cirrhosis according to ITT and PP analysis respectively. SVR12 was 95.8% in non-cirrhosis group in both analysis. Patients with previous protease inhibitor experience had an SVR12 of 87.5%. Common adverse events developed in 28.8% of patients. There were no treatment related severe adverse event or grade-4 laboratory abnormality. CONCLUSIONS: Daclatasvir and asunaprevir dual therapy is found to be effective and safe in difficult-to-treat Turkish patients with HCV genotype 1b infection.

Evaluation of hepatitis B virus transmission and antiviral therapy among hepatitis B surface antigen-positive pregnant women.

AIM: The aim of the present study was to assess the potential risk of hepatitis B virus (HBV) vertical transmission among Turkish parturient women and to evaluate the efficacy and safety of antiviral agents. MATERIAL AND METHODS: Data were collected retrospectively from 114 HBV-infected pregnant women and their infants in eight health institutions in Turkey. RESULTS: The baseline characteristics of the women were: mean age, 28.3 ± 5.2 years; alanine aminotransferase, 57.4 ± 139.0 U/L; aspartate aminotransferase, 56.6 ± 150.0 U/L; and HBV DNA, 8.3 × 10(7) ± 2.6 × 10(8) copies/mL. Family history of HBV infection was detected in 53.5% (n = 61). In total, 60 (52.6%) pregnant women received tenofovir (60.0%), lamivudine (33.3%) or telbivudine (6.7%) therapy at the median gestational age of 22.2 ± 8.5 (1-36) weeks. All infants were vaccinated and hepatitis B immune globulin was administered, with 81 of them (71.1%) available for follow-up. After completion of HBV vaccination course, 71 (87.7%) infants had protective anti-HBs levels, three (3.7%) were hepatitis B surface antigen-positive, and seven (8.6%) were hepatitis B surface antigen-negative with nonprotective anti-HBs levels. Five of the infants had low gestational birthweight but no other birth defects were observed. CONCLUSION: According to our results, viral load may not be the only effecting factor for transmission of HBV to children of infected mothers. Pregnant women with high viral load should be followed-up closely during pregnancy. They should begin to take tenofovir or telbivudine, which are category B drugs for pregnancy, at the beginning of the third trimester at the latest. We need new treatment strategies; and close follow-up of mothers and children is another important issue.

The impact of previous SARS-CoV-2 infection on post-vaccine adverse events in individuals vaccinated with TURKOVAC or CoronaVac -inactivated COVID-19 vaccines.

This study- a secondary analysis of data from a randomized, observer-blinded, non-inferiority study among volunteers between 18-55 y old in Türkiye- evaluated the impact of previous SARS-CoV-2 infection before the first dose of inactive TURKOVAC on post-vaccine local and systemic adverse events (AEs) comparing with CoronaVac. Of 1266 participants analyzed, 27.7% had a previous COVID-19 history. Local and systemic AEs were observed in 37.3% and 39% of the participants. The frequency of AEs was slightly higher in the first 30 minutes and 24 hours among participants with a COVID-19 history; none were severe. 1203 participants had a second dose vaccination, and 27.3% had a history of COVID-19. The frequencies of local and systemic AEs after the second dose were similar between those with and without a COVID-19 history. The TURKOVAC and CoronaVac showed similar frequencies of local and systemic AEs in the first 30 minutes after vaccination.

Treatment initiation rates of patients with positive anti-hepatitis C virus results in tertiary hospitals in Turkey.

INTRODUCTION: The aim of this national, multicenter, cross-sectional, retrospective chart review study was to determine the proportion of patients in Turkey who received hepatitis C virus (HCV) treatment after receiving positive anti-HCV results during HCV screening. METHODOLOGY: Data related to patients' demographics, laboratory results, time interval from obtaining a positive anti-HCV result to treatment initiation, specialty of the physician requesting anti-HCV screening, and type of hospital were analyzed. RESULTS: Among 1,000 patients who received a positive anti-HCV result, 50.3% were male and 78.5% were screened for HCV-RNA. Among HCV-RNA screened patients, 54.8% (n = 430) had a positive result. Among patients who tested positive for HCV-RNA, 72.8% received HCV treatment in line with their positive anti-HCV results. The median time from obtaining a positive anti-HCV result to initiation of HCV treatment was 91.0 days (interquartile range 42.0 to 178.5). Non-surgical branches requested HCV-RNA testing more frequently than surgical branches (p < 0.001). The rate of access to HCV treatment was higher among patients screened in university hospitals than among patients screened in training and research hospitals (p < 0.001). CONCLUSIONS: Our results indicate a higher rate of treatment initiation among patients with HCV infection than is described in the published literature. Furthermore, the time from screening to treatment initiation was considerably shorter compared with other international studies. However, since HCV-RNA testing was not requested in a significant portion of patients with a positive anti-HCV test result, there might be a large patient population with HCV who do not receive treatment.

