Impact of 5 years of hepatitis C testing and treatment in the North East of England prisons.

Hepatitis C virus infection (HCV) is prevalent in prisons. Therefore, effective prison HCV services are critical for HCV elimination programmes. We aimed to evaluate the efficacy of a regional HCV prison testing and treatment programme. Between July 2017 and June 2022, data were collected prospectively on HCV test offer and uptake rates, HCV Antibody (HCV-Ab) and HCV-RNA positivity, treatment starts and outcomes for new inmates incarcerated in three prisons. Rates of HCV-Ab and RNA positivity at reception, incidence of new HCV infections and reinfection following treatment were determined. From a total of 39,652 receptions, 33,028 (83.3%) were offered HCV testing and 20,394 (61.7%) completed testing. Including all receptions, 24.5% of tests (n = 4995) were HCV-Ab positive and 8.4% of tests (n = 1713) were HCV-RNA positive. When considering the first test for each individual (median age 34 years; 88.1% male), 14.8% (n = 1869) and 7.2% (n = 905) were HCV-Ab and HCV-RNA positive, respectively. The incidence of new HCV-Ab and RNA positivity was 5.1 and 3.3 per 100 person-years, respectively. Of 1145 HCV viraemic individuals, 18 died within 6 months and 150 were rapidly transferred out of area, leaving 977 individuals with outcomes. Of these, 835 (85.5%) received antivirals and 47 spontaneously cleared the infection, leaving 95 (9.7%) untreated. 607 (72.7%) achieved SVR. 95 patients had reinfection post-treatment (rate 10.1 cases per 100 person-years). Testing for HCV has increased in our prisons and the majority with viraemia are initiated on antiviral treatment. Reassuringly, a significant fall in frequency of HCV-RNA positivity at prison reception was observed suggesting progress towards HCV elimination.

What is the impact of a Hepatitis C 'test, trace and treat' pilot using peer workers?

Chronic Hepatitis C virus (HCV) infection is a major cause of morbidity and deaths worldwide. HCV treating teams are working toward the goal of eliminating HCV by 2030. People who inject drugs (PWIDs) are at high risk of HCV but contact tracing is not routine practice. Here, we present the outcomes of a HCV 'test, trace and treat' pilot using peer workers to test contacts of individuals with HCV. PWIDs with HCV were invited to participate when they presented for treatment. For those agreeing to participate, a peer approached them to invite potential contacts for HCV testing. Data were collected on uptake, HCV test results, treatment rates and reasons for declining. Overall, 295 individuals (162 recent HCV [<1 year], 69 reinfections, 64 known chronic HCV) were invited to participate, of whom 147 (50%) agreed and 30 (20% of those agreeing) brought forward 120 contacts for testing. Of these, 44 (37%) were HCV RNA positive, including 23 who were not known to services. 34 (77%) started antiviral treatment. HCV RNA positivity was highest in contacts of reinfections (45%) compared with recent HCV (33%) and known chronic HCV (25%). The most common reason for index individuals declining participation was that they reported no longer being in contact with individuals from their injecting network (65%). In conclusion, half of PWIDs with HCV agreed to participate in the pilot, but only 20% of these brought contacts forward. The frequency of active HCV was high in the contacts and the majority started antiviral treatment.

The Role of Sudanese Doctors in the United Kingdom in Mitigating COVID-19 Vaccine Hesitancy Among Their Diaspora Communities.

People from ethnic minority groups are at risk of adverse sequelae of COVID-19, but their vaccine acceptance and enrollment rates remain suboptimal. Diaspora communities are unique in that they continue to engage in epistemic networks related to vaccination with dwellers in their country of origin. We describe the COVID-19 vaccine awareness campaign we conducted from January 2021 to November 2021 for Sudanese diaspora groups in the United Kingdom and the various techniques and methods used by health care professionals from the same ethnocultural background to address vaccine reluctance among this cohort. We explore the impact of our joint efforts with local authorities in Sudan to overcome the initial barriers to the national vaccination program in Sudan. The influence of the intercommunication between the diaspora and their relatives at home regarding COVID-19 vaccine misinformation is also discussed. Finally, we highlight these observations as key areas for future research to improve the global impact of vaccine deployment in pandemic situations.

