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Introduction: The phase 3 PROVENT and STORM CHASER studies evaluated AZD7442 (tixagevimab/cilgavimab) for pre-exposure and post-exposure prophylaxis of symptomatic coronavirus disease 2019 (COVID-19). We report the final 15-month results of both studies. Methods: In PROVENT, participants were randomized 2:1 to receive 300 mg AZD7442 (n = 3460) or placebo (n = 1737). In STORM CHASER, participants were enrolled within 8 days of exposure to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individual and randomized 2:1 to receive 300 mg AZD7442 (n = 749) or placebo (n = 372). Results: In PROVENT, the relative risk reduction (RRR) in symptomatic COVID-19 for AZD7442 versus placebo was 76.7% at primary analysis [95% confidence interval (CI) 46.1, 90.0; p < 0.001], 83.0% at day 183 (95% CI 67.3, 91.2; nominal p < 0.001), and 46.3% at day 366 (95% CI 23.1, 62.4; nominal p < 0.001). Severe/critical COVID-19 was reduced by 91.4% with AZD7442 versus placebo by day 366 (95% CI 61.3, 98.1; nominal p < 0.0001). Adverse events (AEs) occurred in 58.2% and 58.0% of participants administered AZD7442 or placebo, respectively; serious AEs (SAEs) occurred in 6.2% and 5.6%, respectively. In STORM CHASER, the RRR in symptomatic COVID-19 for AZD7442 versus placebo was 33.3% at primary analysis (95% CI − 25.9, 64.7; p = 0.212), 43.3% at day 183 (95% CI 1.4, 67.4; nominal p = 0.044) and 3.4% at day 366 (95% CI − 35.6, 31.2; nominal p = 0.842). Severe/critical COVID-19 did not occur in participants receiving AZD7442 versus 0.5% of participants receiving placebo by day 366. AEs occurred in 46.5% and 51.9% of participants administered AZD7442 or placebo, respectively; SAEs occurred in 2.7% and 4.3%, respectively. In both studies, serum concentration–time profiles over 457 days were similar for tixagevimab and cilgavimab and consistent with the extended half-life reported for AZD7442 (approximately 90 days). Conclusion: This analysis provides proof of concept supporting long-term safety of intramuscularly administered AZD7442 for prevention of symptomatic/severe COVID-19. A graphical abstract is available with this article. Clinicaltrials.gov Identifiers: PROVENT (NCT04625725) and STORM CHASER (NCT04625972). Plain Language Summary: Antibodies are proteins produced by the body's immune system to specifically target foreign substances, such as viruses. AZD7442 is made up of an antibody pair (tixagevimab and cilgavimab) that specifically bind and neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19). AZD7442 was designed to give several months of protection against the virus. These antibodies were tested in two clinical trials to see if they could either protect people from getting COVID-19 (PROVENT trial) or prevent people already exposed to SARS-CoV-2 from getting COVID-19 (STORM CHASER trial). In the two trials, approximately 6000 adults received AZD7442 or placebo (injections that look exactly like AZD7442 but contain no medicine). Protection against COVID-19 was monitored for up to 1 year, and safety for up to 15 months. The percentage of trial participants who reported side effects was similar in the AZD7442 and placebo groups, in both trials. The PROVENT trial showed that AZD7442 reduced the risk of getting COVID-19 up to 6 months and protected against severe COVID-19 for up to 1 year. In STORM CHASER, participants were treated after SARS-CoV-2 exposure but before a positive COVID-19 test. Some participants were already infected with SARS-CoV-2 at the start of the trial, others were not. STORM CHASER showed that AZD7442 protected people against COVID-19 for up to 6 months if they were not already infected at the start. The results of these trials provide proof of concept to support the long-term safety of AZD7442 for the prevention of COVID-19. [ABSTRACT FROM AUTHOR]

