Implementation of AZD7442 (Tixagevimab/Cilgavimab) COVID-19 Pre-exposure Prophylaxis (PrEP) in the Largest Health Maintenance Organization in Israel: Real-world Uptake and Sociodemographic and Clinical Characteristics Across Immunocompromised Patient Groups.

INTRODUCTION: AZD7442 is a combination of two neutralizing antibodies (tixagevimab/cilgavimab) with demonstrated efficacy in reducing the risk of symptomatic coronavirus disease 2019 (COVID-19) among individuals at high risk of severe COVID-19 ≤ 6 months after administration. On February 15, 2022, the Israeli Ministry of Health (IMoH) authorized the administration of 300 mg AZD7442 as pre-exposure prophylaxis (PrEP) against severe acute respiratory syndrome coronavirus 2 infection among immunocompromised individuals aged ≥ 12 years. This study describes the real-world uptake of AZD7442 in Israel. METHODS: This descriptive, observational study analyzed data from Israel's largest health maintenance organization, Clalit Health Services (CHS). Individuals were assessed for AZD7442 eligibility between February 13 and December 11, 2022, and were included if they were aged ≥ 12 years, had ≥ 1 year of continuous CHS membership, had ≥ 1 moderate or severe immunocompromising condition, and were eligible for AZD7442 per IMoH recommendations during this time frame. RESULTS: Overall, 19,161 AZD7442-eligible individuals with immunocompromising conditions were identified during the study period; 2829 (14.8%) received AZD7442. A higher proportion of individuals receiving AZD7442 were older (aged ≥ 65 years), male, not current smokers and residents in large cities; required more physician visits (> 50 visits); and had ≥ 1 COVID-19 hospitalization over 12 months, while uptake was lowest among ultra-orthodox Jewish individuals. AZD7442 uptake was also higher among individuals with multiple comorbidities (Charlson Comorbidity Index ≥ 5), including hypertension, diabetes and chronic kidney disease. In specific immunocompromised types, AZD7442 uptake was highest among individuals with lung transplantation (41%), primary immunodeficiency (32%), bone marrow transplantation (29%) and multiple myeloma (25%) or those receiving anti-CD20 therapy (26%) and was lowest in individuals with lymphoma (8%). CONCLUSION: These results show AZD7442 uptake among the eligible population of Israel in 2022 was relatively low, at 14.8%. Uptake was generally higher among immunocompromised individuals who may be perceived to be frail or at highest risk of COVID-19 infection and complications, although at 25-41%, further improvements in uptake would be more impactful. These results also indicate there is opportunity to expand AZD7442 uptake across immunocompromised groups and ensure more equitable uptake among some other sociodemographic groups. Overall, this study will help inform and reassess future implementation strategies for vulnerable populations.

Impact of COVID-19 on immunocompromised populations during the Omicron era: insights from the observational population-based INFORM study.

Background: Immunocompromised individuals are not optimally protected by COVID-19 vaccines and potentially require additional preventive interventions to mitigate the risk of severe COVID-19. We aimed to characterise and describe the risk of severe COVID-19 across immunocompromised groups as the pandemic began to transition to an endemic phase. Methods: COVID-19-related hospitalisations, intensive care unit (ICU) admissions, and deaths (01/01/2022-31/12/2022) were compared among different groups of immunocompromised individuals vs the general population, using a retrospective cohort design and electronic health data from a random 25% sample of the English population aged ≥12 years (Registration number: ISRCTN53375662). Findings: Overall, immunocompromised individuals accounted for 3.9% of the study population, but 22% (4585/20,910) of COVID-19 hospitalisations, 28% (125/440) of COVID-19 ICU admissions, and 24% (1145/4810) of COVID-19 deaths in 2022. Restricting to those vaccinated with ≥3 doses of COVID-19 vaccine (∼84% of immunocompromised and 51% of the general population), all immunocompromised groups remained at increased risk of severe COVID-19 outcomes, with adjusted incidence rate ratios (aIRR) for hospitalisation ranging from 1.3 to 13.1. At highest risk for COVID-19 hospitalisation were individuals with: solid organ transplant (aIRR 13.1, 95% confidence interval [95% CI] 11.2-15.3), moderate to severe primary immunodeficiency (aIRR 9.7, 95% CI 6.3-14.9), stem cell transplant (aIRR 11.0, 95% CI 6.8-17.6), and recent treatment for haematological malignancy (aIRR 10.6, 95% CI 9.5-11.9). Results were similar for COVID-19 ICU admissions and deaths. Interpretation: Immunocompromised individuals continue to be impacted disproportionately by COVID-19 and have an urgent need for additional preventive measures beyond current vaccination programmes. These data can help determine the immunocompromised groups for which targeted prevention strategies may have the highest impact. Funding: This study was funded by AstraZeneca UK.