Ledipasvir/sofosbuvir and ribavirin for the treatment of ribavirin-refractory persistent hepatitis E virus infection.

Persistent Hepatitis E Virus infection (HEV) is a rare but increasingly recognised condition in immunocompromised individuals. Untreated, this infection can rapidly progress to cirrhosis. Ribavirin is recommended as the first line treatment and the majority achieve sustained viral clearance. However, treatment options are limited for those who fail ribavirin. We report a case of a patients with ribavirin-refractory persistent HEV who responded to ledipasvir/sofosbuvir and ribavirin treatment. This patients had failed 2 course of ribavirin and 1 course of PEG-Interferon and ribavirin and he was known to harbour ribavirin-associated mutations (G1634R, D1384G and K1383N) in the RNA dependent RNA polymerase. He was treated with ledipasvir/sofosbuvir (LDV/SOF; Harvoni 90/400 mg) and ribavirin (R) 400 mg twice daily for 32 weeks. At treatment initiation his HEV RNA was 1.1 × 106 IU/ML and reduced to 1.8 × 104 IU/ML and 43 IU/ML at one and four weeks of treatment, respectively, becoming not detected in blood and stool by week eight. His blood HEV RNA remained undetectable for seven months after treatment completion. Unfortunately, at eight months post-treatment, his blood HEV RNA became detectable at a low level (35 IU/ML). His stool HEV RNA was also detectable at 620 IU/ML consistent with a late relapse. He restarted LDV/SOF+R and by week four of treatment HEV RNA was not detected in blood and stool. He remains on treatment. In conclusion, this is the first report demonstrating the antiviral activity of LDV/SOF+R in the treatment of persistent HEV infection.

HTLV seroprevalence in people using HIV pre-exposure prophylaxis in England.

OBJECTIVES: HTLV-1 is predominantly a sexually-transmitted infection but testing is not mentioned in HIV-PrEP guidelines. We ascertained HTLV-1/HTLV-2 seroprevalence amongst HIV-PrEP users in England. METHODS: An unlinked anonymous seroprevalence study. RESULTS: Amongst 2015 HIV-PrEP users, 95% were men, 76% of white ethnicity and 83% had been born in Europe. There were no HTLV-1/HTLV-2 seropositive cases (95% confidence interval 0% - 0.18%). CONCLUSIONS: There were no HTLV positive cases, likely reflecting the demographic of mostly white and European-born individuals. Similar studies are needed worldwide to inform public health recommendations for HIV-PrEP using populations, particularly in HTLV-endemic settings.

Effectiveness of rapid SARS-CoV-2 genome sequencing in supporting infection control for hospital-onset COVID-19 infection: Multicentre, prospective study.

Background: Viral sequencing of SARS-CoV-2 has been used for outbreak investigation, but there is limited evidence supporting routine use for infection prevention and control (IPC) within hospital settings. Methods: We conducted a prospective non-randomised trial of sequencing at 14 acute UK hospital trusts. Sites each had a 4-week baseline data collection period, followed by intervention periods comprising 8 weeks of 'rapid' (<48 hr) and 4 weeks of 'longer-turnaround' (5-10 days) sequencing using a sequence reporting tool (SRT). Data were collected on all hospital-onset COVID-19 infections (HOCIs; detected ≥48 hr from admission). The impact of the sequencing intervention on IPC knowledge and actions, and on the incidence of probable/definite hospital-acquired infections (HAIs), was evaluated. Results: A total of 2170 HOCI cases were recorded from October 2020 to April 2021, corresponding to a period of extreme strain on the health service, with sequence reports returned for 650/1320 (49.2%) during intervention phases. We did not detect a statistically significant change in weekly incidence of HAIs in longer-turnaround (incidence rate ratio 1.60, 95% CI 0.85-3.01; p=0.14) or rapid (0.85, 0.48-1.50; p=0.54) intervention phases compared to baseline phase. However, IPC practice was changed in 7.8 and 7.4% of all HOCI cases in rapid and longer-turnaround phases, respectively, and 17.2 and 11.6% of cases where the report was returned. In a 'per-protocol' sensitivity analysis, there was an impact on IPC actions in 20.7% of HOCI cases when the SRT report was returned within 5 days. Capacity to respond effectively to insights from sequencing was breached in most sites by the volume of cases and limited resources. Conclusions: While we did not demonstrate a direct impact of sequencing on the incidence of nosocomial transmission, our results suggest that sequencing can inform IPC response to HOCIs, particularly when returned within 5 days. Funding: COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) (grant code: MC_PC_19027), and Genome Research Limited, operating as the Wellcome Sanger Institute. Clinical trial number: NCT04405934.