Background This phase 3 trial assessed AZD7442 (tixagevimab/cilgavimab) for post-exposure prophylaxis against symptomatic coronavirus disease 2019 (COVID-19). Methods Adults without prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or COVID-19 vaccination were enrolled within 8 days of exposure to a SARS-CoV-2–infected individual and randomized 2:1 to a single 300-mg AZD7442 dose (one 1.5-mL intramuscular injection each of tixagevimab and cilgavimab) or placebo. Primary end points were safety and first post-dose SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR)–positive symptomatic COVID-19 event before day 183. Results A total of 1121 participants were randomized and dosed (AZD7442, n = 749; placebo, n = 372). Median (range) follow-up was 49 (5–115) and 48 (20–113) days for AZD7442 and placebo, respectively. Adverse events occurred in 162 of 749 (21.6%) and 111 of 372 (29.8%) participants with AZD7442 and placebo, respectively, mostly mild/moderate. RT-PCR–positive symptomatic COVID-19 occurred in 23 of 749 (3.1%) and 17 of 372 (4.6%) AZD7442- and placebo-treated participants, respectively (relative risk reduction, 33.3%; 95% confidence interval [CI], −25.9 to 64.7; P =.21). In predefined subgroup analyses of 1073 (96%) participants who were SARS-CoV-2 RT-PCR–negative (n = 974, 87%) or missing an RT-PCR result (n = 99, 9%) at baseline, AZD7442 reduced RT-PCR–positive symptomatic COVID-19 by 73.2% (95% CI, 27.1 to 90.1) vs placebo. Conclusions This study did not meet the primary efficacy end point of post-exposure prevention of symptomatic COVID-19. However, analysis of participants who were SARS-CoV-2 RT-PCR–negative or missing an RT-PCR result at baseline support a role for AZD7442 in preventing symptomatic COVID-19. Clinical Trials Registration. NCT04625972. [ABSTRACT FROM AUTHOR]

Background: The monoclonal-antibody combination AZD7442 is composed of tixagevimab and cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that have an extended half-life and have been shown to have prophylactic and therapeutic effects in animal models. Pharmacokinetic data in humans indicate that AZD7442 has an extended half-life of approximately 90 days.Methods: In an ongoing phase 3 trial, we enrolled adults (≥18 years of age) who had an increased risk of an inadequate response to vaccination against coronavirus disease 2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intramuscular injections, one containing tixagevimab and the other containing cilgavimab) of either 300 mg of AZD7442 or saline placebo, and they were followed for up to 183 days in the primary analysis. The primary safety end point was the incidence of adverse events after a single dose of AZD7442. The primary efficacy end point was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-transcriptase-polymerase-chain-reaction assay) occurring after administration of AZD7442 or placebo and on or before day 183.Results: A total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended follow-up at a median of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19-related deaths occurred, all in the placebo group.Conclusions: A single dose of AZD7442 had efficacy for the prevention of Covid-19, without evident safety concerns. (Funded by AstraZeneca and the U.S. government; PROVENT ClinicalTrials.gov number, NCT04625725.). [ABSTRACT FROM AUTHOR]

Elimination of the three blood-borne viruses—human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV)—as public health issues may be plausible in the near future. Spectacular advances have been made with the introduction of highly effective antiviral agents into clinical practice, and prevention strategies are available for all three infections. Effective disease control, laid out by WHO global strategies, is currently feasible for all three viruses. However, for worldwide elimination of these viruses, effective vaccines are required that are currently only available for HBV. In this review differences and parallels among HIV, HCV and HBV will be discussed with a focus on virologic and therapeutic issues, and prospects for the future of HBV will be presented. [ABSTRACT FROM AUTHOR]

Pre-exposure prophylaxis (PrEP) offers a promising new approach to HIV prevention. It is protective against HIV infection across populations and has few significant safety risks and little evidence of behavioural risk compensation. This article summarises the evidence behind HIV PrEP as an intervention, populations that may benefit, current guidelines and programmes, and the cost-effectiveness modelling of this strategy. [ABSTRACT FROM AUTHOR]

Summary: Early in the HIV epidemic it was feared that the disease would undermine leprosy control, as has occurred with tuberculosis. It was predicted that patients with leprosy and HIV coinfection would have an increased risk of lepromatous disease and a faster clinical evolution, and that the leprosy would be more difficult to treat. None of these concerns have materialised and the interaction between HIV and Mycobacterium leprae seems to be far more subtle than that between HIV and tuberculosis. We review the epidemiological, clinical, and pathological data relating to leprosy/HIV coinfection. The published epidemiological data are limited in quality but show neither an increased HIV prevalence among leprosy cases nor an alteration in clinical spectrum of leprosy among coinfected patients. Some data suggest that immune-mediated reactions that complicate leprosy occur at a higher frequency in coinfected patients. Leprosy has now been reported presenting as immune reconstitution disease among patients commencing highly active antiretroviral treatment. Histopathological observations reveal a normal spectrum of appearances in biopsies of leprosy lesions from coinfected patients, even among those with advanced immunodeficiency. These observations suggest that cell-mediated immune responses to M leprae are preserved at the site of disease despite evidence that these responses are abrogated systemically, by contrast with tuberculosis, in which the host granulomatous response is impaired by HIV coinfection. We speculate that this paradox may relate to differences between the activation state and rates of cell turnover within leprosy and tuberculosis granulomas that differentially affect the susceptibility of the granulomas to HIV. The interactions between leprosy and HIV have been little studied and further research on the clinical, pathological, and management aspects of this coinfection is warranted. [Copyright &y& Elsevier]

A letter to the editor is presented about a study on the impact of highly active antiretroviral therapy for the treatment of bacterial disease in human immunodeficiency virus (HIV)-infected patients.