Benralizumab Effectiveness in Severe Asthma Is Independent of Previous Biologic Use.

BACKGROUND: Benralizumab is an IL-5 receptor alpha-directed cytolytic mAb that depletes eosinophils, reducing exacerbations and oral corticosteroid (OCS) use, and improves asthma control for patients with severe eosinophilic asthma (SEA). Data on response in patients previously treated with other biologic therapies are limited. OBJECTIVE: To describe real-world clinical outcomes with benralizumab for patients with and without prior biologic use for uncontrolled SEA. METHODS: This retrospective study compared clinical outcomes before and after benralizumab initiation in adults with uncontrolled SEA with 3 or more asthma exacerbations in the previous 12 months or on maintenance OCS treatment. Outcomes included exacerbations, OCS use, patient-reported outcomes, and health care resource utilization, including emergency department visits and hospitalizations. RESULTS: In all, 208 patients were enrolled, including 90 (43.3%) with previous experience with an alternate biologic for SEA. Benralizumab led to an 81% reduction in exacerbation rate, with 48% of patients with previous exacerbations experiencing none after 48 weeks. Overall, 67% of patients requiring baseline maintenance OCS achieved greater than or equal to 50% reduction in daily OCS dosage, and 53% eliminated maintenance OCS. Clinically meaningful improvements in patient-reported outcomes were seen, with response at 4 weeks predicting longer-term benefits. Health care resource utilization also decreased. Improvements were observed irrespective of previous biologic experience, fractional exhaled nitric oxide concentrations, atopic status, or other baseline characteristics. CONCLUSIONS: In a multicenter real-world setting, patients with uncontrolled SEA achieved substantial improvements in all clinical outcome measures with benralizumab irrespective of previous biologic use, atopic status, or baseline fractional exhaled nitric oxide concentration.

The Healthcare Professionals' Perspective on Impact and Actions Taken Following Severe Infusion Reaction Events in Oncology Centers in Europe.

PURPOSE: The study aim was to describe the management strategies used for severe infusion-related reactions (SIRs) and understand the impact of such events in oncology day hospitals in France, Germany, Spain, and the UK. METHODS: The study was based on qualitative telephone interviews and quantitative self-completion questionnaires and asked healthcare professionals about the impact of SIRs and consequent actions taken. RESULTS: The procedures to prevent and manage SIRs were similar across countries and settings. In all countries, they were part of a larger risk-assessment and adverse events-prevention process. Preventive measures included patient history, risk assessment, pre-medication, and close monitoring of high-risk patients. The management procedures comprised stopping the infusion, triggering of the emergency chain, administering corticosteroids ± antihistamines, and hospitalization if necessary. The recalled SIRs had important consequences to affected patients, healthcare providers, and hospital organizational plans. All affected patients needed to be monitored closely for a prolonged time, thus blocking hospital beds. 44% of patients needed to be hospitalized, 17% needed resuscitation, and one patient died of cardiac arrest immediately after the start of the infusion. Importantly, 82% of patients were not re-challenged with the presumedly SIR-causing regimen or re-challenged in a later line. CONCLUSION: SIRs are unpredictable in nature, may have an extremely rapid onset, and are potentially fatal. Such events have a profound impact on the affected and surrounding patients, the care team and the organizational plan of the day-hospitals. Specific tools to reliably identify high-risk patients and predict the occurrence of events are needed.

Management of EGFR Inhibitor-induced Skin Toxicity and Factors Impacting Patients' Adherence to Skin Toxicity Treatment: Health Care Provider and Patient Surveys in European Oncology Centers.