Determining the frequency and characteristics of Hepatitis C reinfections in North East England.

Hepatitis C virus infection (HCV) is common, and injecting drug use is the major risk factor for acquisition. Understanding HCV reinfection following treatment is an important consideration for HCV elimination programmes. The aim of this work was to assess the frequency and patterns of HCV reinfection in our region to develop avoidance strategies. All individuals who completed anti-HCV treatment with a known outcome in Tyne and Wear, England between January 2016 and May 2021 were included. This was a retrospective analysis of prospectively collected data. HCV reinfection was defined as positive HCV RNA after achieving sustained virological response 12 (SVR12). 788 of 840 patients (76% male; mean age 45.7 ± 11.9 years; 47% Genotype 1; 11% Cirrhosis; 20% started in prison) achieved SVR (94%). 443 patients (56%) had HCV RNA testing post-SVR after a median 0.82 (range 0.1-5.2) years. 56 reinfections (7.1% of all SVRs and 12.6% of SVRs who had post-SVR testing) were diagnosed. The median time to reinfection was 1.37 (range 0.1-4.0) years and the rate of reinfection was 10.5 /100 person years. 45 (80%) reinfections became chronic, 17 of whom were retreated and achieved SVR. 5 individuals developed a second reinfection. Younger age was the only factor independently associated with reinfection (HR 0.91 [0.88-0.94] p < .001). In conclusion, HCV reinfection is common and may slow our HCV elimination efforts. In order to address high reinfection rates, harm minimization approaches need improved, and we have implemented an 'HCV track and trace' pilot to try to reduce onwards HCV transmission.

A fast and sensitive absolute quantification assay for the detection of SARS-CoV-2 peptides using parallel reaction monitoring mass spectrometry.

The on-going SARS-CoV-2 (COVID-19) pandemic has called for an urgent need for rapid and high-throughput methods for mass testing and early detection, prevention as well as surveillance of the disease. We investigated whether targeted parallel reaction monitoring (PRM) quantification using high resolution Orbitrap instruments can provide the sensitivity and speed required for a high-throughput method that could be used for clinical diagnosis. We developed a high-throughput and sensitive PRM-MS assay that enables absolute quantification of SARS-CoV-2 nucleocapsid peptides with short turn-around times by using isotopically labelled synthetic SARS-CoV-2 concatenated peptides. We established a fast and high-throughput S-trap-based sample preparation method and utilized it for testing 25 positive and 25 negative heat-inactivated clinical nasopharyngeal swab samples for SARS-CoV-2 detection. The method was able to differentiate between negative and some of the positive patients with high viral load. Moreover, based on the absolute quantification calculations, our data show that patients with Ct values as low as 17.8 correspond to NCAP protein amounts of around 7.5 pmol in swab samples. The present high-throughput method could potentially be utilized in specialized clinics as an alternative tool for detection of SARS-CoV-2 but will require enrichment of viral proteins in order to compete with RT-qPCR.

Case Report: Severe Acute Pulmonary COVID-19 in a Teenager Post Autologous Hematopoietic Stem Cell Transplant.

Pulmonary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is generally described as mild, and SARS-CoV-2 infection in immunocompromised children are observed as generally mild as well. A small proportion of pediatric patients will become critically ill due to (cardio)respiratory failure and require intensive care treatment. We report the case of a teenager with Hodgkin's lymphoma who acquired SARS-CoV-2 (detected by PCR) on the day of her autologous stem cell transplant and developed acute respiratory distress syndrome, successfully treated with a combination of antivirals, immunomodulation with steroids and biologicals, and ECMO.