Introduction: The delivery of COVID-19 vaccines was successful in reducing hospitalizations and mortality. However, emergence of the Omicron variant resulted in increased virus transmissibility. Consequently, booster vaccination programs were initiated to decrease the risk of severe disease and death among vulnerable members of the population. This study aimed to estimate the effects of the booster program and alternative vaccination strategies on morbidity and mortality due to COVID-19 in the UK. Method: A Susceptible-Exposed-Infectious-Recovered (SEIR) model was used to assess the impact of several vaccination strategies on severe outcomes associated with COVID-19, including hospitalizations, mortality, National Health Service (NHS) capacity quantified by hospital general ward and intensive care unit (ICU) bed days, and patient productivity. The model accounted for age-, risk- and immunity-based stratification of the UK population. Outcomes were evaluated over a 48-week time horizon from September 2022 to August 2023 considering the actual UK autumn 2022/spring 2023 booster campaigns and six counterfactual strategies. Results: The model estimated that the autumn 2022/spring 2023 booster campaign resulted in a reduction of 18,921 hospitalizations and 1463 deaths, compared with a no booster scenario. Utilization of hospital bed days due to COVID-19 decreased after the autumn 2022/spring 2023 booster campaign. Expanding the booster eligibility criteria and improving uptake improved all outcomes, including averting twice as many ICU admissions, preventing more than 20% additional deaths, and a sevenfold reduction in long COVID, compared with the autumn 2022/spring 2023 booster campaign. The number of productive days lost was reduced by fivefold indicating that vaccinating a wider population has a beneficial impact on the morbidities associated with COVID-19. Conclusion: Our modelling demonstrates that the autumn 2022/spring 2023 booster campaign reduced COVID-19-associated morbidity and mortality. Booster campaigns with alternative eligibility criteria warrant consideration in the UK, given their potential to further reduce morbidity and mortality as future variants emerge. [ABSTRACT FROM AUTHOR]

Objectives: To describe the clinical epidemiology of COVID‐19 in people of black ethnicity living with HIV in the UK. Methods: We investigated the incidence and factors associated with COVID‐19 in a previously established and well‐characterized cohort of black people with HIV. Primary outcomes were COVID‐19 acquisition and severe COVID‐19 disease (requiring hospitalization and/or resulting in death). Cumulative incidence was analysed using Nelson–Aalen methods, and associations between demographic, pre‐pandemic immune‐virological parameters, comorbidity status and (severe) COVID‐19 were identified using Cox regression analysis. Results: COVID‐19 status was available for 1847 (74%) of 2495 COVID‐AFRICA participants (median age 49.6 years; 56% female; median CD4 cell count = 555 cells/μL; 93% HIV RNA <200 copies/mL), 573 (31%) of whom reported at least one episode of COVID‐19. The cumulative incidence rates of COVID‐19 and severe COVID‐19 were 31.0% and 3.4%, respectively. Region of ancestry (East/Southern/Central vs. West Africa), nadir CD4 count and kidney disease were associated with COVID‐19 acquisition. Diabetes mellitus [adjusted hazard ratio (aHR) = 2.39, 95% confidence interval (CI): 1.26–4.53] and kidney disease (aHR = 2.53, 95% CI: 1.26–4.53) were associated with an increased risk, and recent CD4 count >500 cells/μL (aHR = 0.49, 95% CI: 0.25–0.93) with a lower risk of severe COVID‐19. Conclusions: Region of ancestry was associated with COVID‐19 acquisition, and immune and comorbidity statuses were associated with COVID‐19 disease severity in people of black ethnicity living with HIV in the UK. [ABSTRACT FROM AUTHOR]

Background We report spike protein-based lineage and AZD7442 (tixagevimab/cilgavimab) neutralizing activity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants identified from breakthrough infections in the PROVENT preexposure prophylaxis trial. Methods Variants identified from PROVENT participants with reverse-transcription polymerase chain reaction-positive symptomatic illness were phenotypically assessed to determine neutralization susceptibility of variant-specific pseudotyped virus-like particles. Results At completion of 6 months' follow-up, no AZD7442-resistant variants were observed in breakthrough coronavirus disease 2019 (COVID-19) cases. SARS-CoV-2 neutralizing antibody titers were similar in breakthrough and nonbreakthrough cases. Conclusions Symptomatic COVID-19 breakthrough cases in PROVENT were not due to resistance-associated substitutions in AZD7442 binding sites or lack of AZD7442 exposure. Clinical Trials Registration NCT04625725. [ABSTRACT FROM AUTHOR]

