Post-authorization safety surveillance of Ad.26.COV2.S vaccine: Reports to the Vaccine Adverse Event Reporting System and v-safe, February 2021-February 2022.

BACKGROUND: On 2/27/2021, FDA authorized Janssen COVID-19 Vaccine (Ad.26.COV2.S) for use in individuals 18 years of age and older. Vaccine safety was monitored using the Vaccine Adverse Event Reporting System (VAERS), a national passive surveillance system, and v-safe, a smartphone-based surveillance system. METHODS: VAERS and v-safe data from 2/27/2021 to 2/28/2022 were analyzed. Descriptive analyses included sex, age, race/ethnicity, seriousness, AEs of special interest (AESIs), and cause of death. For prespecified AESIs, reporting rates were calculated using the total number of doses of Ad26.COV2.S administered. For myopericarditis, observed-to-expected (O/E) analysis was performed based on the number verified cases, vaccine administration data, and published background rates. Proportions of v-safe participants reporting local and systemic reactions, as well as health impacts, were calculated. RESULTS: During the analytic period, 17,018,042 doses of Ad26.COV2.S were administered in the United States, and VAERS received 67,995 reports of AEs after Ad26.COV2.S vaccination. Most AEs (59,750; 87.9 %) were non-serious and were similar to those observed during clinical trials. Serious AEs included COVID-19 disease, coagulopathy (including thrombosis with thrombocytopenia syndrome; TTS), myocardial infarction, Bell's Palsy, and Guillain-Barré syndrome (GBS). Among AESIs, reporting rates per million doses of Ad26.COV2.S administered ranged from 0.06 for multisystem inflammatory syndrome in children to 263.43 for COVID-19 disease. O/E analysis revealed elevated reporting rate ratios (RRs) for myopericarditis; among adults ages 18-64 years, the RR was 3.19 (95 % CI 2.00, 4.83) within 7 days and 1.79 (95 % CI 1.26, 2.46) within 21 days of vaccination. Of 416,384 Ad26.COV2.S recipients enrolled into v-safe, 60.9 % reported local symptoms (e.g. injection site pain) and 75.9 % reported systemic symptoms (e.g., fatigue, headache). One-third of participants (141,334; 33.9 %) reported a health impact, but only 1.4 % sought medical care. CONCLUSION: Our review confirmed previously established safety risks for TTS and GBS and identified a potential safety concern for myocarditis.

Reporting rates for VAERS death reports following COVID-19 vaccination, December 14, 2020-November 17, 2021.

PURPOSE: Despite widely available safety information for the COVID-19 vaccines, vaccine hesitancy remains a challenge. In some cases, vaccine hesitancy may be related to concerns about the number of reports of death to the Vaccine Adverse Event Reporting System (VAERS). We aimed to provide information and context about reports of death to VAERS following COVID-19 vaccination. METHODS: This is a descriptive study evaluating reporting rates for VAERS death reports for COVID-19 vaccine recipients in the United States between December 14, 2020, and November 17, 2021. Reporting rates were calculated as death events per million persons vaccinated and compared to expected all-cause (background) death rates. RESULTS: 9201 death events were reported for COVID-19 vaccine recipients aged 5 years and older (or age unknown). Reporting rates for death events increased with increasing age, and males generally had higher reporting rates than females. For death events within 7 days and 42 days of vaccination, respectively, observed reporting rates were lower than the expected all-cause death rates. Reporting rates for Ad26.COV2.S vaccine were generally higher than for mRNA COVID-19 vaccines, but still lower than the expected all-cause death rates. Limitations of VAERS data include potential reporting bias, missing or inaccurate information, lack of a control group, and reported diagnoses, including deaths, are not causally verified diagnoses. CONCLUSIONS: Reporting rates for death events were lower than the all-cause death rates expected in the general population. Trends in reporting rates reflected known trends in background death rates. These findings do not suggest an association between vaccination and overall increased mortality.

Thrombocytopenia after Ad.26.COV2.S COVID-19 vaccine: Reports to the vaccine adverse event reporting system.

