Efficacy and safety of elbasvir/grazoprevir in participants with hepatitis C virus genotype 1, 4, or 6 infection from the Asia-Pacific region and Russia: Final results from the randomized C-CORAL study.

BACKGROUND AND AIM: Although treatment with direct-acting antivirals has dramatically improved morbidity and mortality attributable to chronic hepatitis C virus infection, universal access to these medicines has been slow in the Asia-Pacific region and Russia. This study evaluated efficacy and safety of elbasvir/grazoprevir in participants with hepatitis C virus infection from Asia-Pacific countries and Russia (C-CORAL). METHODS: C-CORAL was a phase 3, randomized, placebo-controlled study (NCT02251990). Treatment-naive, HIV-negative, cirrhotic and non-cirrhotic participants with chronic hepatitis C genotype 1, 4, or 6 infection were randomized to elbasvir 50 mg/grazoprevir 100 mg once daily for 12 weeks (immediate-treatment group) or placebo followed by deferred treatment with elbasvir/grazoprevir (deferred-treatment group). The primary efficacy outcome was sustained virologic response at 12 weeks, and the primary safety outcome was a comparison between the immediate-treatment group and placebo phase of the deferred-treatment group. RESULTS: A total of 489 participants were randomized (immediate-treatment group, n = 366; deferred-treatment group, n = 123). Sustained virologic response at 12 weeks in the combined immediate/deferred-treatment groups was 94.4% (459/486; 95% confidence interval = 92.4-96.5%). Sustained virologic response at 12 weeks was 98.2% in participants with genotype 1b, 91.9% with genotype 1a, and 66.7% with genotype 6 infection. Similar rates of adverse events and drug-related adverse events were seen in the immediate-treatment group versus placebo phase of the deferred-treatment group (51.0% vs 50.4% and 21.4% vs 21.1%). CONCLUSIONS: Elbasvir/grazoprevir for 12 weeks represents an effective and well-tolerated treatment option for treatment-naive people with genotype 1 infection from Asia-Pacific countries and Russia.

A randomized clinical trial to assess the impact of laser power with constant linear endovenous energy density on outcomes of endovenous laser ablation (SLEDGE trial).

OBJECTIVE: To date, conflicting evidence has been reported regarding the energy settings to use during endovenous laser ablation (EVLA). In the present study, we evaluated the outcomes of EVLA of the great saphenous veins (GSVs) using different power settings with the same linear endovenous energy density (LEED) of ∼70 J/cm. METHODS: We performed a single-center, randomized, controlled noninferiority trial with a blinded outcome assessment of patients with varicose veins of the GSV who underwent EVLA with a wavelength of 1470 nm and a radial fiber. The patients were randomly assigned to three groups according to the energy setting: group 1, 5 W power and an automatic fiber traction speed of 0.7 mm/s (LEED, 71.4 J/cm); group 2, 7 W and 1.0 mm/s (LEED, 70 J/cm); and group 3, 10 W and 1.5 mm/s (LEED, 66.7 J/cm). The primary outcome was the rate of GSV occlusion at 6 months. The secondary outcomes were pain intensity along the target vein the next day and at 1 week and 2 months after EVLA, the necessity for analgesics, and the occurrence of significant complications. RESULTS: From February 2017 to June 2020, 245 lower extremities of 203 patients were enrolled. Groups 1, 2, and 3 included 83, 79, and 83 limbs, respectively. At 6 months of follow-up, 214 lower extremities were examined with duplex ultrasound. GSV occlusion was observed in 72 of 72 limbs (100%; 95% confidence interval [CI], 100%-100%) in group 1 and 70 of 71 limbs (98.6%; 95% CI, 97%-100%) in groups 2 and 3 (P < .05 for noninferiority). No difference was found in the pain level, necessity for analgesics, or rate of any other complications. CONCLUSIONS: The technical results, pain level, and complications of EVLA were not associated with the combination of energy power (5-10 W) and the speed of automatic fiber traction when a similar LEED of ∼70 J/cm was reached.

