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REDS-III Phase 2 Studies

Domestic

1.   The Red Blood Cell-Omics (RBC-Omics) Study explores blood donor genetic factors that may affect red blood cells (RBCs) and lead to increased or decreased susceptibility to certain stressors, ultimately impacting blood storage ability. The study has enrolled nearly 14,000 blood donors and evaluated their RBC donations to determine how the RBCs withstand different storage conditions. This study will help us to understand why some donors’ RBCs store better than others, why some donors can donate more frequently than others, and the occurrence of symptoms often associated with iron deficiency.

2.   Severe Transfusion Reactions Including Pulmonary Edema (STRIPE) is a study of hospitalized patients receiving blood transfusions. The overall objective is to provide evidence to support the development of strategies that will prevent or reduce complications related to blood transfusion, focusing on transfusion associated circulatory overload (known as TACO). The incidence of TACO will be estimated from data gathered during the study. Other severe reactions, including hypotension, anaphylaxis, sepsis, and cardiopulmonary reactions, have also been studied.

3.   Red Cell in the Outpatients Transfusion Outcomes Study (RETRO) To determine the impact of transfusion on functional status and quality of life in patients 50+ years of age receiving blood transfusions, this study will enroll patients receiving an outpatient transfusion as part of their care. The study will measure six-minute walk test performance, quality of life-related fatigue, dyspnea scores, and NT-proBNP levels (used to measure heart failure) before and after transfusion. The ultimate goal of the study is to understand the impact of transfusion on function in the elderly with chronic anemia to help guide physicians in making transfusion decisions.

4.   Hemoglobin and Iron Recovery Study (HEIRS) – Evaluation of HEIRS Donors for TMPRSS6 Polymorphism  TMPRSS6 is a protein that has a key role in regulating iron balance by controlling absorption of dietary iron. This study examined whether differences in the TMPRSS6 are associated with differences in the response to supplemental iron in blood donors.

5.   The Comparison of the History of Donation and Iron Levels in Teen Blood Donors (CHILL) Study  will extend recent research examining iron stores in adult blood donors and characterizing the association between blood donation and iron levels. Very little is known about the iron status of high school-age blood donors, who are an important part of the donor population nationwide. Two blood centers will test the iron status of a large sample of high school donors using the plasma ferritin test. We will characterize the iron levels of teen blood donors and in longitudinal analysis will estimate whether the recovery of iron following donation in similar in teens to adults.

6.   SCANDAT analysis: Repeated Apheresis Donations and Risk of Fractures is a statistical analysis of the association between apheresis blood donation and risk of bone fractures. Scandinavian Donations and Transfusions (SCANDAT) database is a compilation of all available computerized blood donation and transfusion registers from Swedish and Danish blood banks and transfusion medicine clinics. Data from individuals who underwent repeated apheresis donation in Sweden or Denmark and who were recorded in the SCANDAT database were analyzed and compared to whole blood donors with a comparable donation history.

7.   SCANDAT analysis: Using Linked Donor-Recipient Database to Search for New Transfusion-Transmitted Infections will employ the SCANDAT database to search for risk correlations to identify (or exclude) new or unknown transfusion transmitted diseases. Analyses will be conducted using a combination of traditional epidemiologic methods and methods developed for disease surveillance in linked blood donor-recipient data.


International

Brazil

8.  Prevalence, Incidence, Epidemiology and Molecular Variants of HIV in Blood Donors in Brazil.   Extended study of HIV-infected donors in order to determine trends in risk factors associated with HIV infection, as well as HIV subtypes and drug resistance profiles among HIV-positive donors. This aims to determine risk factors associated with HIV infection, HIV subtype, and drug resistance profile among HIV-positive donors according to HIV infection status (NAT yield vs recent vs long-standing seropositives), year of donation and site of collection. The collection of risk factors is achieved using audio computer-assisted self-interviews (ACASI) and an additional blood sample is collected for molecular surveillance. In addition, all HIV-positive donations with residual volume from routine donation testing are tested by a procedure that identifies if the infection was recently acquired and is therefore an incident compared to long standing infection.

9.  Establishing a Brazilian Sickle Cell Disease Cohort and Identifying Molecular Determinants of Response to Transfusions, Genetic Determinants of Alloimmunization, and Risk Factors Associated with HIV Infection. Implementation of this new program focused on transfusion practices and predictors of health outcomes in patients with Sickle Cell Disease (SCD) began in the Fall of 2013. The four primary aims of this study are: 1) Aim A - Establish a cohort of SCD patients with a comprehensive centralized, electronic database of detailed clinical, laboratory and transfusion information, as well as establish a repository of blood samples to support biological studies relevant to SCD pathogenesis and transfusion complications; 2) Aim B - Characterize changes in markers of inflammation in response to transfusion by analyzing chemokine/cytokine panels in serial post transfusion specimens; 3) Aim C -- Identify single nucleotide polymorphisms (SNPs) that contribute to the risk of red blood cell alloimmunization in SCD by performing a genome-wide association (GWA)study in transfused SCD patients; and, 4) Aim D – Characterize risk of HIV and HIV outcomes in the Brazilian SCD population and compare SCD outcomes among HIV sero-positive and sero-negative SCD patients. Patients are enrolled from six hospitals affiliated with the participating four REDS-III Brazil hemocenters.