INTRODUCTION: This study aimed to provide a description of existing measures for the prevention and management of epidermal growth factor receptor inhibitor monoclonal antibody-induced skin toxicities and factors impacting patients' adherence to those measures in France, Germany, and Spain. MATERIALS AND METHODS: The study consisted of 2 separate surveys. Health care professionals (HCPs; oncologists and nurses) in France, Germany, and Spain were interviewed, and patients with metastatic colorectal cancer and head-and-neck cancer in France and Germany self-completed questionnaires. The study was conducted between February and July 2018. RESULTS: A total of 53 oncologists, 44 nurses, and 143 patients participated in the study. HCPs stated that skin toxicities moderately (52%) or severely (28%) impacted patient care. Ninety percent of HCPs reported routine provision of prophylactic measures. The great majority of patients self-reported adherence with the prophylactic (80% to 88% depending on the type of measures) and reactive (93% to drug prescription) skin toxicity recommendations. HCPs estimated patient adherence to be 45% for full adherence and 40% for partial adherence. Most HCPs reported a positive or very positive impact of preventive measures and recommendations on skin toxicity incidence and severity, patients' quality of life, and various aspects of quality of anti-cancer treatment. CONCLUSIONS: Skin toxicities are an important adversity negatively impacting on patient care. However, despite the positive perception of the effectiveness of skin toxicity prophylaxis, almost one-third of oncology centers did not provide formal guidelines, and 10% of HCPs did not provide routine prophylactic measures. Patient adherence appears to be high for epidermal growth factor receptor inhibitor monoclonal antibody-induced skin toxicity prevention measures.

Measuring and correcting biased child mortality statistics in countries with generalized epidemics of HIV infection.

OBJECTIVE: Under Millennium Development Goal 4, countries are required to reduce child mortality by two-thirds between 1990 and 2015. In countries with generalized epidemics of human immunodeficiency virus (HIV) infection, standard statistics based on fertility history may misrepresent progress towards this target owing to the correlation between deaths among mothers and early childhood deaths from acquired immunodeficiency syndrome. METHODS: To empirically estimate this bias, child mortality data and fertility history, including births to deceased women, were collected through prospective household surveys in eastern Zimbabwe during 1998-2005. A mathematical model was then used to investigate the determinants and temporal dynamics of the bias, first in Zimbabwe and then in other countries with different background mortality rates and HIV-related epidemic profiles. FINDINGS: According to the empirical data, standard cross-sectional survey statistics underestimated true infant and under-5 mortality by 6.7% and 9.8%, respectively. These estimates were in agreement with the output from the model, in which the bias varied according to the magnitude and stage of the epidemic of HIV infection and background mortality rates. The bias was greater the longer the period elapsed before the survey and in later stages of the epidemic. Bias could substantially distort the measured effect of interventions to reduce non-HIV-related mortality and of programmes to prevent mother-to-child transmission, especially when trends are based on data from a single survey. CONCLUSION: The correlation between the HIV-related deaths of mothers and their children can bias survey estimates of early child mortality. A mathematical model with a user-friendly interface is available to correct for this bias when measuring progress towards Millennium Development Goal 4 in countries with generalized epidemics of HIV infection.

HIV decline in Zimbabwe due to reductions in risky sex? Evidence from a comprehensive epidemiological review.

BACKGROUND: Recent data from antenatal clinic (ANC) surveillance and general population surveys suggest substantial declines in human immunodeficiency virus (HIV) prevalence in Zimbabwe. We assessed the contributions of rising mortality, falling HIV incidence and sexual behaviour change to the decline in HIV prevalence. METHODS: Comprehensive review and secondary analysis of national and local sources on trends in HIV prevalence, HIV incidence, mortality and sexual behaviour covering the period 1985-2007. RESULTS: HIV prevalence fell in Zimbabwe over the past decade (national estimates: from 29.3% in 1997 to 15.6% in 2007). National census and survey estimates, vital registration data from Harare and Bulawayo, and prospective local population survey data from eastern Zimbabwe showed substantial rises in mortality during the 1990s levelling off after 2000. Direct estimates of HIV incidence in male factory workers and women attending pre- and post-natal clinics, trends in HIV prevalence in 15-24-year-olds, and back-calculation estimates based on the vital registration data from Harare indicated that HIV incidence may have peaked in the early 1990s and fallen during the 1990s. Household survey data showed reductions in numbers reporting casual partners from the late 1990s and high condom use in non-regular partnerships between 1998 and 2007. CONCLUSIONS: These findings provide the first convincing evidence of an HIV decline accelerated by changes in sexual behaviour in a southern African country. However, in 2007, one in every seven adults in Zimbabwe was still infected with a life-threatening virus and mortality rates remained at crisis level.

The impact of monitoring HIV patients prior to treatment in resource-poor settings: insights from mathematical modelling.