Persistent SARS-CoV-2 infection in patients with secondary antibody deficiency: successful clearance following combination casirivimab and imdevimab (REGN-COV2) monoclonal antibody therapy.

BACKGROUND: There is growing evidence that antibody responses play a role in the resolution of SARS-CoV-2 infection. Patients with primary or secondary antibody deficiency are at increased risk of persistent infection. This challenging clinical scenario is associated with adverse patient outcome and potentially creates an ecological niche for the evolution of novel SARS-CoV-2 variants with immune evasion capacity. Case reports and/or series have implied a therapeutic role for convalescent plasma (CP) to secure virological clearance, although concerns have been raised about the effectiveness of CP and its potential to drive viral evolution, and it has largely been withdrawn from clinical use in the UK. CASE PRESENTATION: We report two cases in which persistent SARS-CoV-2 infection was cleared following administration of the monoclonal antibody combination casirivimab and imdevimab (REGN-COV2, Ronapreve). A 55-year-old male with follicular lymphoma, treated with B cell depleting therapy, developed SARS-CoV-2 infection in September 2020 which then persisted for over 200 days. He was hospitalised on four occasions with COVID-19 and suffered debilitating fatigue and malaise throughout. There was no clinical response to antiviral therapy with remdesivir or CP, and SARS-CoV-2 was consistently detected in nasopharyngeal swabs. Intrahost evolution of several spike variants of uncertain significance was identified by viral sequence analysis. Delivery of REGN-COV2, in combination with remdesivir, was associated with clinical improvement and viral clearance within 6 days, which was sustained for over 150 days despite immunotherapy for relapsed follicular lymphoma. The second case, a 68-year-old female with chronic lymphocytic leukaemia on ibrutinib, also developed persistent SARS-CoV-2 infection. Despite a lack of response to remdesivir, infection promptly cleared following REGN-COV2 in combination with remdesivir, accompanied by resolution of inflammation and full clinical recovery that has been maintained for over 290 days. CONCLUSIONS: These cases highlight the potential benefit of REGN-COV2 as therapy for persistent SARS-CoV-2 infection in antibody deficient individuals, including after failure of CP treatment. Formal clinical studies are warranted to assess the effectiveness of REGN-COV2 in antibody-deficient patients, especially in light of the emergence of variants of concern, such as Omicron, that appear to evade REGN-COV2 neutralisation.

SARS-CoV-2 Testing of 11,884 Healthcare Workers at an Acute NHS Hospital Trust in England: A Retrospective Analysis.

Healthcare workers (HCWs) are known to be at increased risk of infection with SARS-CoV-2, although whether these risks are equal across all roles is uncertain. Here we report a retrospective analysis of a large real-world dataset obtained from 10 March to 6 July 2020 in an NHS Foundation Trust in England with 17,126 employees. 3,338 HCWs underwent symptomatic PCR testing (14.4% positive, 2.8% of all staff) and 11,103 HCWs underwent serological testing for SARS-CoV-2 IgG (8.4% positive, 5.5% of all staff). Seropositivity was lower than other hospital settings in England but higher than community estimates. Increased test positivity rates were observed in HCWs from BAME backgrounds and residents in areas of higher social deprivation. A multiple logistic regression model adjusting for ethnicity and social deprivation confirmed statistically significant increases in the odds of testing positive in certain occupational groups, most notably domestic services staff, nurses, and health-care assistants. PCR testing of symptomatic HCWs appeared to underestimate overall infection levels, probably due to asymptomatic seroconversion. Clinical outcomes were reassuring, with only a small minority of HCWs with COVID-19 requiring hospitalization (2.3%) or ICU management (0.7%) and with no deaths. Despite a relatively low level of HCW infection compared to other UK cohorts, there were nevertheless important differences in test positivity rates between occupational groups, robust to adjustment for demographic factors such as ethnic background and social deprivation. Quantitative and qualitative studies are needed to better understand the factors contributing to this risk. Robust informatics solutions for HCW exposure data are essential to inform occupational monitoring.