[First case of hepatitis B virus genotype H infection in Turkey]. / Türkiye'de ilk kez saptanan hepatit B virus genotip H enfeksiyonu olgusu.

Clinical studies reported from Turkey indicate that hepatitis B virus (HBV) genotype D is more prevalent than other genotypes. Epidemiological and clinical information on genotype H infection is currently limited. Genotype H infection is most likely due to its regional (Central and South America) prevalence throughout the world. The aim of this report is to present the first HBV genotype H infection in a chronic hepatitis B patient in Turkey. Laboratory findings of a 42 years old male patient admitted to our hospital revealed HBsAg (+), anti-HBs (-), HBeAg (-), anti-HBe (+), anti-HBc IgM (-), anti-HBc IgG (+), anti-HAV IgG (+), HBV-DNA: 5.689.776 IU/ml and high liver enzymes (ALT: 223 U/L, AST: 121 U/L). History of the patient indicated no risk factor (intravenous drug use, blood transfusion, suspicious sexual contact) related to HBV transmission. Since liver ultrasonography showed multiple hemangiomas, biopsy was performed and histologic activity index was found as 6/18 and fibrosis as 2/6, according to modified Knodell score system. HBV DNA isolated from the serum sample of the patient was amplified by polymerase chain reaction and polymerase gene segment of HBV was directly sequenced. UPGMA method was used for phylogenetic analysis, and the genotype of the virus was identified accordingly. The nucleotide sequence was compared to those from the international DNA data bank (GenBank). The genotyping of the patient revealed that the isolated HBV was genotype H. Treatment with tenofovir disoproxil fumarate was initiated and the patient responded to the treatment. This finding suggested that other HBV genotypes, except the predominant genotype D may also be in circulation in Turkey. In conclusion, detection of epidemiologic and molecular characteristics of HBV genotype H which is related to chronic hepatitis, seems to be necessary in order to better understand its circulation and progression around the world.

Evaluation of lateral flow and ELISA techniques for detecting IgG and IgM antibodies in COVID-19 cases in Türkiye.

Background: Antibody testing can complement molecular assays for detecting COVID-19. Aims: We evaluated the concurrence between lateral flow assay and enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Methods: The study was conducted at Kocaeli University, Türkiye. We used a lateral flow assay and ELISA to test serum samples from COVID-19 cases, confirmed by polymerase chain reaction assays (study group) and pre-pandemic stored serum samples (control group). We used Deming regression to evaluate the antibody measurements. Results: The study group included 100 COVID-19 cases, and the control group included pre-pandemic samples from 156 individuals. The lateral flow assay detected immunoglobulin M (IgM) and G (IgG) antibodies in 35 and 37 study group samples. ELISA detected IgM nucleocapsid (N) antibodies in 18 samples, and IgG (N) and IgG spike 1 (S1) antibodies in 31 and 29 samples, respectively. None of the techniques detected antibodies in the control samples. Strong correlations were found between lateral flow IgG (N+ receptor-binding domain + S1) and ELISA IgG (S) (r = 0.93, P < 0.01) and ELISA IgG (N) (r = 0.81, P < 0.01). Weaker correlations were seen between ELISA IgG S and IgG N (r = 0.79, P < 0.01) and lateral flow assay and ELISA IgM (N) (r = 0.70, P < 0.01). Conclusion: Lateral flow assay and ELISA techniques gave consistent results for IgG/IgM antibody measurements towards spike and nucleocapsid proteins, suggesting that both methods can be used to detect COVID-19 where access to molecular test kits is difficult.

Comparison of Immunological and Virological Recovery with Rapid, Early, and Late Start of Antiretroviral Treatment in Naive Plwh: Real-World Data.