Objectives: We examined follicle‐stimulating hormone (FSH) levels in women living with HIV aged > 45 reporting ≥ 12 months' amenorrhoea, and investigated correlation with menopausal symptoms. Methods: A cross‐sectional substudy of 85 women from the Positive Transitions through the Menopause (PRIME) Study who reported irregular periods at entry into the PRIME Study and ≥ 12 months' amenorrhoea at recruitment into this substudy. Serum FSH was supplemented with clinical data and menopausal symptom assessment. Serum FSH > 30 mIU/mL was defined as consistent with postmenopausal status. Associations between FSH and menopausal symptom severity were assessed using Pearson's correlation and the Kruskal–Wallis test. Results: Median age was 53 years [interquartile range (IQR): 51–55]; all were on antiretroviral therapy, three‐quarters (n = 65) had a CD4 T‐cell count > 500 cells/μL and 91.8% (n = 78) had an HIV viral load (VL) < 50 copies/mL. Median FSH was 65.9 mIU/mL (IQR: 49.1–78.6). Only four women (4.7%) had FSH ≤ 30 mIU/mL; none reported smoking or drug use, all had CD4 T‐cell count ≥ 200 cells/μL, and one had viral load (VL) ≥ 50 copies/mL. Median body mass index (BMI) was elevated compared with women with FSH > 30 mIU/mL (40.8 vs. 30.5 kg/m2). Over a quarter (28.2%) reported severe menopausal symptoms, with no correlation between FSH and severity of menopausal symptoms (p = 0.21), or hot flushes (p = 0.37). Conclusions: Four women in this small substudy had low FSH despite being amenorrhoeic; all had BMI ≥ 35 kg/m2. We found that 95% of women with HIV aged > 45 years reporting ≥ 12 months' amenorrhoea had elevated FSH, suggesting that menopausal status can be ascertained from menstrual history alone in this group. [ABSTRACT FROM AUTHOR]

The article presents a case study of an 86-year-old woman who complained of pain in the lower back and the leg since past 6 weeks, followed by attack of diarrhoea and vomiting. There was a history of Duke’s B carcinoma of the colon. Multilevel degenerative disc disease, worse at L4/5 and L5/S1, were diagnosed. No degeneration of spinal cord or nerve roots were detected. Initial blood tests detected hypokalaemia, while the raised serum C reactive protein resulted in diarrhoea.

The article presents management advice for healthcare professionals in non-endemic countries, who may advise individuals concerned about pregnancy and conception before or after travel to an area with Zika virus. It also offers an accompanying article discussing the epidemiology and the evidence of what is known, including a possible relation to Guillain-Barré syndrome. A figure showing how to protect oneself from mosquito bites is provided.

The article provides an overview of the treatment of malaria. The authors claim that malaria often goes undiagnosed in countries where it is not endemic. The article provides a detailed review of evidence in support of drugs used to treat malaria. Treatments for severe cases of falciparum malaria are reviewed. Adjunctive therapies for malaria include exchange transfusion, hemofiltration, and antibiotics. INSETS: Indicators of severe or potentially complicated malaria in adults;Clinical tips.

An online survey was conducted to compare the safety, tolerability and reactogenicity of available COVID-19 vaccines in different recipient groups. This survey was launched in February 2021 and ran for 11 days. Recipients of a first COVID-19 vaccine dose ≥7 days prior to survey completion were eligible. The incidence and severity of vaccination side effects were assessed. The survey was completed by 2002 respondents of whom 26.6% had a prior COVID-19 infection. A prior COVID-19 infection was associated with an increased risk of any side effect (risk ratio 1.08, 95% confidence intervals (1.05–1.11)), fever (2.24 (1.86–2.70)), breathlessness (2.05 (1.28–3.29)), flu-like illness (1.78 (1.51–2.10)), fatigue (1.34 (1.20–1.49)) and local reactions (1.10 (1.06–1.15)). It was also associated with an increased risk of severe side effects leading to hospital care (1.56 (1.14–2.12)). While mRNA vaccines were associated with a higher incidence of any side effect (1.06 (1.01–1.11)) compared with viral vector-based vaccines, these were generally milder (p < 0.001), mostly local reactions. Importantly, mRNA vaccine recipients reported a considerably lower incidence of systemic reactions (RR < 0.6) including anaphylaxis, swelling, flu-like illness, breathlessness and fatigue and of side effects requiring hospital care (0.42 (0.31–0.58)). Our study confirms the findings of recent randomised controlled trials (RCTs) demonstrating that COVID-19 vaccines are generally safe with limited severe side effects. For the first time, our study links prior COVID-19 illness with an increased incidence of vaccination side effects and demonstrates that mRNA vaccines cause milder, less frequent systemic side effects but more local reactions. [ABSTRACT FROM AUTHOR]