Hepatobiliary system and intestinal injury in new coronavirus infection (COVID-19): A retrospective study.

BACKGROUND: An important area of effective control of the coronavirus disease 19 (COVID-19) pandemic is the study of the pathogenic features of severe acute respiratory syndrome coronavirus 2 infection, including those based on assessing the state of the intestinal microbiota and permeability. AIM: To study the clinical features of the new COVID-19 in patients with mild and moderate severity at the stage of hospitalization, to determine the role of hepatobiliary injury, intestinal permeability disorders, and changes in the qualitative and quantitative composition of the microbiota in the development of systemic inflammation in patients with COVID-19. METHODS: The study was performed in 80 patients with COVID-19, with an average age of 45 years, 19 of whom had mild disease, and 61 had moderate disease severity. The scope of the examination included traditional clinical, laboratory, biochemical, instrumental, and radiation studies, as well as original methods for studying microbiota and intestinal permeability. RESULTS: The clinical course of COVID-19 was studied, and the clinical and biochemical features, manifestations of systemic inflammation, and intestinal microbiome changes in patients with mild and moderate severity were identified. Intestinal permeability characteristics against the background of COVID-19 were evaluated by measuring levels of proinflammatory cytokines, insulin, faecal calprotectin, and zonulin. CONCLUSION: This study highlights the role of intestinal permeability and microbiota as the main drivers of gastroenterological manifestations and increased COVID-19 severity.

Prevalence of resistance-associated substitutions and phylogenetic analysis of hepatitis C virus infection in Russia.

OBJECTIVES: Due to limited hepatitis C virus (HCV) sequence availability from patients in Russia, the relationship between subtypes and baseline resistance-associated substitutions (RAS) to direct antiretroviral treatment outcome is not fully understood. METHODS: Deep sequencing of HCV NS3, NS5A, and NS5B sequences was performed on plasma HCV samples from 412 direct-acting antiviral (DAA)-naïve patients from Russia. Phylogenetic analysis was performed to investigate sequence similarities between HCV strains from Russia, Asia, Europe, and North America. Pretreatment HCV RAS was assessed with a 15% cutoff. RESULTS: HCV genotype GT1b and GT3a sequences in Russia were related to strains in Europe and Asia. The prevalence of GT1a and GT2a was low in Russia. In GT1b, the prevalence of NS5A Y93H was lower in Russia (6%) compared with Asia (15%). The prevalence of NS5B L159F was similar between Russia and Europe (26-39%). GT3a RAS prevalence was similar between Russia and Asia, Europe, and North America. The 2k/1b recombinant strain in Russia was related to strains from Europe. A higher prevalence of the NS5A RAS L31M (10%) was observed in 2k/1b sequences compared to GT1b (1-6%). CONCLUSIONS: The prevalence of RASs and the phylogenetic analysis showed similarities in HCV strains between Russia, Europe, and North America. This information may be useful for HCV regimens in Russia.

Reflux volume is determined by ejected blood volume from the calf venous reservoir.

OBJECTIVE: This study investigated the relationship between the ejected blood volume from the calf venous reservoir and the reflux volume (RV) during the automatic cuff inflation-deflation maneuver in limbs with incompetent great saphenous vein. METHODS: There were 48 patients with chronic venous disease (C1-5, Ер, Аs, Pr2,3) included in the study. A noncycling operator-dependent distal cuff inflation-deflation was used as the reflux-provoking maneuver. Duplex ultrasound was used to measure the cross-sectional area of the common femoral vein and great saphenous vein as well as hemodynamic parameters (time-averaged mean velocity and flow duration) of the outflow during cuff inflation and reflux during cuff deflation. The cuff pressure was set at 60, 90, and 120 mm Hg sequentially. The RV flow rate (Q), RV, anterograde ejection volume (EV), and ratio RV/EV (reflux index, IR) were calculated for each pressure setting. RESULTS: RV correlated with EV and Qreflux (r2 = 0.366 and r2 = 0.647, respectively; P < .0001). Qreflux was not significantly different between different cuff inflation pressures. RV and EV were statistically different at different cuff pressure settings (analysis of variance, P < .0001). The IR was almost identical at different pressure settings (0.43 ± 0.23 at 60 mm Hg, 0.43 ± 0.20 at 90 mm Hg, and 0.42 ± 0.19 at 120 mm Hg). CONCLUSIONS: The amount of reflux is primarily determined by the value of EV in a distal cuff compression-decompression maneuver. Both the ratio RV/EV (IR) and RV were related to the severity of the disease, more severe forms having larger IR and RV values.

