Source: https://www.federalregister.gov/documents/2004/05/24/04-11643/testing-for-primary-hiv-infection-in-seronegative-patients
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Federal Register :: Testing for Primary HIV Infection in Seronegative Patients
69 FR 29546
29546-29551 (6 pages)
04-11643
https://www.federalregister.gov/d/04-11643 https://www.federalregister.gov/d/04-11643
Funding Opportunity Number: 04119.
Letter of Intent Deadline: June 23, 2004.
Summary: The technology for human immunodeficiency virus (HIV) screening tests has progressively improved over the first generation HIV-1 enzyme-linked immunoassay (EIA) tests licensed in 1985. Newer testing technology can identify infected individuals earlier in the course of their infection. Identifying individuals earlier in the course of infection holds the potential for reducing transmission, increasing diagnosis of infected persons, and improving health outcomes for infected individuals. Because of the high viral load during acute infection, the risk of HIV transmission through sexual and needle contact may be particularly high during this time period.
In both domestic (US) and international settings, methods have been piloted to demonstrate detection of HIV infection early in the course of infection. In these approaches, individuals were tested with standard antibody tests. Individual specimens from patients testing negative on initial screening tests were grouped into pools, which were tested by ribonucleic acid (RNA) amplification. Such pooling strategies have been demonstrated to identify persons with early HIV infection, or primary HIV infection (PHI), before they would have otherwise been identified with early generation, less sensitive EIAs.
Based on experiences reported in the medical literature, RNA screening for PHI appears to be feasible in a setting with moderate HIV prevalence, without anonymous testing, and with sufficient staff to contact those identified with PHI who do not return for their results. However, the utility and costs of screening for acute infection among other populations needs study. Issues include: (1) Whether testing for acute infection can be accomplished in real-time; (2) whether patients return for their test results, particularly those with non-reactive rapid HIV tests; (3) whether patients with PHI who do not return for test results can be contacted for followup; (4) whether identifying PHI increases the yield from partner contact and referral services (PCRS); and (5) whether the utility of the strategy differs in the context of anonymous testing.
Furthermore, pooled RNA testing must be compared not only to insensitive EIAs, but also to other methods that may identify HIV infection earlier than the insensitive EIAs, such as p24 antigen testing (positive approximately 5 days after RNA); third generation EIAs (positive approximately 10 days after RNA); or OraQuick testing (similar to third-generation EIAs). Laboratory results from multiple testing technologies can also be compared to determine potential laboratory criteria for identifying certain specimens which would warrant further testing for PHI (e.g., supplemental testing if a single EIA is positive or if the Western blot is negative or indeterminate, or an EIA is in the “grey zone” as defined by signal/cutoff ratios less than 1.0, but greater than a specified threshold). The marginal utility of pooled RNA screening needs to be compared to these other methods of identifying earlier HIV infection.
Identifying persons with acute HIV infection can also serve as the basis for collecting longitudinal follow-up specimens from recently infected individuals, essential for developing, validating, and comparing potential HIV incidence assays.
In this program, specimens from all patients presenting for voluntary HIV testing will be tested with standard antibody tests (EIA or rapid test). Specimens that test antibody-negative on screening tests and those that test antibody-positive on screening tests but negative or indeterminate by confirmatory Western blot or immunofluorescence will be tested with multiple other testing technologies, including pooled nucleic acid testing, p24 antigen testing, a third generation EIA (if not already performed), and (for some specimens) OraQuick and Western blot (if not previously performed). (Please note that patients testing negative with tests performed on finger stick or oral specimens will only be able to participate in this project if venous blood samples are drawn.) Nucleic acid testing and p24 antigen testing must be performed in real-time so that results would be available as soon as usual confirmatory test results (typically two weeks). Demographic data, testing history, and information about self-perceived risk, recent exposures, and PHI symptoms would be collected on all patients who had preliminary evidence Start Printed Page 29547of PHI, but were antibody negative by standard screening. RNA-positive, antibody-negative patients would be followed with antibody tests to confirm seroconversion. All persons with preliminary evidence of PHI would be offered enrollment in a follow-up study to collect additional information by interview and to collect longitudinal (seroconversion and post-seroconversion) specimens in larger quantities.
This activity will be funded in 2 parts. Part 1 applicants will propose collaboration with testing sites to identify and secure appropriate specimens from a variety of setting types with various prevalences within their jurisdiction; they will conduct client follow-up activities and assimilate study data. Part 2 applicants will be laboratories that propose to perform laboratory testing for specimens collected by Part 1 sites and refine pooling strategies for screening antibody negative specimens by nucleic acid testing.