Background: Rapid initiation of antiretroviral therapy (ART) reduces the transmission of HIV infection in the community. This study aimed to determine whether rapid ART initiation is effective compared to standard ART treatment in our country. Methods: Patients were grouped based on time to treatment initiation. HIV RNA levels, CD+4 T cell count, CD4/CD8 ratio, and ART regimens were recorded at baseline and follow-up visits for 12 months. Results: There were 368-ART naive adults (treatment initiated at the time of HIV diagnosis; 143 on the first day, 48 on the second-seventh day, and 177 after the seventh day). Although virological suppression rates at 12th months were higher in all groups, over 90% on average, there were no statistically significant differences in HIV-1 RNA suppression rates, CD+4 T cell count, and CD4/CD8 ratio normalization in the studied months but in multivariate logistic regression analysis; showed a significant correlation between both virological and immunological response and those with CD4+ T <350 cells/mL at 12th month in total patients. Conclusion: Our findings support the broader application of recommendations for rapid ART initiation in HIV patients.

Integrase Strand Transfer Inhibitor (INSTI) Genotypic Resistance Analysis in Treatment-Naive, INSTI Free Antiretroviral-Experienced and INSTI-Experienced Turkish Patients Infected with HIV-1.

BACKGROUND AND OBJECTIVE: Integrase strand transfer inhibitors (INSTIs) are currently the standard of practice for first-line HIV therapy for most patients. We evaluated the mutations associated with INSTI resistance in naive HIV-1 infected patients and treated them with antiretrovirals (ART). METHODS: The study, conducted in the 2018 - 2020 period, included 50 ART-naïve patients, 69 INSTI free ART-experienced patients, and 82 INSTI-experienced patients. INSTI resistance mutations were interpreted using the Stanford University HIVdb Program algorithm. RESULTS: INSTI resistance was not detected in ART naïve patients. At least one INSTI resistance mutation was detected in 10% of the INSTI-free patients and 29% of the INSTI-treated patients. Major INSTI-mutations E138K, Y143R, S147G, Q148R, N155H, and E157Q were found in raltegravir. Additional mutations, E92Q, E138K, G140A, S147G, and Q148R were found in elvitegravir; E192Q, E138K/T, G140A/S, S147G, Q148H/R, N155H, E157Q were found in dolutegravir (DTG) experienced patients. According to all drug classes, drug resistance mutation prevalences were determined at the rate of 60%, 46%, and 46% in the RAL, EVG, and DTG groups, respectively. CONCLUSION: Our findings provide data for treatment and resistance management of INSTIs and may provide feedback for INSTIs resistance surveillance consensus-building efforts. In viral rebound under INSTI treatment, INSTI-resistant mutations follow typical INSTI resistance pathways and high resistance rates. INSTI resistance genotypic analysis should be considered before any DTG-based regimes can be initiated in the future, and reduced DTG susceptibility should be carefully monitored and investigated.

Charlson Comorbidity Index in Predicting Poor Clinical Outcomes and Mortality in Patients with COVID-19.

OBJECTIVE: As known, older age and comorbidities are associated with poor clinical outcomes in patients with coronavirus disease 19. The aim of this study was to investigate the effect of the Charlson Comorbidity Index in predicting poor clinical outcomes in coronavirus disease 19 patients. MATERIAL AND METHODS: Demographic characteristics and poor clinical outcomes (presence of pneumonia, respiratory failure, intensive care unit admission, and mortality) of the patients were evaluated retrospectively. Classical and modified Charlson Comorbidity Index was calculated and adjusted according to age. RESULTS: In this study, 106 women and 107 men were included. The comorbidity rate was 50.7% and the most common comorbidities were hypertension (21.6%) and diabetes mellitus (15%). The rates of respiratory failure, intensive care unit admission, and mortality were 15%, 2.3%, and 2.8%, respectively. Older age was a high risk for poor outcomes. Pneumonia (odds ratio: 6.6; 95% CI: 3.4-12.7), respiratory failure (odds ratio: 5.2; 95% CI: 2.03-13.2), and intensive care unit admission (odds ratio: 1.1; 95% CI: 1.01-1.1) were significantly higher in patients with comorbid diseases than patients without any comorbidity (P < .05). Both median-modified and classical Charlson Comorbidity Index and their age-adjusted scores were significantly higher in patients with poor outcomes. CONCLUSIONS: It is suggested that evaluation of the Charlson Comorbidity Index might contribute to the management of the patients with coronavirus disease 19 by predicting risk group for poor clinical outcomes and mortality.

Efficacy, Immunogenicity, and Safety of the Two-Dose Schedules of TURKOVAC versus CoronaVac in Healthy Subjects: A Randomized, Observer-Blinded, Non-Inferiority Phase III Trial.