Elbasvir/Grazoprevir for HCV Infection in Russia: A Randomized Trial.

PURPOSE: Hepatitis C virus (HCV) infection is a major healthcare concern in Russia, where almost 5 million individuals are viremic. Elbasvir/grazoprevir is a fixed-dose combination therapy for the treatment of HCV genotype 1 and genotype 4 infection. The present analysis aimed to assess the safety and efficacy of elbasvir/grazoprevir in individuals with HCV infection enrolled at Russian study sites in the C-CORAL study. PATIENTS AND METHODS: C-CORAL (Protocol PN-5172-067; NCT02251990) was a Phase 3, placebo-controlled, double-blind study conducted throughout Asia and Russia. Treatment-naive participants with chronic HCV infection were randomly assigned to receive immediate or deferred treatment with elbasvir 50 mg/grazoprevir 100 mg once daily for 12 weeks. Participants in the immediate-treatment group received elbasvir/grazoprevir for 12 weeks, and those in the deferred-treatment group received placebo for 12 weeks, followed by open-label elbasvir/grazoprevir for 12 weeks. The primary endpoint was sustained virologic response at 12 weeks after completion of therapy (SVR12). RESULTS: One hundred and nineteen Russian participants were randomized (immediate-treatment group, n=88; deferred-treatment group, n=31). Most participants were white (99%) with HCV genotype 1b infection (97%) and mild-to-moderate (F0-F2) fibrosis (70%). SVR12 was achieved by 98.9% participants in the immediate-treatment group and by 100% of those receiving deferred elbasvir/grazoprevir in the deferred-treatment group. One participant relapsed with nonstructural protein 5A (NS5A) L28M and Y93H resistance-associated substitutions at baseline and at time of failure. Drug-related adverse events were reported by 19% of participants receiving elbasvir/grazoprevir in the immediate-treatment group and by 16% of those receiving placebo in the deferred-treatment group. No serious adverse event or deaths occurred, and no participant discontinued treatment owing to an adverse event. CONCLUSION: Elbasvir/grazoprevir for 12 weeks was highly effective in treatment-naive Russian individuals with HCV genotype 1b infection.

Observational study of nasopharyngeal carriage of Neisseria meningitidis in applicants to a military academy in the Russian Federation.

OBJECTIVE: To determine the carriage and the serogroup distribution of Neisseria meningitidis in military academy applicants in the Russian Federation. DESIGN: This was a prospective, observational study of adults aged >18years from a military academy; applicants who had samples taken on arrival (Day 1), and applicants who had samples taken after passing exams (Day 30) and 60days after arrival. N. meningitidis serogrouping was determined by slide agglutination tests of isolates and real-time PCR. RESULTS: Samples were provided by 671 applicants on Day 1 and 261 applicants on Day 30, with 232 of these also providing samples on Day 60. N. meningitidis was detected in 16.2% of samples from Day 1, 7.7% of samples from Day 30 and 15.9% of samples from Day 60. Serogroup composition was most diverse at Day 1, with serogroups B and W dominant (40% [17/43 isolates] and 9% [4/43], respectively; 30% [13/43] ungroupable); by Day 60, there was a low diversity, with 58% (14/24 isolates) serogroup W. CONCLUSIONS: While carriage of N. meningitidis in this study appeared stable, there was an increase in carriers of serogroup W in this population. Given recent increases in outbreaks attributed to serogroup W, further monitoring may be considered.