Authority: This program is authorized under the Public Health Service Act sections 301 and 317 (42 U.S.C. 241 and 247b), as amended.
Purpose: The purpose of the program is to determine the feasibility, effectiveness, and costs of screening for acute infection among seronegative individuals tested for HIV. This program addresses the “Healthy People 2010” focus area of HIV.
1. To compare different tests and testing algorithms that could be used to detect acute infection (nucleic acid testing, p24 antigen testing, third-generation EIA, OraQuick, alterations in current diagnostic algorithm) where possible with regard to feasibility, sensitivity, specificity, predictive value, and cost.
2. To determine optimal settings/venues and/or individuals to be screened with a test sensitive for PHI.
3. To collect a panel of longitudinal specimens from a cohort of recently infected individuals.
4. To obtain preliminary information on alternative pooling strategies for nucleic acid testing to optimize cost and predictive value of test results.
Develop a protocol in collaboration with other funded sites (including the laboratory funded through part 2 of this announcement) and the CDC. The protocol must be reviewed by the CDC and local IRBs. (Project timeline and budget must allow for sufficient time—approximately 6 months—for the development of the protocol and determination of human subjects status and consent procedures.)
Identify approximately 50,000 seronegative and indeterminate specimens through customary HIV testing procedures from a variety of setting types with various prevalence within their jurisdiction. Prepare and ship specimens according to applicable regulations within a mutually agreed upon time period to the laboratory funded through Part 2 of this announcement for additional testing. (Please note that patients testing negative with tests performed on finger stick or oral specimens will only be able to participate in this project if venous blood samples are drawn.)
Collect and maintain database of information linked to initial and follow-up tests, including data routinely collected by the Counseling and Testing System on characteristics of the patient, the testing site, and the HIV test(s) performed. Obtain additional information from the routine HIV diagnostic tests performed, including EIA or rapid test kit manufacturer, EIA signal to cut-off ratio, and, if performed, Western blot manufacturer and banding patterns; maintain this information in an electronic database.
Work with the CDC to develop and implement post-test counseling messages that incorporate the findings of additional tests performed for identification of PHI as part of this announcement.
Contact clients who test positive for PHI and who do not return as scheduled 2 weeks following initial testing. Document time and effort required for follow-up activities.
To patients who test positive for PHI, offer enrollment in a research study to obtain additional data by interview and to collect longitudinal specimens:
◦ Obtain human subjects clearance from CDC and local IRB and consent for participation. (This may require a second protocol.)
◦ Conduct interview to collect demographic data, testing history, and information about self-perceived risk, recent exposures, and PHI symptoms.
◦ Collect follow-up specimens at 2-week intervals until the initial positive test for PHI can be determined to be a true positive or a false positive test result according to the combination of tests performed at the original testing site and at the funded laboratory. These samples should be tested by the laboratory routinely used by the original testing site and according to routine HIV testing protocols. Specimens should also be prepared and sent to the laboratory funded in Part 2 for further testing for PHI.
◦ Obtain a total of 10 longitudinal samples (large volume) on all patients testing positive for PHI at appropriate intervals over a 9-12 month period (as permitted by the project period), with at least 6 of these samples obtained during the first 6 months of follow-up. Utilize DIS services as necessary. Prepare and ship specimens to the funded testing laboratory.
Participate in periodic conference calls and grantee meetings with other funded sites and the CDC.
Participate with CDC and the health departments funded through Part 1 of this application in the development of testing protocols for the identification of PHI among approximately 100,000 specimens supplied by the Part 1 grantees. Identification of PHI should include pooled, automated HIV nucleic acid, p24 antigen, and 3rd generation EIA testing (if not performed at field site) on all specimens submitted. Other tests, including OraQuick and Western blot testing, should be performed on up to 150 specimens with preliminary evidence of PHI that were not previously tested with these tests in order to evaluate potential laboratory criteria for identification of PHI.
Secure IRB review and approval by the local IRB. (Project timeline and budget must allow for sufficient time—approximately 6 months—for the development of the protocol and determination of human subjects status.)
Conduct pooled, automated nucleic acid testing on initial seronegative specimens in real time. All test results must be transmitted to the designated Start Printed Page 29548contact at testing facility within 7 calendar days of receipt of specimens.
Individually test follow-up specimens of patients who tested positive for PHI at baseline with HIV nucleic acid and p24 antigen tests. Follow-up nucleic acid and p24 antigen testing will be conducted at 2-week intervals until the initial positive test for PHI can be determined to be a true positive or a false positive according to the combination of tests performed at the original testing site and at the funded laboratory.