We present the interim results of the efficacy, immunogenicity, and safety of the two-dose schedules of TURKOVAC versus CoronaVac. This was a randomized, observer-blinded, non-inferiority trial (NCT04942405). Volunteers were 18-55 years old and randomized at a 1:1 ratio to receive either TURKOVAC or CoronaVac at Day 0 and Day 28, both of which are 3 µg/0.5 mL of inactivated severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) adsorbed to aluminum hydroxide. The primary efficacy outcome was the prevention of polymerase chain reaction (PCR)-confirmed symptomatic coronavirus disease 2019 (COVID-19) at least 14 days after the second dose in the modified per-protocol (mPP) group. Safety analyses were performed in the modified intention-to-treat (mITT) group. Between 22 June 2021 and 7 January 2022, 1290 participants were randomized. The mITT group consisted of 915 participants, and the mPP group consisted of 732 participants. During a median follow-up of 90 (IQR 86-90) days, the relative risk reduction with TURKOVAC compared to CoronaVac was 41.03% (95% CI 12.95-60.06) for preventing PCR-confirmed symptomatic COVID-19. The incidences of adverse events (AEs) overall were 58.8% in TURKOVAC and 49.7% in CoronaVac arms (p = 0.006), with no fatalities or grade four AEs. TURKOVAC was non-inferior to CoronaVac in terms of efficacy and demonstrated a good safety and tolerability profile.

Real-World Data from Turkey: Is Sofosbuvir/Ledipasvir With or Without Ribavirin Treatment for Chronic Hepatitis C Really Effective?

BACKGROUND: In this study, we aimed to investigate the efficacy and safety of sofosbuvir-based therapies in the treatment of chronic hepatitis C in real-world clinical practice. METHODS: Data from patients with chronic hepatitis C treated with SOF/LDV ± RBV or SOF/RBV in 31 centers across Turkey between April 1, 2017, and August 31, 2018, were recorded in a nationwide database among infectious disease specialists. Demographics, clinical, and virological outcomes were analyzed. RESULTS: A total of 552 patients were included in the study. The mean age of the patients was 51.28 ± 14.2, and 293 (55.8%) were female. The majority had HCV genotype 1b infection (65%), 75.04% of the patients underwent treatment, and non-cirrhosis was present at baseline in 381 patients (72.6%). SOF/LDV ± RBV treatment was given to 477 patients and 48 patients received SOF/RBV according to HCV genotype. The total SVR12 rate was 99% in all patients. Five patients experienced disease relapse during the study and all of them were genotype 2. In patients infected with HCV GT2, SVR12 was 77.3%. SVR was 100% in all patients infected with other HCV genotypes. All treatments were well tolerated by patients without causing severe adverse events. Side effects and side effects-associated treatment discontinuation rates were 28.2% and 0.4%, respectively. Weakness (13.7%) was the common side effect. CONCLUSION: The present real-world data of 525 patients with HCV genotypes 1, 1a, 1b, 3, 4, and 5 who underwent SOF/LDV ± RBV treatment in Turkey demonstrated a high efficacy and safety profile. HCV GT2 patients should be treated with more efficacious treatment.

Investigation of compatibility of severe acute respiratory syndrome coronavirus 2 reverse transcriptase-PCR kits containing different gene targets during coronavirus disease 2019 pandemic.

AIM: In the diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), reverse transcriptase-PCR (RT-PCR) technique is often used. We evaluated the compatibility of SARS-CoV-2 RT-PCR kits containing different gene targets during the pandemic. MATERIALS & METHODS: Samples were tested by Bio-Speddy® (RdRp gene) and Diagnovital® (RdRp + E genes). The correlation between two assays were determined by Deming regression analysis and chi-square analyses. RESULTS: Diagnovital PCR kit showed amplification in a narrow Ct range and conveniently sharper exponential amplification curves than Bio-Speedy PCR kit. While the correlation between the findings of the two kits was apparent even with single gene target, this correlation increased when a secondary biomarker was added to the correlation calculations. CONCLUSION: We have observed high correlation between different PCR kits, however, using different PCR kits during the pandemic may provide a more accurate diagnosis of SARS-CoV-2, since despite correlation there are a number of patients showing contradicting diagnosis.

Intravoxel incoherent motion imaging for diagnosing and staging the liver fibrosis and inflammation.