BACKGROUND: On February 27, 2021, the Food and Drug Administration (FDA) issued an Emergency Use Authorization for Ad.26.COV2.S COVID-19 vaccine. As part of post-authorization safety surveillance, the FDA has identified a potential safety concern for thrombocytopenia following receipt of Ad.26.COV2.S COVID-19 vaccine. METHODS: Reports of thrombocytopenia were identified in a passive reporting system (Vaccine Adverse Event Reporting System; VAERS) February-December 2021. Demographics, clinical characteristics, laboratory values, and relevant medical history were reviewed. The reporting rate was analyzed, including calculation of the observed-to-expected ratio based on vaccine administration data and the background rate of thrombocytopenia in the general (unvaccinated) population. RESULTS: As of December 31, 2021, 100 reports of thrombocytopenia were identified in VAERS following vaccination with Ad.26.COV2.S. The median platelet count was 33,000 per µL (interquartile range 8,000-86,000). Fifteen reports (15%) documented a platelet count of 5,000 per µL or lower. The median time to onset of thrombocytopenia was 9 days (interquartile range 3-18.5), with most cases (69; 69%) beginning within 14 days after vaccination. A large majority of cases (84; 84%) were serious, including six deaths. With approximately 16,292,911 doses of Ad.26.COV2.S administered to adults in the US, the crude reporting rate was 0.61 cases of thrombocytopenia per 100,000 doses administered. The overall estimated observed-to-expected rate ratio was 2.43 (95% CI 1.97, 2.95). CONCLUSIONS: These findings suggest an increased risk of thrombocytopenia following receipt of Ad.26.COV2.S.

Association of Receipt of the Ad26.COV2.S COVID-19 Vaccine With Presumptive Guillain-Barré Syndrome, February-July 2021.

Importance: As part of postauthorization safety surveillance, the US Food and Drug Administration (FDA) has identified a potential safety concern for Guillain-Barré syndrome (GBS) following receipt of the Ad26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccine. Objective: To assess reports of GBS received in the Vaccine Adverse Event Reporting System (VAERS) following Ad26.COV2.S vaccination. Design, Setting, and Participants: Reports of presumptive GBS were identified in a US passive reporting system (VAERS) February-July 2021 and characterized, including demographics, clinical characteristics, and relevant medical history. Exposures: Receipt of the Ad26.COV2.S vaccine; the comparator was the background rate of GBS in the general (unvaccinated) population that had been estimated and published based on a standardized case definition. Main Outcomes and Measures: Presumptive GBS; the reporting rate was analyzed, including calculation of the observed to expected ratio based on background rates and vaccine administration data. Because of limited availability of medical records, cases were not assessed according to the Brighton Collaboration criteria for GBS. Results: As of July 24, 2021, 130 reports of presumptive GBS were identified in VAERS following Ad26.COV2.S vaccination (median age, 56 years; IQR, 45-62 years; 111 individuals [86.0%] were < 65 years; 77 men [59.7%]). The median time to onset of GBS following vaccination was 13 days (IQR, 10-18 days), with 105 cases (81.4%) beginning within 21 days and 123 (95.3%) within 42 days. One hundred twenty-one reports (93.1%) were serious, including 1 death. With approximately 13 209 858 doses of vaccine administered to adults in the US, the estimated crude reporting rate was 1 case of GBS per 100 000 doses administered. The overall estimated observed to expected rate ratio was 4.18 (95% CI, 3.47-4.98) for the 42-day window, and in the worst-case scenario analysis for adults 18 years or older, corresponded to an estimated absolute rate increase of 6.36 per 100 000 person-years (based on a rate of approximately 8.36 cases per 100 000 person-years [123 cases per 1 472 162 person-years] compared with a background rate of approximately 2 cases per 100 000 person-years). For both risk windows, the observed to expected rate ratio was elevated in all age groups except individuals aged 18 through 29 years. Conclusions and Relevance: These findings suggest a potential small but statistically significant safety concern for Guillain-Barré syndrome following receipt of the Ad26.COV2.S vaccine. However, the findings are subject to the limitations of passive reporting systems and presumptive case definition, and they must be considered preliminary pending analysis of medical records to establish a definitive diagnosis.