BACKGROUND: The roll-out of antiretroviral treatment (ART) in developing countries concentrates on finding patients currently in need, but over time many HIV-infected individuals will be identified who will require treatment in the future. We investigated the potential influence of alternative patient management and ART initiation strategies on the impact of ART programmes in sub-Saharan Africa. METHODS AND FINDINGS: We developed a stochastic mathematical model representing disease progression, diagnosis, clinical monitoring, and survival in a cohort of 1,000 hypothetical HIV-infected individuals in Africa. If individuals primarily enter ART programmes when symptomatic, the model predicts that only 25% will start treatment and, on average, 6 life-years will be saved per person treated. If individuals are recruited to programmes while still healthy and are frequently monitored, and CD4(+) cell counts are used to help decide when to initiate ART, three times as many are expected to be treated, and average life-years saved among those treated increases to 15. The impact of programmes can be improved further by performing a second CD4(+) cell count when the initial value is close to the threshold for starting treatment, maintaining high patient follow-up rates, and prioritising monitoring the oldest (> or = 35 y) and most immune-suppressed patients (CD4(+) cell count < or = 350). Initiating ART at higher CD4(+) cell counts than WHO recommends leads to more life-years saved, but disproportionately more years spent on ART. CONCLUSIONS: The overall impact of ART programmes will be limited if rates of diagnosis are low and individuals enter care too late. Frequently monitoring individuals at all stages of HIV infection and using CD4 cell count information to determine when to start treatment can maximise the impact of ART.

Estimating vertically acquired HIV infections and the impact of the prevention of mother-to-child transmission program in Zimbabwe: insights from decision analysis models.

BACKGROUND: The World Health Organization recommends a single-dose nevirapine (NVP) regimen for prevention of mother-to-child transmission (PMTCT) of HIV in settings without the capacity to deliver more complex regimens, but the population-level impact of this intervention has rarely been assessed. METHODS: A decision analysis model was developed, parameterized, and applied using local epidemiologic and demographic data to estimate vertical transmission of HIV and the impact of the PMTCT program in Zimbabwe up to 2005. RESULTS: Between 1980 and 2005, of approximately 10 million children born in Zimbabwe, a cumulative 504,000 (range: 362,000 to 665,000) were vertically infected with HIV; 59% of these infections occurred in nonurban areas. Mother-to-child transmission (MTCT) of HIV decreased from 8.2% (range: 6.0% to 10.7%) in 2000 to 6.2% (range: 4.9% to 8.9%) in 2005, predominantly attributable to declining maternal HIV prevalence rather than to the PMTCT program. Between 2002 and 2005, the single-dose NVP PMTCT program may have averted 4600 (range: 3900 to 7800) infections. In 2005, 32% (range: 26% to 44%) and 4.0% (range: 2.7% to 6.2%) of infections were attributable to breast-feeding and maternal seroconversion, respectively, and the PMTCT program reduced infant infections by 8.8% (range: 5.5% to 12.1%). Twice as many infections could have been averted had a more efficacious but logistically more complex NVP + zidovudine regimen been implemented with similar coverage (50%) and acceptance (42%). DISCUSSION: The decline in MTCT from 2000 to 2005 is attributable more to the concurrent decrease in HIV prevalence in pregnant women than to PMTCT at the current level of rollout. To improve the impact of PMTCT, program coverage and acceptance must be increased, especially in rural areas, and local infrastructure must then be strengthened so that single-dose NVP can be replaced with a more efficacious regimen.

Voluntary counselling and testing: uptake, impact on sexual behaviour, and HIV incidence in a rural Zimbabwean cohort.

OBJECTIVES: To examine the determinants of uptake of voluntary counselling and testing (VCT) services, to assess changes in sexual risk behaviour following VCT, and to compare HIV incidence amongst testers and non-testers. METHODS: Prospective population-based cohort study of adult men and women in the Manicaland province of eastern Zimbabwe. Demographic, socioeconomic, sexual behaviour and VCT utilization data were collected at baseline (1998-2000) and follow-up (3 years later). HIV status was determined by HIV-1 antibody detection. In addition to services provided by the government and non-governmental organizations, a mobile VCT clinic was available at study sites. RESULTS: Lifetime uptake of VCT increased from under 6% to 11% at follow-up. Age, increasing education and knowledge of HIV were associated with VCT uptake. Women who took a test were more likely to be HIV positive and to have greater HIV knowledge and fewer total lifetime partners. After controlling for demographic characteristics, sexual behaviour was not independently associated with VCT uptake. Women who tested positive reported increased consistent condom use in their regular partnerships. However, individuals who tested negative were more likely to adopt more risky behaviours in terms of numbers of partnerships in the last month, the last year and in concurrent partnerships. HIV incidence during follow-up did not differ between testers and non-testers. CONCLUSION: Motivation for VCT uptake was driven by knowledge and education rather than sexual risk. Increased sexual risk following receipt of a negative result may be a serious unintended consequence of VCT. It should be minimized with appropriate pre- and post-test counselling.