This contract program was established to accurately determine the prevalence of retrovirus in blood donors. It enrolled the largest number of non-AIDS, retrovirus-positive blood donors found from screening. The researchers evaluated the demographic, risk factor, and behavioral characteristics of blood donors with high risks who continue to donate. A blood specimen repository was also established as a mechanism for evaluating new tests for known viruses, and as a sentinel for as-yet-unrecognized viruses.
Six contracts were supported and the program will continue through 1998.
N01 HB97077 - Edward Murphy - University of California, San Francisco, CA
N01 HB97078 - Ronald Gilcher - Oklahoma Blood Institute, Oklahoma City, OK
N01 HB97079 - Alan Williams - ARC, Chesapeake Region, Rockville, MD
N01 HB97080 - Steven Kleinman - American Red Cross, Los Angeles, CA
N01 HB97081 - A. William Shafer - American Red Cross, Detroit, MI
N01 HB97082 - George Schreiber - Westat, Inc., Rockville, MD
The Retrovirus Epidemiology Donor Study (REDS) has conducted a series of studies directed at assessing HIV risk in the blood supply; evaluating HIV risk factors in donors; and evaluating the blood safety screening procedures. Major results from several analyses are outlined below. Results from several of these analyses have been presented to the Food and Drug Administration (FDA) Blood Products Advisory
Committee to assist the committee in policy decisions and have been published in refereed journals.
HIV Incidence and the Safety of the Blood Supply
REDS has initiated and published a number of studies related to HIV infection derived from the comprehensive database routinely compiled from the five participating REDS blood centers. Accurate estimates of the risk of HIV infection are essential for monitoring the safety of the blood supply and evaluating the potential effect of introducing new screening tests. Donations during 1991-1993 from 586,507 donors were used to calculate the incidence rates of seroconversion among those whose donations passed all other screening tests and was transfusible. From the incidence and current window period estimates, the risk of giving an infectious unit of blood was estimated as 1 in 493,000 for HIV among donors whose units passed all screening tests. Estimates of transfusion-transmitted risk were also derived for HCV, HBv, and HTLV. Although the risk of transmitting HIV infection by the transfusion of screened blood is very small, new screening tests will further reduce the risk. Estimates of reductions to the risk were derived for the new and more sensitive viral-antigen or nucleic acid screening test.
The incorporation of new assays for viral antigens and nucleic acids in the battery of screening tests has been controversial. Blood centers have recently implemented p24 antigen screening tests to help identify donors who are infected with HIV-1 but have not antibody seroconverted due to window-period infection. There is concern that people at higher risk for HIV infection will be attracted to blood centers to obtain the results of the more sensitive HIV assay that is not routinely available elsewhere. The benefit of antigen testing may be offset by an increase in the HIV incidence rate among blood donors. REDS investigators evaluated the possible impact of HIV test seeking against the reduction in the window period by antigen testing. The beneficial effect of antigen screening exceeded the potential detrimental effect of attracting higher-risk, test-seeking donors until the percentage of test seekers exceeded 13 percent. A highly unlikely scenario. This analysis was presented at the FDA Blood Products Advisory Committee.
Historically, the effectiveness of the test for antibody to hepatitis B core antigen (anti-HBc) as a surrogate screening assay in the absence of sensitive, virus-specific screening tests has been well established. However, since the introduction of virus specific tests for HIV, the residual value of anti-HBc screening has been questioned as well as its usefulness as a lifestyle marker to identify persons at risk for HIV infection. Although anti-HBc reactive donations are more likely to be seropositive for a retrovirus than are anti-HBc nonreactive donations, the low positive predictive value limits the test's effectiveness.
Although no case of proven transmission of Creutzfeldt-Jakob disease (CJD) through blood transfusion or blood derivatives has been documented, there remains a theoretical possibility. The FDA has recommended deferral of donors with family members who developed CJD, as well as recall of prior products and notification of prior recipients, depending upon medical judgement, in cases where former donors developed CJD or had more than two family members with CJD. The age-related incidence of CJD has led to consideration of deferral of older donors from donation. An analysis was conducted to examine the impact of excluding selected age groups of donors on the projected residual risk of known transmissible agents. Prevalence of HIV was significantly greater for younger compared to older donor groups. Incidence rates were non-significantly elevated for HIV. Blanket removal of donors over the age of 50 would potentially lead to a 12 percent increase risk of HIV infected units. Deferral of older donors from whole blood donations could have an adverse impact on both blood availability and safety.