Age- and risk factor-based serologic screening for Hepatitis C virus among an Urban, high-risk population.

Hepatitis C virus (HCV) screening among individuals born between 1945 and 1965 (ie birth cohort) may augment risk factor-based screening. We assessed HCV seropositivity among injection drug users (IDUs) and birth cohort members from New York City. We assessed HCV risk factors and seropositivity in 7722 participants from community health, HIV prevention, syringe exchange and drug treatment programmes. A total of 26.6% were HCV seropositive, 55.8% were born between 1945 and 1965, and 82.2% had ever injected drugs. Among all participants, HCV seropositivity was higher among IDUs compared to non-IDUs (60.5% versus 7.7%, odds ratio (OR) = 18.5, 95% confidence interval (CI) [16.2, 21.1], P < .0001) and among birth cohort members compared to non-birth cohort members (31.3% versus 22.3%, OR = 1.6, 95%CI [1.4, 1.8], P < .0001). Within the birth cohort, HCV seroprevalence among IDUs was 68.5% versus 11.8%, OR = 16.2, 95%CI [13.7, 19.3]. After adjustment, HCV seroprevalence was higher in IDUs, previously incarcerated, whites (<42 years) and 'other races' (versus blacks), HIV-infected, those who snorted heroin, those with liver disease history, and those who had sex with an HCV-seropositive partner. HCV seroprevalence among IDU, birth cohort members, was considerably higher than among the general population. In this high-risk, urban population, the association between IDU and HCV seropositivity was approximately ten times that between birth cohort membership and HCV seropositivity.

Fibrosis Progression in Patients With Chronic Hepatitis C Virus Infection.

BACKGROUND: Fibrosis progression varies markedly in hepatitis C virus (HCV)-infected individuals. We investigated factors that influence fibrosis progression in chronic HCV infection. METHODS: HCV-infected patients who underwent at least 2 liver biopsies were included in this study. Associations between fibrosis progression and epidemiologic, virologic, and disease-associated factors were analyzed using logistic regression and multistate Markov modeling. RESULTS: We analyzed 936 biopsy specimens obtained from 378 individuals. Mean age (±SD) at first biopsy was 48.3 ± 9.3 years, 59.3% of patients were male, 59.9% were white, and 86.7% were infected with HCV genotype 1. Fibrosis progression and cirrhosis occurred in 57.4% and 5.8%, respectively. Fibrosis progression between the first and last biopsies was associated with lower fibrosis in the first biopsy specimen (P < .001) and with the occurrence of at least 1 flare in the alanine aminotransferase (ALT) level (>200 U/L; P = .007). We found the highest fibrosis progression rate between stages 0 and 1 and the lowest between stages 2 and 3. Increased necroinflammation and higher ALT level were associated with faster progression. HCV genotype 3-infected patients were more likely to progress to cirrhosis (P < .001). CONCLUSIONS: Fibrosis progression in HCV is not linear but varies according to stage, with the highest progression in patients with the lowest fibrosis severity. Patients who experience flares in the ALT level are also more likely to progress.

Inappropriate statistical method in a parallel-group randomized controlled trial results in unsubstantiated conclusions.

The conclusions of Cassani et al. in the January 2015 issue of Nutrition Journal (doi: 10.1186/1475-2891-14-5 ) cannot be substantiated by the analysis reported nor by the data themselves. The authors ascribed the observed decrease in inflammatory markers to the components of flaxseed and based their conclusions on within-group comparisons made between the final and the baseline measurements separately in each arm of the randomized controlled trial. However, this is an improper approach and the conclusions of the paper are invalid. A correct analysis of the data shows no such effects.

Improvements in HCV-related Knowledge Among Substance Users on Opioid Agonist Therapy After an Educational Intervention.