PURPOSE: To evaluate the diagnostic accuracy of intravoxel incoherent motion (IVIM) model parameters for the diagnosis and staging of liver fibrosis and inflammation in patients with chronic hepatitis B. METHODS: Fifty-four patients with chronic hepatitis B and 42 healthy volunteers were included in the study. All subjects were examined by 3 T magnetic resonance imaging. Diffusion-weighted imaging was undertaken with sixteen b values. IVIM parameters [D (true diffusion coefficient), D* (pseudo-diffusion coefficient), f (perfusion fraction)] were calculated. Histological evaluation of biopsy samples was considered the reference standard for the staging of liver fibrosis and inflammation. Differences in IVIM parameters between patient and control groups were analyzed. In the patient group, fibrosis stage and inflammation grade groups were analyzed with respect to IVIM parameters. The correlation was assessed between IVIM parameters and Ishak-modified scale of fibrosis stages and inflammation grades. RESULTS: The D was significantly lower in the patient group than the control group, p = 0.038 with Cohen's d effect size of 0.452. D was significantly different between fibrosis stage levels. D values decreased in fibrosis stages from the minimal to moderate to marked fibrosis. Fibrosis grades significantly negatively correlated with D and D* values, p = 0.001, and 0.021, respectively. In addition, inflammation grades negatively correlated with f values, p = 0.047. CONCLUSION: D values measured with IVIM imaging may help to diagnose liver fibrosis. IVIM imaging could be an alternative to liver biopsy for the staging of liver fibrosis.

NS5A resistance - associated substitutions in chronic hepatitis C patients with direct acting antiviral treatment failure in Turkey.

OBJECTIVES: Chronic hepatitis C (CHC) is now a more curable disease with new direct acting antivirals (DAA). Although high sustained virologic response rates, failures still occur in DAA regimens. Our objective in this study was to characterize the real-life presence of clinically relevant resistance - associated substitutions (RASs) in the HCV NS5A gene in CHC patients whose DAA regimen has failed. METHODS: The study enrolled 53 CHC patients who experienced failure with DAA regimen as the prospective longitudinal cohort between 2017-2019. Genotypic resistance testing was performed via the viral population sequencing method and The Geno2pheno HCV tool was used for RAS analysis. RESULTS: The most frequent failure category was relapse (88%) followed by non-responder (12%). For a total of 36% of patients, RASs was detected in NS5A, Y93H was the most detected RAS in GT1b infected patients (89%). CONCLUSIONS: This study establishes an HCV failure registry for Turkey in which samples were combined with clinical, virologic and molecular data of adult patients whose DAA therapy failed. RASs can occur in CHC patients with DAA treatment failures. Evaluation of RAS after DAA failure is very important before re-treatment is initiated to prevent virologic failure.

[Entecavir resistance in entecavir naive lamivudine treated chronic hepatitis B patients]. / Lamivudin tedavisi uygulanmis ve entekavir naif kronik hepatit B'li hastalarda entekavir ilaç direnci.

Approved hepatitis B virus (HBV) therapies include interferon-alpha and nucleos(t)ide analogues. Lamivudine (LVD) is a nucleoside analogue and following long term LVD therapy, resistance emerges in a significant number of patients. Entecavir (ETV) is a novel deoxyguanosine analogue with potent activity against HBV in chronically infected patients. ETV is highly efficacious in treating nucleoside naive and LVD refractory patients. The aim of the present study was to determine the prevalence of ETV drug resistance in LVD treated/ETV naive (study group) and in untreated naive (control group) patients with chronic B hepatitis. DNA sequencing was applied to 80.-250. amino acid positions on HBV polymerase gene to investigate the ETV resistance and also HBV genotype and HBV polymerase gene overlapped S-gene segment mutations. Primary LVD and ETV drug resistance were detected in 37 (42.6%) and 4 (4.5%) of 87 patients, respectively in the study group. rtT184A, rtT1841 and rtT1845 mutations were found related to primary ETV resistance. In these patients also rtL180M and rtQ215S mutations were detected as compensatory mutations and YVDD and YIDD variants were observed at the 204. amino acid codon position. None of the patients in the control group had LVD or ETV resistance. Two of the patients in the study group had mutations at the positions sG145R and sC137G in the overlapped S-gene segment. However, mutations at the overlapped S-gene segment were not affected by the mutations associated with ETV resistance. All of the patients in the study and the control group were of HBV genotype D. The results obtained from this study may guide the treatment choices with ETV in chronic HBV patients treated with LVD and developed resistance to LVD.