BACKGROUND Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Gluco-corticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. METHODS In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the final results of this assessment. RESULTS A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.996) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical 7 ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.096; rate ratio, 1.19; 95% CI, 0.92 to 1.55). CONCLUSIONS In patients hospitalized with Covid-19, the use of dexamethasone resulted in ower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National In stitute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673 .) [ABSTRACT FROM AUTHOR]

Using data from the PRIME Study, an observational study of the menopause in women living with HIV in England, we explored the association between menopausal symptoms and: (i) antiretroviral therapy (ART) adherence and (ii) HIV clinic attendance. We measured menopausal symptom severity with the Menopause Rating Scale (MRS, score ≥17 indicating severe symptoms), adherence with the CPCRA Antiretroviral Medication Adherence Self-Report Form, and ascertained HIV clinic attendance via self-report. Odds ratios were obtained using logistic regression. Women who reported severe menopausal symptoms had greater odds of suboptimal ART adherence (adjusted odds ratio (AOR) 2.22; 95% CI 1.13, 4.35) and suboptimal clinic attendance (AOR 1.52; 95% CI 1.01, 2.29). When psychological, somatic and urogenital domains of the MRS were analysed individually there was no association between adherence and severe symptoms (all p > 0.1), however there was an association between suboptimal HIV clinic attendance and severe somatic (AOR 1.98; 95% CI 1.24, 3.16) and psychological (AOR 1.76; 95% CI 1.17, 2.65) symptoms. Severe menopausal symptoms were significantly associated with sub-optimal ART adherence and HIV clinic attendance, however we cannot infer causality, highlighting the need for longitudinal data. [ABSTRACT FROM AUTHOR]

Whilst the benefit of direct‐acting antiviral agents (DAAs) in achieving sustained virological response (SVR) is now well‐accepted, their impact on liver function, particularly in relation to achievement of SVR, has not been well documented. We studied 2394 patients with chronic HCV infection, 1276 receiving DAAs and 1118 interferon‐based therapy. Liver function was assessed by the albumin‐bilirubin (ALBI) score or grade. Overall survival according to SVR status and baseline ALBI grade was examined. We also studied time to first decompensation according to ALBI grade, as well as longitudinal changes in ALBI score over time according to SVR. Among the patients receiving DAAs, 89% achieved SVR (Japan = 99%, UK = 78%). Amongst the decompensated patients in the UK cohort, three distinct risk groups according to ALBI grade at baseline were observed. The UK patients receiving DAAs, who had predominantly decompensated disease, showed clear evidence of improvement of liver function detectable within 2 years of the start of treatment, especially in those achieving SVR. These early changes in liver function were very similar to those observed in the first 2‐3 years after interferon‐based therapy. DAAs improve liver function especially in those with decompensated disease who achieve SVR. Experience with interferon‐based therapy suggests that failure to achieve SVR is associated with long‐term decline in liver function and, in contrast, patients who do achieve SVR can expect long‐term disease improvement and subsequent stabilization of liver function. Our initial analysis suggests that those receiving DAAs are likely, in the long term, to follow a similar course. [ABSTRACT FROM AUTHOR]

Chickenpox and shingles can be more severe and occasionally life threatening in immunosuppressed patients. As such, some groups warrant a more detailed history, serological testing and consideration of prophylaxis following contact with the virus. Active disease may also require more aggressive treatment with antivirals. Guidance for the use of varicella zoster immunoglobulin has recently been updated by Public Health England with important implications for rheumatology patients. [ABSTRACT FROM AUTHOR]