OBJECTIVES: Lack of knowledge about hepatitis C virus (HCV) is a principal barrier to substance users' engagement into care for the infection. As a step toward their increased engagement into HCV care, the objective of this study was to deliver an HCV-related educational intervention to substance users on opioid agonist therapy and to assess the change in HCV-related knowledge after the intervention. METHODS: We designed a comprehensive and interactive hepatitis C-related educational intervention, composed of two 30 to 60-minute sessions conducted during 2 consecutive weeks. Patients' knowledge about hepatitis C was assessed immediately before and after the intervention using a 7-item questionnaire. RESULTS: A total of 110 patients completed both educational sessions. Patients' mean age was 54.7 ±â€Š7.8 years, 58.7% were men, 70.4% African American, and 30% were Hispanic. We observed a significant increase in HCV-related knowledge after completion of the educational intervention. Whereas 65.45% of patients answered 5 or more questions correctly before the intervention, 83.64% had 5 or more questions answered correctly on the posteducational quiz (P < 0.001). Male sex, ever receiving an HCV diagnostic test before the educational intervention, and a higher level of HCV knowledge on the preeducational quiz were found to be significantly associated with HCV-related knowledge after the educational intervention. CONCLUSIONS: Patients' knowledge about hepatitis C was found to be significantly improved after the educational intervention. Therefore, HCV-related education could be the first step toward effective enrollment of patients on opioid agonist therapy into hepatitis C care.

Intrahepatic and Peripheral CXCL10 Expression in Hepatitis C Virus-Infected Patients Treated With Telaprevir, Pegylated Interferon, and Ribavirin.

UNLABELLED: We assessed peripheral and liver CXCL10 levels in 15 patients treated with telaprevir/pegylated interferon/ribavirin. Induction of peripheral CXCL10 messenger RNA (mRNA) peaked (mean fold-induction [±SD], 3.1 ± 1.9) between treatment hour 6 and day 2, while induction of intrahepatic CXCL10 mRNA peaked (mean fold-induction [±SD], 1.3 ± 0.54) at hour 10 or day 4. Peripheral CXCL10 levels were higher at treatment hour 10 (P = .032) and day 2 (P = .009) in patients with undetectable virus 2 weeks after treatment initiation. Treatment hour 10 (P = .023) and peak (P = .034) intrahepatic CXCL10 levels were also higher in these patients. CXCL10 did not distinguish treatment responders from nonresponders. In conclusion, CXCL10 identified very rapid virological response in patients treated with a direct-acting antiviral. CLINICAL TRIALS REGISTRATION: NCT00892697.

FibroSURE as a noninvasive marker of liver fibrosis and inflammation in chronic hepatitis B.

BACKGROUND: Noninvasive markers of liver fibrosis have not been extensively studied in patients with chronic hepatitis B virus (HBV) infection. Our aim was to evaluate the capacity of FibroSURE, one of the two noninvasive fibrosis indices commercially available in the United States, to identify HBV infected patients with moderate to severe fibrosis. METHODS: Forty-five patients who underwent liver biopsy at a single tertiary care center were prospectively enrolled and had FibroSURE performed within an average interval of 11 days of the biopsy. RESULTS: Of the 45 patients, 40% were Asian, 40% were African American, and 13% were Caucasian; 27% were co-infected with HIV and 67% had no or mild fibrosis. We found FibroSURE to have moderate capacity to discriminate between patients with moderate to high fibrosis and those with no to mild fibrosis (area under receiver operating characteristic [AUROC] curve = 0.77; 95% confidence interval [CI] [0.61, 0.92]). When we combined the fibrosis score determined by FibroSURE with aspartate aminotransferase (AST) measurements and HIV co-infection status, the discriminatory ability significantly improved reaching an AUROC of 0.90 (95% CI [0.80, 1.00]). FibroSURE also had a good ability to differentiate patients with no or mild from those with moderate to high inflammation (AUROC = 0.83; 95% CI [0.71, 0.95]). CONCLUSIONS: FibroSURE in combination with AST levels has an excellent capacity to identify moderate to high fibrosis stages in chronic HBV-infected patients. These data suggest that FibroSURE may be a useful substitute for liver biopsy in chronic HBV infection.

Telaprevir-based treatment effects on hepatitis C virus in liver and blood.