Response to direct-acting antiviral agents in chronic hepatitis C patients with end-stage renal disease: a clinical experience.

OBJECTIVE: The recent development of direct-acting antiviral agents (DAAs) has dramatically changed the treatment of chronic hepatitis C, and interferon-based regimes have become a poor treatment choice in clinical practice. Today DAAs offer shorter, well-tolerated, highly effective curative therapies. This study aimed to evaluate the effectiveness and safety of DAAs in patients with end-stage renal disease and HCV genotype 1 infection in real clinical practice. METHODS: Thirty-six patients who attended our clinic, were diagnosed with chronic hepatitis C (CHC), undergoing hemodialysis, and fulfilled the criteria of age >18 years, genotype 1 infection, with a detectable HCV RNA level were considered for the study. Patients with GT1a infection received OBV/PTV/r plus DSV plus RBV for 12 weeks; GT1b infected patients received this regimen without RBV for 12 weeks. RESULTS: The study was conducted on 33 patients. The mean age was 52.30 ±13.77 years, and 70 % of them were male. By the fourth week of treatment, HCV RNA levels decreased below 15 IU/ml in all patients. Sustained virologic response (SVR) 12 rate was 100%. Nine patients had side effects during treatment. Of the patients with side effects, 89.9% were in group 1a and 11.1% in group 1b. CONCLUSION: In this study, treatment with OBV/PTV/r and DSV with or without RBV resulted in high rates of sustained virologic response in HCV GT1-infected patients with end-stage renal disease (ESRD). SVR was achieved in all patients with few side effects.

[Comparison of quantitative hepatitis B virus DNA levels in serum and liver biopsy samples of chronic hepatitis B patients]. / Kronik hepatit B hastalarinin serum ve karaciger biyopsi örneklerinde hepatit B virus DNA düzeyinin karsilastirilmasi.

Chronic hepatitis B (CHB) is an important health problem worldwide. Relapses in CHB patients, even treated, create a major problem in patient management. The aims of this study were the detection of quantitative levels of hepatitis B virus (HBV) DNA in the sera and liver biopsy specimens of CHB patients and the comparison of the results. A total of 69 patients (49 male, 20 female; age range: 19-68 years, mean age: 36.91+11.03 years) who were prediagnosed as CHB in the Infectious Diseases and Clinical Microbiology Department of Kocaeli University (northwestern region of Turkey) were included to this prospective study. HBV-DNA levels of all of the patients were initially measured in the routine laboratory of our hospital by using a commercial real-time polymerase chain reaction (RQ-PCR; iCycler IQ System, BioRad Laboratories) and the mean HBV-DNA level (Serum DNA #2) was detected as 5.6E+6 +/- 8.5E+6 copies/mL. The mean level of ALT in CHB patients was 79.59 +/- 69.7. In our study the HBV-DNA levels of the serum and liver biopsy specimens were also measured by using an "in-house" real-time PCR (RT-PCR) (Techne Quantica, London, UK). Nucleic acid extractions were performed with the use of QIAamp DNA Mini Kit (Qiagen Inc, Hilden, Germany) according to the manufacturer's recommendations. The primers were specific for the X gene region of HBV (forward primer: 5'-TTCGCTTCACCTCTGCACG-3', reverse primer: 5'-CCCAACTCCCAGTCTTTAA-3'; probe: 5'-AATGTCAACGACCGACCTT GAGGCA-pBHQ-3'). Statistical analysis was carried out with Spearman rank analysis. With the use of "in-house" real-time PCR, mean levels of HBV-DNA were found to be 8.99E+6 +/- 3.1E+7 copies/mL in the liver biopsy samples, and 4E+6 +/- 4.4E+6 copies/ mL in serum samples (Serum DNA 1). There were significant positive correlations between the results obtained from in-house (Serum DNA 1) and commercial RT-PCR (Serum DNA 2) (r = 0.300; p = 0.024) methods. Although HBV-DNA levels in the liver tissues were found higher than those in serum samples, no correlation between the HBV-DNA levels of liver biopsy and serum samples (both serum DNA 1 and 2) was detected. This result was attributed to the standardization problems of in-house RT-PCR. In conclusion, liver biopsies performed at the beginning of the therapy to detect the grade of chronic liver disease, would also be searched by means of quantitative HBV-DNA levels, however, since the determination of HBV-DNA load in liver tissues may be difficult, standardized sensitive methods should be used for this purpose.