Sofosbuvir/velpatasvir for the treatment of HCV: excellent results from a phase-3, open-label study in Russia and Sweden.

BACKGROUND: In both Russia and Sweden, the dominant hepatitis C virus (HCV) is genotype 1, but around one-third of patients have genotype 3 infection. For such countries, HCV genotype testing is recommended prior to therapy. An effective pangenotypic therapy may potentially eliminate the need for genotyping. In this study, we evaluated the efficacy and safety of sofosbuvir/velpatasvir for 12 weeks in patients from Russia and Sweden. METHODS: In an open-label, single-arm phase-3 study, patients could have HCV genotype 1-6 infection and were treatment-naïve or interferon treatment-experienced. All patients received sofosbuvir/velpatasvir, once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). RESULTS: Of 122 patients screened, 119 were enrolled and treated. Overall, half (50%) were male, 18% had cirrhosis, and 24% had failed prior interferon-based therapy. In total, 66% of patients were infected with HCV genotype 1 (59% 1b and 7% 1a), 6% with genotype 2, and 29% with genotype 3. The overall SVR12 rate was 99% (118/119, 95% confidence interval 95-100%). One treatment-experienced patient infected with HCV genotype 3 experienced virologic relapse after completing treatment. The most common adverse events were headache (16%) and fatigue (7%). Serious adverse events were observed in four patients, but none were related to treatment. No patients discontinued treatment due to adverse events. CONCLUSION: Sofosbuvir/velpatasvir as a pangenotypic treatment for 12 weeks was highly effective in patients from Russia and Sweden infected with HCV genotypes 1, 2, or 3. Sofosbuvir/velpatasvir was safe and well-tolerated. Clinical trial number: ClinicalTrials.gov NCT02722837.

Ledipasvir-Sofosbuvir for 8 Weeks in Non-Cirrhotic Patients with Previously Untreated Genotype 1 HCV Infection ± HIV-1 Co-Infection.

BACKGROUND AND OBJECTIVES: The efficacy of < 12 weeks of hepatitis C virus (HCV) treatment in patients co-infected with HCV and human immunodeficiency virus type 1 (HIV-1) has not been established. We assessed the efficacy and safety of ledipasvir-sofosbuvir for 8 weeks in HCV mono-infected and HCV/HIV-1 co-infected patients. METHODS: We enrolled patients mono-infected with genotype 1 HCV or co-infected with HCV and HIV-1 who were HCV treatment-naive and did not have cirrhosis. HCV/HIV-1 co-infected patients were either not receiving antiretroviral treatment and had a CD4 T-cell count > 500 cells/mm3 or were receiving a protocol-approved antiretroviral regimen for ≥ 8 weeks (or ≥ 6 months for abacavir-containing regimens) and had HIV-1 RNA < 50 copies/mL and a CD4 T-cell count > 200 cells/mm3. Patients received ledipasvir-sofosbuvir (90/400 mg) once daily for 8 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after treatment discontinuation (SVR12). RESULTS: The SVR12 rate was 100% (67/67) for HCV mono-infected patients and 97% (57/59) for HCV/HIV-1 co-infected patients. Two patients relapsed by the week 4 post-treatment visit. Overall, the most common adverse events were headache (52%) and upper abdominal pain (26%). There were no serious adverse events or treatment discontinuations due to adverse events. No HCV/HIV-1 co-infected patients receiving antiretroviral treatment experienced HIV virologic rebound, and no clinically meaningful changes in CD4 T-cell counts were observed in any co-infected patient. CONCLUSIONS: Non-cirrhotic, treatment-naive patients with genotype 1 HCV mono-infection and HCV/HIV-1 co-infection achieved high rates of SVR12 with 8 weeks of treatment with ledipasvir/sofosbuvir. ClinicalTrials.gov identifier: NCT02472886.