UNLABELLED: Understanding hepatitis C virus (HCV) replication has been limited by access to serial samples of liver, the primary site of viral replication. Our understanding of how HCV replicates and develops drug-resistant variants in the liver is limited. We studied 15 patients chronically infected with genotype 1 HCV treated with telaprevir (TVR)/pegylated-interferon alpha/ribavirin. Hepatic fine needle aspiration was performed before treatment and at hour 10, days 4 and 15, and week 8 after initiation of antiviral therapy. We measured viral kinetics, resistance patterns, TVR concentrations, and host transcription profiles. All patients completed all protocol-defined procedures that were generally well tolerated. First-phase HCV decline (baseline/treatment day 4) was significantly slower in liver than in plasma (slope plasma: -0.29; liver, -0.009; P < 0.001), whereas second-phase decline (posttreatment days 4-15) did not differ between the two body compartments (-0.11 and -0.15, respectively; P = 0.1). TVR-resistant variants were detected in plasma, but not in liver (where only wild-type virus was detected). Based upon nonstructural protein 3 sequence analysis, no compartmentalization of viral populations was observed between plasma and liver compartments. Gene expression profiling revealed strong tissue-specific expression signatures. Human intrahepatic TVR concentration, measured for the first time, was lower, compared to plasma, on a gram per milliliter basis. We found moderate heterogeneity between HCV RNA levels from different intrahepatic sites, indicating differences in hepatic microenvironments. CONCLUSION: These data support an integrated model for HCV replication wherein the host hepatic milieu and innate immunity control the level of viral replication, and the early antiviral response observed in the plasma is predominantly driven by inhibition of hepatic high-level HCV replication sites.

Hepatitis C virus-related knowledge and willingness to receive treatment among patients on methadone maintenance.

OBJECTIVES: Although persons who inject drugs have high prevalence of hepatitis C virus (HCV) infection, few receive treatment mostly because of lack of knowledge about the infection and its treatment. We assessed the level of HCV-related knowledge and willingness to participate in HCV treatment among methadone-maintained patients. METHODS: A 30-item survey covering HCV-related knowledge and willingness to engage in HCV-related education and treatment was developed and completed by 320 methadone-maintained patients. RESULTS: Respondents' mean age was 53 ± 8.7 years, 59.5% were male, 55.1% were African American, and 38.3% were Hispanic. The mean duration of methadone maintenance was 7 ± 6.7 years. In the preceding 6 months, 6.9% of patients reported injection drug use, whereas 37.3% used noninjection drugs. Hepatitis C virus seropositivity was self-reported by 46.3% of patients. The majority of patients (78%) expressed willingness to participate in HCV-related education and to receive HCV treatment. Most patients (54.7%) correctly answered 5 or more of 7 questions assessing HCV knowledge. Hepatitis C virus-seropositive individuals and prior attendees at HCV-related educational activities demonstrated a higher level of HCV-related knowledge (P < 0.001 and P = 0.002, respectively). Younger patients (P = 0.014), those willing to attend an HCV-related educational activity (P < 0.001), and those with higher-HCV-related knowledge (P = 0.029) were more accepting of HCV treatment. Fear of medication-related side effects was the most common reason for treatment avoidance. CONCLUSIONS: The majority of patients reported willingness to receive HCV-related education and treatment. Treatment willingness was significantly associated with previous attendance at an HCV educational activity and a higher level of HCV-related knowledge.

IL28B polymorphism, pretreatment CXCL10, and HCV RNA levels predict treatment response in racially diverse HIV/HCV coinfected and HCV monoinfected patients.