COVID-19 Management in a UK NHS Foundation Trust with a High Consequence Infectious Diseases Centre: A Retrospective Analysis.

Recent large national and international cohorts describe the baseline characteristics and outcome of hospitalised patients with COVID-19, however there is limited granularity to these reports. We aimed to provide a detailed description of a UK COVID-19 cohort, focusing on management and outcome. We performed a retrospective single-centre analysis of clinical management and 28-day outcomes of consecutive adult inpatients with SARS-CoV-2 PCR-confirmed COVID-19 from 31 January to 16 April 2020 inclusive. In total, 316 cases were identified. Most patients were elderly (median age 75) with multiple comorbidities. One quarter were admitted from residential or nursing care. Mortality was 84 out of 316 (26.6%). Most deaths occurred in patients in whom a ceiling of inpatient treatment had been determined and for whom end of life care and specialist palliative care input was provided where appropriate. No deaths occurred in patients aged under 56 years. Decisions to initiate respiratory support were individualised after consideration of patient wishes, premorbid frailty and comorbidities. In total, 59 (18%) patients were admitted to intensive care, of which 31 (10% overall cohort) required intubation. Multiple logistic regression identified associations between death and age, frailty, and disease severity, with age as the most significant factor (odds ratio 1.07 [95% CI 1.03-1.10] per year increase, p < 0.001). These findings provide important clinical context to outcome data. Mortality was associated with increasing age. Most deaths were anticipated and occurred in patients with advance decisions on ceilings of treatment.

High rate of hepatitis C reinfection following antiviral treatment in the North East England Prisons.

To achieve elimination of hepatitis C (HCV), a critical group to prioritise for diagnosis and treatment is the prison population, where HCV prevalence is high. A universal offer of blood-borne virus testing (UOBBVT) programme and a new treatment pathway were introduced to seven North East England (NEE) Prisons. Our aim was to assess: (a) the proportion of individuals with active HCV commencing direct-acting antivirals (DAAs); (b) the outcomes following DAA treatment; (3) the reinfection rate following sustained virological response (SVR). Data were collected prospectively on BBVT uptake, HCV positivity, HCV treatment outcomes and reinfection from March 2016 onwards. 8538 individuals had BBV testing. In total, 612 (7.2%) and 374 (4.4%) were HCV antibody positive and HCV RNA positive, respectively. Ultimately, 266 (71%) individuals commenced DAAs. Overall 111 achieved a documented SVR (42%), 17 (6%) failed treatment, 30 (11%) were still on treatment or had not reached 12 weeks post-treatment at time of analysis, and 108 (41%) were lost to follow-up. In those with a known outcome (n = 128), 87% achieved SVR. Worryingly, of those who achieved SVR, 21 (19%) were subsequently identified as having been reinfected (median time from SVR to documented reinfection 13 (range 7-25) months). The reinfection rate was 0.406 cases per person-year follow-up. In conclusion, Implementation of a UOBBVT programme and new treatment pathway resulted in increased diagnosis and treatment of HCV in the NEE prison population. However, the high HCV reinfection rate suggests a need to improve harm reduction approaches.

Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-ß1b (MIRACLE trial): study protocol for a randomized controlled trial.

BACKGROUND: It had been more than 5 years since the first case of Middle East Respiratory Syndrome coronavirus infection (MERS-CoV) was recorded, but no specific treatment has been investigated in randomized clinical trials. Results from in vitro and animal studies suggest that a combination of lopinavir/ritonavir and interferon-ß1b (IFN-ß1b) may be effective against MERS-CoV. The aim of this study is to investigate the efficacy of treatment with a combination of lopinavir/ritonavir and recombinant IFN-ß1b provided with standard supportive care, compared to treatment with placebo provided with standard supportive care in patients with laboratory-confirmed MERS requiring hospital admission. METHODS: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. Hospitalized adult patients with laboratory-confirmed MERS will be enrolled in this recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The trial is initially designed to include 2 two-stage components. The first two-stage component is designed to adjust sample size and determine futility stopping, but not efficacy stopping. The second two-stage component is designed to determine efficacy stopping and possibly readjustment of sample size. The primary outcome is 90-day mortality. DISCUSSION: This will be the first randomized controlled trial of a potential treatment for MERS. The study is sponsored by King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. Enrollment for this study began in November 2016, and has enrolled thirteen patients as of Jan 24-2018. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02845843 . Registered on 27 July 2016.