Elbasvir/grazoprevir in Asia-Pacific/Russian participants with chronic hepatitis C virus genotype 1, 4, or 6 infection.

The prevalence of hepatitis C virus (HCV) infection in Asian countries is high. This study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) in participants with HCV infection from Asia-Pacific countries and Russia. In this phase 3, randomized, placebo-controlled, double-blind study, treatment-naive participants with HCV genotype (GT) 1, 4, or 6 infection were randomized to EBR 50 mg/GZR 100 mg (immediate-treatment group [ITG]) or placebo (deferred-treatment group [DTG]) once daily for 12 weeks (Protocol PN-5172-067, NCT02251990). The primary efficacy variable was a nonrandomized comparison of sustained virologic response at 12 weeks after the end of therapy (SVR12) for the ITG with a historical control. The primary safety outcome was a randomized comparison between the ITG and DTG. Three hundred thirty-seven participants were randomized to the ITG (n = 251) or DTG (n = 86); 199 (59.2%) participants were Asian, and 250 (74.4%) had HCV GT1b infection. Overall, 232/250 (92.8%) participants in the ITG achieved SVR12 (97.5% confidence interval, 89.1, 96.5). Of the 18 participants who failed to attain SVR12, 1 was lost to follow-up and 17 had virologic failure, 13 of whom had HCV GT6 infection. The incidence of adverse events was similar between participants receiving EBR/GZR and placebo (50.8% versus 51.2%; difference, -0.3%; 95% confidence interval, -12.3, 11.9). Conclusion: EBR/GZR for 12 weeks provides an effective and well-tolerated regimen for chronic HCV GT1 infection in treatment-naive people from Asia-Pacific countries and Russia, particularly for the large population with GT1b infection. EBR/GZR is not recommended for the treatment of individuals with HCV GT6 infection. (Hepatology Communications 2018;2:595-606).

Efficacy of sofosbuvir plus ribavirin in treatment-naive patients with genotype-1 and -3 HCV infection: results from a Russian Phase IIIb study.

BACKGROUND: In this Phase IIIb study, we evaluated the efficacy and safety of the oral nucleotide analogue inhibitor sofosbuvir plus ribavirin, with special attention given to viral resistance, in Russian patients with HCV genotype-1 or -3. METHODS: Treatment-naive patients with and without compensated cirrhosis were randomized (1:1) to receive 16 or 24 weeks of once-daily sofosbuvir 400 mg plus twice-daily oral ribavirin 1,000 or 1,200 mg/day. The primary efficacy end point was the proportion of patients with sustained viral response 12 weeks after the end of treatment (SVR12). Viral resistance testing was performed by deep sequencing on all baseline samples and for patients who experienced virological failure. RESULTS: SVR12 rates for patients with genotype-1 HCV were 50% and 76% for those in the 16-week and 24-week groups, respectively, and for patients with genotype-3 HCV, SVR12 rates were 87% and 90% for patients in the 16-week and 24-weeks groups, respectively. Genotype-1 patients with the L159F resistance-associated variant who received 16 weeks of treatment had lower SVR12 rates than those without, but in patients who received 24 weeks of treatment, response rates were similar in those with and without L159F (80% versus 74%). Sofosbuvir plus ribavirin was well tolerated with no deaths, adverse event-related study drug discontinuations, or grade 3 or 4 adverse events, and few grade 3 or 4 laboratory abnormalities. CONCLUSIONS: Sofosbuvir plus ribavirin for 16 or 24 weeks was associated with a high SVR rate in patients with HCV genotype-3. Among HCV genotype-1b patients, the presence of the L159F variant at baseline was associated with a lower SVR rate in those treated for 16 weeks but not in those treated for 24 weeks. Sofosbuvir plus ribavirin was safe and well tolerated regardless of treatment duration. Clinicaltrials.gov number NCT01896193.