Aliquot and store longitudinal specimens from patients who test positive for PHI at baseline (approximately 10 samples per patient collected periodically over a 9-12 month period, see Part I above). Note that no testing will be performed upon longitudinal samples collected after a patient who initially tested positive for PHI has been determined to be infected or not.
Maintain a database containing all test results and specimen numbers.
Store frozen samples at −70 °C until the end of the project. Ship all samples to CDC-designated laboratory or permanent storage site.
In the second year of the project, conduct additional automated, pooled nucleic acid testing (not in real time) to determine alternative pooling strategies to optimize cost and predictive value of pooled, RNA screening.
Obtain human subjects clearance from local IRB and consent for participation, if required.
Assist in the development and review of the required protocols.
Provide guidance and assistance in the development of forms and data collection instruments as well as data management systems and procedures.
Work with Part I grantees to develop post-test counseling messages that incorporate the findings of the additional tests performed as part of this announcement for the identification of PHI.
Fiscal Year Funds: 2004, 2005.
Approximate Total Funding: $2,000,000/2 years.
Approximate Number of Awards: 3 awards: Part 1: 2 awards; Part 2: 1 award.
Approximate Average Award: Part 1: $500,000; Part 2: $1,000,000 (This amount is to be divided over the two-year project period, and includes both direct and indirect costs. Applications should include a budget indicating separately how the funds will be used in Year 1 and Year 2. The award need not be equal for the 2 funding years.)
Applicants for Part 1 must demonstrate their ability to provide, in a 12 month period, samples from 50,000 seronegative individuals (the required sample size) tested by serologic methods as part of the CDC-funded Counseling and Testing System in the proposed jurisdiction. In addition, areas must demonstrate that the seropositivity rate of HIV tests in the CDC-funded Counseling and Testing System which will be the source of the specimens is at least 1.5 percent. A sufficiently high level of HIV morbidity is required of the participating sites in order to evaluate the feasibility of this activity at higher morbidity areas and in order to complete this research within the required timeframe.
Applicants for Part 2 must demonstrate experience using automated methods for conducting pooled nucleic acid testing, the ability to return results within 7 calendar days of specimen receipt, and the ability to process 8,000-10,000 specimens per month for the required testing. It is critical that the grantee be able to conduct the pooled nucleic acid testing with automated methods, because nucleic acid testing is vulnerable to contamination and false positive results. Automated methods minimize this problem. Also, because it is expected that results must be available before the client returns to retrieve test results at the testing point, it is required that the grantee be able to accommodate the expected specimen volume and be able to complete test results in a timely manner.
Individuals Eligible to Become Principal Investigators: Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from racial and ethnic groups underrepresented in the field as well as Start Printed Page 29549individuals with disabilities are always encouraged to apply for CDC programs.
Maximum number of pages: Three.
Evidence, as listed under “III.3. Eligibility Information—Other,” that:
○ For Part 1: The applicant can provide the required sample size of 50,000 seronegative individuals with an HIV seropositivity rate of at least 1.5 percent.
○ For Part 2: The applicant has experience using automated methods for conducting pooled nucleic acid testing, the ability to return results within 7 calendar days of specimen receipt, and the ability to process 8,000 to 10,000 specimens per month.
LOI Deadline Date: June 23, 2004.
LOI Submission Address: Submit your LOI by express mail, delivery service, fax, or e-mail to: Noreen Qualls, Dr., P.H., Scientific Review Administrator, CDC, National Center for HIV, STD, and TB Prevention, Office of the Associate Director for Science, 1600 Clifton Road, NE., Mailstop E-07, Atlanta, GA 30333, telephone Number: (404) 639-8006, fax: (404) 639-8600, e-mail address: nqualls@cdc.gov.
Application Submission Address: Submit the original and five hard copies of your application by mail or express delivery service to: Technical Information Management-PA# 04119, CDC Procurement and Grants Office, 2920 Brandywine Road, Atlanta, GA 30341.
Applications may not be submitted electronically at this time. Start Printed Page 29550
The scientific review group will address and consider each of the following criteria in assigning the application's overall score, weighting them as appropriate for each application.
1. Capacity (40 points): Does the applicant have the appropriate facilities and staff to conduct this research? Is adequate and objective information provided to demonstrate the availability of sufficient numbers of clients tested and sufficient seropositivity rates? Is the primary investigator well qualified, by education and experience, to lead the project team, hire and train appropriate staff, and provide scientific oversight? Does the applicant currently demonstrate effort, willingness, and success in contacting HIV-infecting clients tested confidentially who do not return for their test results?