HIV Infection and Laboratory Testing
As the number of HIV cases increase, the need for relatively inexpensive CD4+ lymphocyte testing will be needed. The U.S. Public Health Service currently recommends that HIV-infected persons be tested for CD4+ lymphocyte levels every 3 to 6 months to monitor disease progression. A laboratory study was conducted to evaluate four new "alternative" methods for determining absolute CD4+ T-lymphocyte counts which were less expensive and did not require fresh blood as the standard methods. The four alternative CD4+ T-lymphocyte counting methods performed well relative to standard methods.
Studies from the mid-1980s showed that 1 to 5 percent of blood donors tested reactive for HIV enzyme immunoassay (EIA) but indeterminate by Western blot although infected with HIV-1 and were in the process of seroconverting. A study was conducted to determine the rate of HIV infection among previously HIV EIA reactive and Western blot indeterminate donors. Consenting donors were enrolled and blood samples taken and tested 4 to 8 weeks after donation. We found that blood donors classified as indeterminate in supplemental HIV testing are not infected with HIV. This has important implications not only for blood donors but also for counseling individuals with indeterminate supplemental tests. Donors whose follow-up samples test negative in HIV EIA and negative or persistently indeterminate in Western blot could be considered eligible for reinstatement.
The loss of potential donors was also addressed by an analysis which examined donors who tested EIA repeatedly reactive but did not confirm positive. The prevalence of EIA false positive screening tests for HIV was higher in black donors and HIV indeterminate tests were more common in Hispanics and blacks. It was concluded that there may be a sex, race, and/or age-linked cross-reactive proteins reacting with the test kit materials. Further investigation of factors relating to false positive HIV tests is being conducted.
Donor Screening for HIV Behavioral Risks
Donor screening by interview was examined for its effectiveness of deferring donors at high-risk for HIV infection. Most blood centers in the U.S. use a confidential unit exclusion (CUE) process to allow high-risk donors to confidentially exclude their blood from use for transfusion. The purpose of this procedure is to reduce the risk of transfusion-associated HIV infection. 1.8 million units donated during 1991-1992 were included in this study. Those who were CUE(+) were 40 times more likely to be positive for HIV compared to CUE(-) donors. While CUE appears to identify high risk donors, the current CUE process has low sensitivity and low positive predictive value which suggests that efforts to improve the CUE process may be warranted. Improving donor screening procedures to reduce the risk of infection from HIV and viruses is a major area of research interest in REDS.
Donors who do not respond accurately to questions about HIV infection risk factors at the time of blood donation represent a potential threat to the safety of the blood supply. A study was conducted to estimate the prevalence of undetected behavioral risk in current blood donors. A stratified random sample of 50,162 allogeneic donors were administered anonymous questionnaires by mail. Completed questionnaires were received for 34,726 donors. HIV deferrable risks that were present at the time of their last donation were reported by 1.9 percent of the respondents. Rates of deferrable risk behaviors were 1.4 times higher for males than females, 1.6 times higher for first time than repeat donors, 2.7 times higher for donors with any reactive screening test, and 7.6 times higher for donors who used the CUE option. Despite the high degree of transfusion safety in the U.S. today, there appears to be a low level of failure in the regulated donor qualification process, and suggest the need for further refinements in the blood donor screening process. REDS is currently revising its donor survey to allow for a more in-depth exploration of risk factors and to assess the effect of offering donor incentives on blood safety.
The retention of donors who do not have any HIV behavior risks is critical to both the safety and adequacy of the blood supply. Factors adversely impacting on a donor's decision to donate has been examined. Donors who did not report behavioral risks and did not screen positive for transfusion transmitted infections were identified as "safe" donors and examined for factors related to their reported intention to provide another donation. Most of these "safe" donors reported a high likelihood of donating again within the next 12 months. The highest loss among "safe" donors was seen for those who gave a fair to poor assessment of their treatment by blood center staff, or how they felt after donating. Efforts to improve donors' perceptions of their donation experience, as well as being attentive to the physical effects of blood donation may contribute to improved retention of donors with no HIV behavior risks.