OBJECTIVE: We sought to develop a score to predict sustained virological response (SVR) in racially diverse HIV/hepatitis C virus (HCV)-coinfected and HCV-monoinfected pegylated interferon/ribavirin-treated patients. METHODS: We retrospectively evaluated 374 patients (259 monoinfected and 115 coinfected) treated at a single tertiary care center. The IL28B rs12979860 single nucleotide polymorphism genotyping was performed in 335 patients, and plasma CXCL10 levels were measured by enzyme-linked immunosorbent assay in 171 patients. RESULTS: Of the 374 patients, 64.9% were white, 17.2% were African American, 76.5% were HCV genotype 1 infected, and 49.3% had advanced fibrosis. Sustained virological response was achieved by 151 (40.4%) patients, 106 (40.9%) patients monoinfected, and 45 (39.1%) patients coinfected. Patients with IL28B C/C genotype were significantly more likely to achieve an SVR compared with non-C/C genotype patients, but only if they were infected with HCV genotypes 1/4 (59.1% vs 21.1%, P < 0.0001). No significant differences existed in IL28B predictive capacity between coinfected and monoinfected patients. Pretreatment CXCL10 levels were significantly higher in nonresponders, both monoinfected and coinfected, compared with SVR patients (P = 0.0018). Coinfected patients had higher CXCL10 levels compared with monoinfected patients (P = 0.03). The combination of IL28B genotype, pretreatment CXCL10 and HCV RNA levels, and HCV genotype had the best ability to predict treatment response in both patient groups (area under the receiver operating characteristic curve = 0.85). Among all patients, a cutoff score of -0.94 or more had a sensitivity of 0.93 and specificity of 0.59. In coinfected patients, a score of -0.55 or more had sensitivity of 0.81 and specificity of 0.80. CONCLUSIONS: IL28B genotype, pretreatment CXCL10, and HCV RNA levels have very good capacity to predict pegylated interferon/ribavirin-treatment outcome in both HIV/HCV coinfected and HCV monoinfected patients.

Assessment of methadone clinic staff attitudes toward hepatitis C evaluation and treatment.

We used a 25-item, self-administered questionnaire to assess staff's perceived barriers and willingness to engage in onsite treatment of hepatitis C virus (HCV) at the Beth Israel Medical Center methadone maintenance treatment program (MMTP) at its Harlem sites. Of 80 participants, 50% were counselors and 24% were directly involved in referral or HCV testing. Although 92% of the MMTP staff indicated that they discuss HCV evaluation and treatment with patients at least annually, 70% believed that less than 25% of patients accept referral for HCV treatment and attend their initial appointment. Most staff (66%) supported onsite HCV evaluation and treatment, although support was higher among those with a bachelor's degree or higher (p = 0.046). Lack of infrastructure was perceived as the greatest obstacle to onsite treatment. Educational interventions and skill building for staff to confidently engage and support MMTP patients in HCV treatment may be necessary prerequisites for onsite HCV management in MMTPs.

Determinants of hepatitis C virus treatment completion and efficacy in drug users assessed by meta-analysis.

BACKGROUND: Hepatitis C virus (HCV)-infected drug users (DUs) have largely been excluded from HCV care. We conducted a systematic review and meta-analysis of the literature on treatment completion and sustained virologic response (SVR) rates in DUs. We assessed the effects of different treatment approaches and services to promote HCV care among DUs as well as demographic and viral characteristics. METHODS: Studies of at least 10 DUs treated with pegylated interferon/ribavirin that reported SVR were analyzed. Heterogeneity was assessed (Cochran test) and investigated (meta-regression), and pooled rates were estimated (random effects). RESULTS: Thirty-six studies comprising 2866 patients were retrieved. The treatment completion rate among DUs was 83.4% (95% confidence interval [CI], 77.1%-88.9%). Among studies that included addiction-treated and untreated patients during HCV therapy, the higher the proportion of addiction-treated patients, the higher the HCV treatment completion rate (P < .0001). After adjusting for human immunodeficiency virus (HIV)/HCV coinfection, sex, and treatment of addiction, support services during antiviral therapy increased treatment completion (P < .0001). The pooled SVR rate was 55.5% (95% CI, 50.6%-60.3%). Genotype 1/4 (P = .0012) and the proportion of HIV-coinfected DUs (P = .0173) influenced the SVR rate. After adjusting for HCV genotype 1/4 and HIV/HCV coinfection, the SVR rate was positively correlated with involvement of a multidisciplinary team (P < .0001). CONCLUSIONS: Treatment of addiction during HCV therapy results in higher treatment completion. Our pooled SVR rate is similar to that obtained in registration trials in the general population. Treatment of addiction during HCV therapy will likely be important for HCV-infected DUs undergoing treatment with more complex regimens including direct-acting antivirals.