2. Methods (30 points): Are the proposed methods feasible? Will they accomplish program goals? Does the applicant address required follow-up activities and methods to complete them in a timely manner? Does the applicant address changes to their HIV testing program required to return all results within 2 weeks, to schedule clients to return and to find clients with evidence of PHI who do not return for scheduled post test counseling? Does the applicant provide a reasonable timeline for the completion of the awardee activities?
3. Objectives (30 points): Are the objectives reasonable, time-phased and measurable? Does the applicant provide reasonable methods to evaluate their progress toward the timely accomplishment of objectives?
4. Does the application adequately address the requirements of 45 CFR part 46 for the protection of human subjects? (Not scored; however, an application can be disapproved if the research risks are sufficiently serious and protection against risks is so inadequate as to make the entire application unacceptable.)
5. Does the applicant adequately address the CDC Policy requirements regarding the inclusion of women, ethnic, and racial groups in the proposed research. This includes:
6. Budget (not scored): Is the budget reasonable for the proposed activities?
1. Capacity (50 points): Does the applicant have the appropriate facilities and staff to conduct this research including equipment required to conduct automated sample processing and testing and the ability to hire and train appropriate staff? Does the applicant demonstrate their ability to process the required number of specimens within the required timeframe? Does the applicant have specific experience conducting the tests required for this activity and have the required knowledge to provide scientific oversight for the conduct of the research?
2. Methods (25 points): Are the proposed methods feasible? Will they accomplish program goals? Are the proposed methods scientifically sound and do they demonstrate understanding of the problem to be evaluated? Is a specific proposed pooling strategy articulated and justified? Does the applicant provide a reasonable timeline for the completion of awardee activities?
3. Objectives (25 points): Are the objectives reasonable, time-phased and measurable? Does the applicant provide reasonable methods to evaluate their progress toward the timely accomplishment of objectives?
4. Budget (not scored): Is the budget reasonable for the proposed activities?
Applications will be reviewed for completeness by the Procurement and Grants Office (PGO) staff and for responsiveness by the National Center for HIV/STD/TB Prevention, Division of HIV/AIDS Prevention. Incomplete applications and applications that are non-responsive to the eligibility criteria will not advance through the review process. Applicants will be notified that their application did not meet submission requirements.
Applicants may apply for Parts 1 or 2 or both. A separate application should be submitted for each Part proposed. Each Part will be evaluated independently by the objective review panel.
Preference will be given to applicants for Part 1 that have larger numbers of clients tested through publicly funded HIV testing programs and higher historical HIV seropositivity rates. For Part 2, laboratories that have demonstrated experience in using automated methods for conducting pooled nucleic acid screening studies will be given preference.
AR-1— Human Subjects Requirements
AR-2—Requirements for Inclusion of Women and Racial and Ethnic Minorities in Research Start Printed Page 29551
AR-24—Health Insurance Portability and Accountability Act Requirements
1. Interim progress report, (use form PHS 2590, OMB Number 0925-0001, rev. 5/2001 as posted on the CDC website) no less than 90 days before the end of the first 12 month budget period. The progress report will serve as your non-competing continuation application, and must contain the following elements:
For general questions about this announcement, contact: Technical Information Management Section—PA #04119, CDC Procurement and Grants Office, 2920 Brandywine Road, Atlanta, GA 30341, telephone: 770-488-2700.
Sheryl Lyss, MD, Extramural Project Officer, CDC, National Center for HIV, STD, and TB Prevention, 1600 Clifton Road, MS E-46, Atlanta, Georgia 30333, telephone: 404-639-2093, e-mail: SLyss@cdc.gov.
For questions about peer review, contact: Noreen Qualls, Dr.P.H., Scientific Review Administrator, CDC, National Center for HIV, STD, and TB Prevention, Office of the Associate Director for Science, 1600 Clifton Road, NE., Mailstop E-07, Atlanta, GA 30333, telephone number: 404-639-8006, fax: 404-639-8600, e-mail address: nqualls@cdc.gov.
For financial, grants management, or budget assistance, contact: Brenda D. Hayes, Grants Management Specialist, CDC Procurement and Grants Office, 2920 Brandywine Road, Atlanta, GA 30341, telephone: 770-488-2741, e-mail: bkh4@cdc.gov.
For financial, grants management, or budget assistance in the territories, contact: Vincent Falzone, Contract Specialist, CDC Procurement and Grants Office, 2920 Brandywine Road, Atlanta, GA 30341, telephone: 770-488-2763, e-mail: vcf6@cdc.gov.
[FR Doc. 04-11643 Filed 5-21-04; 8:45 am]