Ongoing HIV Related Analyses
There are a number of ongoing HIV related studies: HIV risk among potential young donors; impact of incentives on attracting high-risk donors; demographic profile of HIV seroconverting donors; and, investigation of HIV antigen repeat reactive donors who fail to neutralize. These analyses should provide important information to help reduce the residual risk of HIV and other viruses in the blood supply.
This contract program is sponsored by both the Division of Heart and Vascular Diseases and the Division of Lung Diseases. It focuses on the cardiovascular problems and pulmonary diseases that affect infants and children with vertically acquired HIV infection.
The P2C2 HIV study is unique in providing serial follow-up of pulmonary function and echocardio-raphic parameters in both HIV-infected children and uninfected children born to HIV-infected mothers. Using these measures and other means of detecting pulmonary and cardiovascular disease, e.g., DTPA lung scans, chest radiography, oximetry, ECG, and Holter monitoring, the investigators will be able to track the course of the pulmonary and cardiovascular events and see how they may associate with immunologic markers of disease and the presence of viral cofactors (Epstein-Barr virus and cytomegalovirus). Furthermore, the investigators hope to determine whether the diagnostic methods used for tracking facilitate early diagnosis of cardiovascular and pulmonary complications.
Six contracts were supported and the program has been completed. The study is now in the data analysis phase.
N01 HR96037 - Mark Schluchter - Cleveland Clinic Foundation, Cleveland, OH
N01 HR96038 - Samuel Kaplan - University of California, Los Angeles, CA
N01 HR96040 - William Shearer - Baylor College of Medicine, Houston, TX
N01 HR96041 - Steven Lipschultz - Children's Hospital Corporation, Boston, MA
N01 HR96042 - Meyer Kattan - Mt. Sinai School of Medicine, New York, NY
N01 HR96043 - Robert Mellins - Presbyterian Hospital Medical Center, New York, NY
Although recruitment of the desired cohort for the P2C2 HIV study was completed in January 1994, it has been extended primarily because of a lower-than-projected transmission rate of HIV from mother to infant. The anticipated rate had been 30 percent, whereas the actual accrual rate observed in this and other pediatric HIV studies is closer to 18 percent.
Demographics on the 800 enrolled subjects indicate that 49 percent of the children are black, 33 percent are Hispanic and 12 percent are white, less than 1 percent are Asian or American Indian, and the remaining 5 percent are listed as "other." About half of the mothers were screened for drugs and, of these, more than 50 percent tested positive for illicit drugs. Both mothers and infants have high rates of EBV infection, 63 percent and 33 percent (at age one year), respectively. Preliminary P2C2 data on infant CD4 counts have already been helpful in establishing pediatric norms and criteria for treating HIV-infected children. Low maternal CD4 cell counts were also found to correlate with low neonatal CD4 cell counts. Furthermore, the percent of CD4 lymphocytes was observed to identify HIV-infected maternal risk for HIV transmission. In the infants low CD4 counts were associated with P. Carinii pneumonia (PCP) in the first year of life. Bacterial, viral, and PCP pneumonias were significantly increased in the HIV-infected infants during the first year of life. Lung function in uninfected children born to HIV+ mothers appears to be normal during the first year. The number of congenital cardiac defects identified both HIV-infected and uninfected infants born to HIV+ mothers is larger than reported for the general population. The reasons for this are not yet clear and may be related to the way in which screening was performed. The P2C2 study screens all children whereas general population studies screen referred children. Preliminary echo data show that left ventricular function is commonly depressed in HIV-infectedchildren and that depressed left ventricular function correlates with decreased immune function and possibly encephalopathy.
In 1996 P2C2 joined in an international effort with nine other pediatric and perinatal AIDS studies, under the leadership of the National Institute of Child Health and Human Development, to select the pertinent data from all the studies and perform a meta-analysis to determine the effect of method of delivery on the risk of transmission of HIV from mother to infant.