Background Treatment with direct acting antiviral agents (DAAs) has provided sustained virological response rates in >95% of patients with chronic hepatitis C virus (HCV) infection. However treatment is costly and market access, reimbursement and governmental restrictions differ among countries. We aimed to analyze these differences among European and Eurasian countries. Methods A survey including 20-item questionnaire was sent to experts in viral hepatitis. Countries were evaluated according to their income categories by the World Bank stratification. Results Experts from 26 countries responded to the survey. As of May 2016, HCV prevalence was reported as low (≤1%) in Croatia, Czech Republic, Denmark, France, Germany, Hungary, the Netherlands, Portugal, Slovenia, Spain, Sweden, UK; intermediate (1–4%) in Azerbaijan, Bosnia and Herzegovina, Italy, Kosovo, Greece, Kazakhstan, Romania, Russia, Serbia and high in Georgia (6.7%). All countries had national guidelines except Albania, Kosovo, Serbia, Tunisia, and UK. Transient elastography was available in all countries, but reimbursed in 61%. HCV-RNA was reimbursed in 81%. PegIFN/RBV was reimbursed in 54% of the countries. No DAAs were available in four countries: Kazakhstan, Kosovo, Serbia, and Tunisia. In others, at least one DAA combination with either PegIFN/RBV or another DAA was available. In Germany and the Netherlands all DAAs were reimbursed without restrictions: Sofosbuvir and sofosbuvir/ledipasvir were free of charge in Georgia. Conclusion Prevalence of HCV is relatively higher in lower-middle and upper-middle income countries. DAAs are not available or reimbursed in many Eurasia and European countries. Effective screening and access to care are essential for reducing liver-related morbidity and mortality. [ABSTRACT FROM AUTHOR]

Although current therapies can be successful at suppressing hepatitis B viral load, long-term viral cure is not within reach. Subsequent strategies combining pegylated interferon alfa with nucleoside/nucleotide analogues have not resulted in any major paradigm shift. An improved understanding of the hepatitis B virus (HBV) lifec ycle and virus-induced immune dysregulation has, however, revealed many potential therapeutic targets, and there are hopes that treatment of hepatitis B could soon be revolutionized. This review summarizes the current developments in HBV therapeutics-both virus directed and host directed. [ABSTRACT FROM AUTHOR]

Introduction: BICSTaR (GS-EU-380-4472/GS-CA-380-4574/GS-IL-380- 5335) is an ongoing, multinational, observational cohort study evaluating real-world effectiveness and safety of B/F/TAF in ART naïve (TN) and ARTexperienced (TE) PLWH. Materials and Methods: This 12M pooled analysis included PLWH starting B/F/TAF in clinical practice from June 2018 to September 2020 (latterly during the COVID-19 pandemic) in Europe/Israel/Canada. Outcomes included virological effectiveness (HIV‐1 RNA <50 copies/ml [missing=excluded]), persistence, drug‐related adverse events (DRAEs), and laboratory parameters. Results: One-thousand one hundred thirty-five PLWH were included (Table 1). The TE group had older median age than TN. Of TE participants, 65%/20%/16% switched from INSTI/NNRTI/PI-based regimens (36% TDF/46% TAF/13% ABC); 12% had prior virologic failure. Baseline resistance was documented in 124/535 participants (NRTI/NNRTI/PI/ INSTI=6%/6%/3%/0.2%). Prevalence of comorbidities (47%/72% TN/TE) and concomitant medication usage was high. At 12M, 97% (149/154) of TN and 96% (771/800) of TE participants had HIV-1 RNA <50 copies/ml, and persistence on B/F/TAF was high [91% (1032/1135)]. In a multivariable analysis, TE participants with neuropsychiatric disorder ongoing at baseline had lower odds for viral suppression (odds ratio=0.45, 95% CI: 0.21-0.96). There was no emergence of resistance to the components of B/F/TAF. DRAEs occurred in 13% (148/1135) of participants; gastrointestinal and neuropsychiatric DRAEs were the most common (3% each). Discontinuations due to DRAEs were low (TN 4%; TE 6%). Serious DRAEs were rare (0.2%; 2 TE participants with depression). Lipidchanges are shown (Figure 1). Conclusion: B/F/TAF was associated with high levels of effectiveness and persistence after 12M in this large real-world cohort of TN and TE PLWH with a high comorbidity burden. Effectiveness was demonstrated across key subgroups (females, older participants, late presenters). Importantly, there were no new or unexpected safety findings. Collectively, these real-world data continue to support the use of B/F/TAF in clinical practice. [ABSTRACT FROM AUTHOR]

The central nervous system has been proposed as a sanctuary site where HIV can escape antiretroviral control and develop drug resistance. HIV-1 RNA can be at higher levels in CSF than plasma, termed CSF/plasma discordance. We aimed to examine whether discordance in CSF is associated with low level viraemia (LLV) in blood. In this MRC-funded multicentre study, we prospectively recruited patients with LLV, defined as one or more episode of unexplained plasma HIV-1 RNA within 12 months, and undertook CSF examination. Separately, we prospectively collected CSF from patients undergoing lumbar puncture for a clinical indication. Patients with durable suppression of viraemia and no evidence of CNS infection were identified as controls from this group. Factors associated with CSF/plasma HIV-1 discordance overall were examined. One hundred fifty-three patients were recruited across 13 sites; 40 with LLV and 113 undergoing clinical lumbar puncture. Seven of the 40 (18 %) patients with LLV had CSF/plasma discordance, which was significantly more than 0/43 (0 %) with durable suppression in blood from the clinical group ( p = 0.005). Resistance associated mutations were shown in six CSF samples from discordant patients with LLV (one had insufficient sample for testing), which affected antiretroviral therapy at sampling in five. Overall discordance was present in 20/153 (13 %) and was associated with nadir CD4 but not antiretroviral concentrations in plasma or CSF. CSF/plasma discordance is observed in patients with LLV and is associated with antiretroviral resistance associated mutations in CSF. The implications for clinical practice require further investigation. [ABSTRACT FROM AUTHOR]