Feasibility of Using Convalescent Plasma Immunotherapy for MERS-CoV Infection, Saudi Arabia.

We explored the feasibility of collecting convalescent plasma for passive immunotherapy of Middle East respiratory syndrome coronavirus (MERS-CoV) infection by using ELISA to screen serum samples from 443 potential plasma donors: 196 patients with suspected or laboratory-confirmed MERS-CoV infection, 230 healthcare workers, and 17 household contacts exposed to MERS-CoV. ELISA-reactive samples were further tested by indirect fluorescent antibody and microneutralization assays. Of the 443 tested samples, 12 (2.7%) had a reactive ELISA result, and 9 of the 12 had reactive indirect fluorescent antibody and microneutralization assay titers. Undertaking clinical trials of convalescent plasma for passive immunotherapy of MERS-CoV infection may be feasible, but such trials would be challenging because of the small pool of potential donors with sufficiently high antibody titers. Alternative strategies to identify convalescent plasma donors with adequate antibody titers should be explored, including the sampling of serum from patients with more severe disease and sampling at earlier points during illness.

Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol.

As of September 30, 2015, a total of 1589 laboratory-confirmed cases of infection with the Middle East respiratory syndrome coronavirus (MERS-CoV) have been reported to the World Health Organization (WHO). At present there is no effective specific therapy against MERS-CoV. The use of convalescent plasma (CP) has been suggested as a potential therapy based on existing evidence from other viral infections. We aim to study the feasibility of CP therapy as well as its safety and clinical and laboratory effects in critically ill patients with MERS-CoV infection. We will also examine the pharmacokinetics of the MERS-CoV antibody response and viral load over the course of MERS-CoV infection. This study will inform a future randomized controlled trial that will examine the efficacy of CP therapy for MERS-CoV infection. In the CP collection phase, potential donors will be tested by the enzyme linked immunosorbent assay (ELISA) and the indirect fluorescent antibody (IFA) techniques for the presence of anti-MERS-CoV antibodies. Subjects with anti-MERS-CoV IFA titer of ≥1:160 and no clinical or laboratory evidence of MERS-CoV infection will be screened for eligibility for plasma donation according to standard donation criteria. In the CP therapy phase, 20 consecutive critically ill patients admitted to intensive care unit with laboratory-confirmed MERS-CoV infection will be enrolled and each will receive 2 units of CP. Post enrollment, patients will be followed for clinical and laboratory outcomes that include anti-MERS-CoV antibodies and viral load. This protocol was developed collaboratively by King Abdullah International Medical Research Center (KAIMRC), Gulf Cooperation Council (GCC) Infection Control Center Group and the World Health Organization-International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC-WHO) MERS-CoV Working Group. It was approved in June 2014 by the Ministry of the National Guard Health Affairs Institutional Review Board (IRB). A data safety monitoring board (DSMB) was formulated. The study is registered at http://www.clinicaltrials.gov (NCT02190799).

Using recent infection testing algorithm tests in clinical practice.

OBJECTIVES: Recent Infection Testing Algorithm (RITA) tests are used in public health surveillance to identify the incidence of recently acquired HIV infection. This can then be used to direct public health interventions and evaluate their effects. We aimed to outline how RITA tests may be used in clinical practice with individual patients, as well as highlighting the cautions needed. METHODS: The clinical and laboratory aspects of RITA tests have been reviewed in the paper together with their clinical applications. RESULTS: For individuals, RITA tests can help to confirm primary HIV infection and can be useful with elements of partner notification. However, careful evaluation of the result is required and it should be considered in conjunction with the clinical history and findings. CONCLUSIONS: There are major epidemiological and public health advantages in using RITA testing but there are also advantages to using the RITA test on an individual basis, provided that it is used appropriately.