10.  Improving the Safety of Blood Donation in Brazil through an Assessment of the Effectiveness of Notification and Counseling and Linkage of HIV-Positive Donors to Health Care. To study the impact of notification and the effectiveness of counseling among HIV-positive donors at four blood centers in Brazil, this project includes the following components: (1) An analysis of the proportion of donors who are successfully notified for the infections for which donations are tested in Brazil. (2) Assessment of whether HIV-positive donors that returned to the blood center for notification and counseling subsequently attend HIV referral centers for additional counseling, treatment and follow-up, and to determine self-reported behavioral change among HIV-positive donors using ACASI. (3) To use HIV positive blood donors as key informants by inquiring through ACASI about ways we can improve the disclosure of HIV risks in donors during eligibility assessment.

11.  US natural history cohort of Zika virus RNA positive blood donors: This study, which is being conducted in collaboration with CDC, will enroll up to 130 blood donors found to be RNA positive for the Zika virus by the Roche assay (under Investigational New Drug) in a cohort in Puerto Rico, and probably additional cohorts in Florida and Texas. Participants will be followed at regular intervals during a period of 6 months for persistence and outcomes of Zika virus infection. The study will characterize viral and serological markers of early stages of asymptomatic Zika virus infection; identify and store index blood components that can be further studied to characterize the performance of existing and future assays, and provide standards for assay development; study the evolution of viral markers; and establish a biorepository of blood, urine, saliva, and semen samples. It is anticipated that this study will be launched in June-July of 2016.

12.  Zika, Chikungunya, and Dengue incidence in Brazilian blood donors: This study will calculate the rates of blood donor viremia for Chikungunya, Dengue, and Zika viruses in Brazil between April 2016 and June 2017 at four large, geographically dispersed blood centers using a research-use only assay that is available in the US. This project will monitor the rates of viremia in donors which are a reasonable proxy of the rates of viremia in the general population for arbovirus infections. Results from this study will allow transfusion medicine experts and government officials (Brazil and US) to better evaluate which strategies to implement to enhance the safety of the blood supply vis-à-vis these three viruses.

13.  Impact of Zika and Chikungunya viruses acquisition through blood transfusion::This study, which was launched in April 2016, will 1) establish whether Zika virus is transmitted by blood in this Dengue endemic setting; 2) collect data on the relationship between viral burden and the frequency of transfusion-transmitted infection and duration of viral persistence without symptoms; and 3) assess the frequency and manifestations of clinically apparent disease in infected recipients (which may be less common than in mosquito¬ acquired infections in healthy individuals). Pre- and post-transfusion blood samples will be collected from all transfusion recipients who agree to participate in this four-month study; these samples will be tested for the presence of Zika, Chikungunya, or Dengue viruses. This information will allow us to identify patients who did not have Zika virus before the transfusion but appear to have acquired the infection after transfusion. For these patients, samples of the blood products they received will be retrieved and tested for the presence of Zika virus. Additionally, their clinical symptoms will be ascertained. The presence of Zika virus in the blood product that was transfused will provide evidence of a possible transfusion transmission and will trigger additional follow-up and ascertainment. Such data are critically needed to help guide donor testing and deferral strategies in endemic and non-endemic settings.

14.  Zika virus research study in chronically transfused Brazilian patients with sickle cell disease:: The purpose of this study is to evaluate the rate of transfusion-transmission and more generally the clinical consequences of Chikungunya, Dengue, and Zika virus infection in this chronically-transfused population. The consequences of Zika virus infection in patients with sickle cell disease are unknown at this time. It is anticipated that this study will be launched in early 2017.

China

15.   Blood Utilization Study.   To capture the prevalence by demographics and diagnosis of HIV in hospitalized patients who may undergo transfusion, and to compare the rate to that of the general population and blood donors. The REDS-III China Program investigators will evaluate transfusion practices at five top-tier hospitals in China to study the utilization of red blood cells. Information on the clinical settings, frequency, and indications for transfusion will be collected from the participating hospitals. In addition, investigators will compare patient characteristics and hemoglobin concentration in patients who receive red blood cell transfusions to a control group of patients with the same diagnosis who do not receive transfusions. This study will provide a better understanding of how red blood cell transfusion is used in China and will lay a foundation to study how red blood cell can be optimally utilized to improve clinical outcomes in various clinical settings.

16.  HIV Study in Blood Donors from Five Chinese Regions.   Understanding the changing risk factors for HIV infection in donors is critical for improving blood safety, identifying new transmission routes, and HIV prevention and treatment for recently infected individuals. In this study, we will conduct a survey to evaluate the risk factors associated with HIV infection among Chinese blood donors. This is a case-control study with “cases” defined as post-donation screening reactive and Western blot confirmed positive donors and “controls” defined as post-donation screening reactive but Western blot confirmed negative donors. Conducting this study in the rapidly changing HIV epidemic in China is of particular importance because with China’s huge population size and rapid globalization, the HIV epidemic in China, if uncurbed, may have potentially significant impact  globally. Results of this study will be linked to the HIV molecular surveillance study results to identify risk factors associated with molecular epidemiology features and whether the risk factors vary between new or long-term HIV infections.