Introduction HIV-1 RNA can be found at higher levels in cerebrospinal fluid (CSF) than in plasma, termed CSF/plasma discordance. The clinical significance of CSF/plasma discordance is not known and the degree of discordance considered important varies. We aimed to determine whether a panel of CSF cytokines, chemokines and associated mediators were raised in patients with CSF/plasma discordance at different levels. Methods A nested case-control study of 40 CSF samples from the PARTITION study. We used a cytometric bead array to measure CSF mediator concentrations in 19 discordant and 21 non-discordant samples matched for plasma HIV-1 RNA. Discordant samples were subdivided into ‘high discordance’ (>1log 10 ) and ‘low discordance’ (0.5–1log 10 , or ultrasensitive discordance). CSF mediators significant in univariate analysis went forward to two-way unsupervised hierarchical clustering based on the patterns of relative mediator concentrations. Results In univariate analysis 19 of 21 CSF mediators were significantly higher in discordant than non-discordant samples. There were no significant differences between samples with high versus low discordance. The samples grouped into two clusters which corresponded to CSF/plasma discordance (p < 0.0001). In cluster one all mediators had relatively high abundance; this included 18 discordant samples and three non-discordant samples. In cluster two all mediators had relatively low abundance; this included 18 non-discordant samples and one non-discordant sample with ultrasensitive discordance only. Conclusions CSF/plasma discordance is associated with potentially damaging neuroinflammatory process. Patients with discordance at lower levels (ie. 0.5–1log 10 ) should also be investigated as mediator profiles were similar to those with discordance >1log 10 . Sensitive testing may have a role to determine whether ultrasensitive discordance is present in those with low level CSF escape. [ABSTRACT FROM AUTHOR]

The goal of this research was to establish a new and innovative framework for cost-effectiveness modeling of HIV-1 treatment, simultaneously considering both clinical and epidemiological outcomes. EPICE-HIV is a multi-paradigm model based on a within-host micro-simulation model for the disease progression of HIV-1 infected individuals and an agent-based sexual contact network (SCN) model for the transmission of HIV-1 infection. It includes HIV-1 viral dynamics, CD4+ T cell infection rates, and pharmacokinetics/pharmacodynamics modeling. Disease progression of HIV-1 infected individuals is driven by the interdependent changes in CD4+ T cell count, changes in plasma HIV-1 RNA, accumulation of resistance mutations and adherence to treatment. The two parts of the model are joined through a per-sexual-act and viral load dependent probability of disease transmission in HIV-discordant couples. Internal validity of the disease progression part of the model is assessed and external validity is demonstrated in comparison to the outcomes observed in the STaR randomized controlled clinical trial. We found that overall adherence to treatment and the resulting pattern of treatment interruptions are key drivers of HIV-1 treatment outcomes. Our model, though largely independent of efficacy data from RCT, was accurate in producing 96-week outcomes, qualitatively and quantitatively comparable to the ones observed in the STaR trial. We demonstrate that multi-paradigm micro-simulation modeling is a promising tool to generate evidence about optimal policy strategies in HIV-1 treatment, including treatment efficacy, HIV-1 transmission, and cost-effectiveness analysis. [ABSTRACT FROM AUTHOR]

Summary Evidence over the past decades have shown that HIV/HCV coinfected patients did not respond as well to HCV therapy as HCV mono-infected patients. However, these paradigms are being recently reassessed with the improvements of care for HIV and HCV patients. This article reviews these original paradigms and how the new data is impacting upon them. Treatment efficacy now appears comparable for HIV/HCV coinfected and HCV mono-infected patients, while liver fibrosis progression is increasingly similar in optimally managed patients. Additional importance of therapy is directed to drug-drug interactions and the impact of HCV reinfection, as well as the possibility of transmitted drug resistance. [ABSTRACT FROM AUTHOR]

The article discusses a study focusing on interferon (IFN)-free therapy for hepatitis C virus (HCV) for treatment with direct-acting antivirals (DAAs). Topics discussed include the use of ledipasvir (LDV) or daclatasvir (DCV) for treatment, the use of next generation sequence (NGS) analysis, and the HCV genotype and subtype.