South Africa

17.  Transfusion in Pregnancy Study (TIPS) - Phase 2.   During Phase 2, the Transfusion in Pregnancy (TIP) study was conducted with three aims: (1) Determine the influence of HIV and other risk factors for allogeneic blood transfusion among a sample of South African women. (2) Investigate the causes of antenatal anemia in both HIV positive and negative patients referred to a specialist antenatal anemia clinic (Chris Hani-Baragwanath Hospital) and to determine whether there is a difference in the response to oral iron therapy (for those with iron deficiency anemia) between HIV positive and HIV negative patients (after controlling for treatment regimens) and (3) Characterize reasons for transfusion among patients who are transfused prior to the peripartum period. Pregnant women were recruited into the study and assigned an aim depending on eligibility criteria. Data were collected using standardized forms and included interviews and record abstraction/chart review of eligible pregnant or recently delivered women at four major hospitals in South Africa: Chris-Hani Baragwanath Hospital (Soweto), King Edward VIII Hospital (Durban), and Mowbray Maternity and Groote Schuur Hospitals (both Cape Town). Data collection for all three aims was completed December 2015.

18.  Incident HIV and HBV Infection in South African Blood Donors.   Routine molecular and antibody testing of South African blood donors provides a unique opportunity to identify very recent (incident) infections of HIV and/or hepatitis B virus (HBV) in this population. Using a frequency-matched case-control design, this study will compare incident HIV and HBV cases to infectious marker negative controls from a geographically diverse pool of blood donors at the South African National Blood Service (SANBS). The aim of the study is to (1) evaluate the current demographic and behavioral risk factors for incident HIV and HBV infections and (2) determine viral loads for all cases, characterize HIV clade and drug resistance profiles for all incident HIV cases, and determine HBV genotype for all incident HBV cases. Routine antibody and nucleic acid testing (NAT), as well as detuned (antibody avidity) serological testing, will be used to expand the identification of recent infections. A similar characterization of donors with recent HBV infection will be performed using HBV NAT and serological testing. The study began enrollment in November 2014 and anticipates on-going enrollment until March 2017.

19.  Blood Donor Recruitment and Retention.  Currently, Black South Africans comprise almost 90% of the population but constitute less than 30% of the blood donor base. SANBS has committed to reversing this legacy of the apartheid era, and is actively embarking upon recruitment in the black population while keeping HIV risk as low as possible. Social science research methods will be applied to understanding motivations for and deterrence against blood donation and epidemiologic study designs will assess reasons for return/non-return after a first donation and the efficacy of specific recruitment interventions. Improved representation of Black donors is important to ensure sustainable provision of blood. However, understanding the motivators for blood donation can also help to select for low risk for HIV and other transfusion transmissible infections.

20.  A Prospective Cohort Study of the Virology and Immunology of HIV Infection in South African Blood Donors: Implementation of Antiretroviral Therapy (ART) in Very Early HIV Infection and Evolution of Elite Controllers (aka Monitoring and Acute Treatment of HIV Study – MATHS). Recent developments in the field of HIV cure research have indicated that very early initiation of antiretroviral treatment (ART) is likely to have a beneficial effect on the course of HIV disease and may even be curative in some people. By virtue of antibody and RNA testing performed on all blood donors and the high incidence of HIV infection in South Africa, SANBS is able to identify donors with very early (Fiebig stage I and II) HIV infection, exactly the group for whom very early ART is being proposed. We therefore feel that there is both an ethical and research imperative to conduct a supplemental treatment study to include the offer of ART to blood donors in South Africa with very early HIV infection; to enroll these participants in a study that will provide both clinical and pharmaceutical care; and to implement more intensive monitoring of the participants’ virologic and immunologic response to treatment. In addition, 25 participants with recent HIV infection as determined by antibody avidity assays and 20 HIV elite controllers (individual donation HIV nucleic acid test negative, low level anti-HIV positive) and recent HIV infection (HIV nucleic acid positive, anti-HIV positive, LAg avidity recent) identified by routine SANBS blood donor screening will also be enrolled. Donors with acute and recent HIV infection will be offered ART and both they and elite controllers will have frequent study visits to monitor HIV disease progression including virologic and immunologic response in parallel to very early HIV infection subjects receiving ART.
We propose the following objectives:
1. Determine Fiebig stage at the time of blood donation. For donors identified as being Fiebig stage I or II as well as having a recent HIV infection (anti-HIV positive, LAg avidity recent), we shall initiate ART therapy, and ascertain Fiebig stage at the time of therapy initiation.
2. Establish the size of the peripheral blood viral reservoir at the initiation of ART and at defined time points post ART initiation for donors enrolled in the treatment study.
3. Conduct a “proof of concept study” to show how blood donors identified as having so-called “hyperacute” HIV infection by blood testing can be successfully linked to care with the initiation of early HIV treatment.


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