Background. Our aim was to document how often travel histories were taken and the quality of their content. Methods. Patients admitted over 2 months to acute medical units of two hospitals in the Northwest of England with a history of fever, rash, diarrhea, vomiting, jaundice, or presenting as ''unwell post-travel'' were identified. The initial medical clerking was assessed. Results. A total of 132 relevant admissions were identified. A travel history was documented in only 26 patients (19.7%). Of the 16 patients who had traveled, there was no documentation of pretravel advice or of sexual/other activities abroad in 15 (93.8%) and 12 (75.0%) patients, respectively. Conclusions. There needs to be better awareness and education about travel-related illness and the importance of taking an adequate travel history. [ABSTRACT FROM AUTHOR]

Objectives. To evaluate the risk of serious infections (SIs) in patients with RA treated with anti-TNF therapy with emphasis on the risk across different ages.Methods. Using data from the British Society for Rheumatology Biologics Register, a prospective observational study, we compared the risk of SI between 11 798 anti-TNF-treated patients and 3598 non-biologic DMARD (nbDMARD)-treated patients.Results. A total of 1808 patients had at least one SI (anti-TNF: 1512; nbDMARD: 296). Incidence rates were: anti-TNF 42/1000 patient-years of follow-up (95% CI 40, 44) and nbDMARD 32/1000 patient-years of follow-up (95% CI 28, 36). The adjusted hazard ratio (adjHR) for SI in the anti-TNF cohort was 1.2 (95% CI 1.1, 1.5). The risk did not differ significantly between the three agents adalimumab, etanercept and infliximab. The risk was highest during the first 6 months of therapy [adjHR 1.8 (95% CI 1.3, 2.6)]. Although increasing age was an independent risk factor for SI in both cohorts, there was no difference in relative risk of infection in patients on anti-TNF therapy in the older population. There was no difference in hospital stay for SI between cohorts. Mortality within 30 days of SI was 50% lower in the anti-TNF cohort [odds ratio 0.5 (95% CI 0.3, 0.8)].Conclusions. These data add to currently available evidence suggesting that anti-TNF therapy is associated with a small but significant overall risk of SI. This must be balanced against the risks associated with poor disease control or alternative treatments. [ABSTRACT FROM AUTHOR]

Background While advances in treatment have dramatically improved the lives of people living with HIV (PLHIV), a number of important unmet needs remain. We conducted an international survey of PLHIV to explore their treatment experience and emotional challenges of ART. Methods Qualitative in-depth interviews were performed with PLHIV to identify key hypotheses. A steering group (led by community members) developed the survey tool which was fielded online from November 2016 to July 2017 in 8 high-income countries in North America (NA), Europe, and Australia. A mixed sampling/recruitment approach was used to ensure a broad cross-section of PLHIV. Respondents were screened for eligibility prior to receiving access to the online survey. Results 1111 PLHIV were surveyed (74% male, 41% 35–49 years; 39% from NA). The majority (98%) were currently taking ARTs with 53% taking a single tablet regimen. Of those on treatment, 87% were satisfied with their current ART. Overall, results for NA respondents were similar to the global results. Many participants reported emotional challenges associated with their daily HIV treatment experience: 66% agreed taking ART every day was a reminder of their HIV status; 25% agreed being tied to a daily medication limited their day-to-day life; and 29% agreed they felt stressed and under pressure to take their HIV medication at the right time every day. Those not "open" about their HIV status were more likely to feel stressed by their medication and felt that it limited them. 37% of participants frequently or quite often hid their HIV medication to avoid revealing their HIV status, particularly amongst those who reported experiencing stigma or high emotional impact of HIV. 89% felt that advances in treatment will improve their quality of life. Reducing long-term adverse effects of ART and lowering dosing frequency were considered the most important areas for improvement; this was similar across demographics such as country, age, and gender. Conclusion In this international survey of PLHIV, despite overall satisfaction with current ART, significant emotional burden and daily impact of treatment persists. PLHIV consider the reduction of long-term adverse effects and dosing frequency important areas for improving ART. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Is widespread screening for hepatitis C justified?" by Ronald L. Koretz, Kenneth W. Lin, John P. A. Ioannidis, and Jeanne Lenzer in the January 13, 2015 issue.

A letter to the editor is presented in response to the article "Improving the Uptake of HIV Testing in Patients With Tuberculosis" by N. Clerk et al., which appeared in a previous issue.