PKG00258220-instructions.pdf

Centers for Disease Control and Prevention

National Center for HIV-AIDS, Viral Hepatitis, STD, and TB Prevention Extramural Research

Program Office

Evaluation of New HIV Testing Technologies in Clinical Settings with High HIV Incidence

RFA-PS-20-001

Application Due Date: 04/14/2020

Evaluation of New HIV Testing Technologies in Clinical Settings with High HIV Incidence

RFA-PS-20-001

TABLE OF CONTENTS

Part 1. Overview Information Key Dates Required Application Instructions Executive Summary

Part 2. Full Text Section I. Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV. Application and Submission Information Section V. Application Review Information Section VI. Award Administration Information Section VII. Agency Contacts Section VIII. Other Information

Part 1. Overview Information Participating Organization(s) Centers for Disease Control and Prevention Components of Participating Organizations National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Notice of Funding Opportunity (NOFO) Title Evaluation of New HIV Testing Technologies in Clinical Settings with High HIV Incidence Activity Code U01 - Research Project - Cooperative Agreement

Notice of Funding Opportunity Type New Agency Notice of Funding Opportunity Number

RFA-PS-20-001

Assistance Listings (CFDA) Number(s) 93.941 Category of Funding Activity:

Health NOFO Purpose The purpose of this Notice of Funding Opportunity (NOFO) is to develop and implement protocols and recruitment strategies to evaluate the performance (sensitivity and specificity) of HIV tests under development, and/or newly available HIV tests, for use in point-of-care settings in the United States using fresh (unprocessed) specimens such as whole blood and oral fluid.

Key Dates Publication Date: To receive notification of any changes to RFA-PS-20-001, return to the synopsis page of this announcement at www.grants.gov and click on the "Send Me Change Notification Emails" link. An email address is needed for this service.

Letter of Intent Due Date: 03/16/2020

Application Due Date: 04/14/2020

On-time submission requires that electronic applications be error-free and made available to CDC for processing from the NIH eRA system on or before the deadline date. Applications must be submitted to and validated successfully by Grants.gov no later than 5:00 PM U.S.

Eastern Time. Applications must be submitted using the Application Submission System & Interface for Submission Tracking (ASSIST) module which is a web-based service used for the preparation and submission of grant applications to CDC through Grants.gov. ASSIST provides the ability for applicants to prepare their applications online, and offers the applicant additional https://www.grants.gov capabilities including the ability to preview the application image, validate the application against required business rules, and prepopulate data from an applicant organization's records, therefore identifying issues earlier in the application submission process.

Note: HHS/CDC grant submission procedures do not provide a grace period beyond the application due date time to correct any error or warning notices of noncompliance with application instructions that are identified by Grants.gov or eRA systems (i.e., error correction window).

Scientific Merit Review: 06/09/2020

Secondary Review: 07/09/2020

Estimated Start Date: 09/30/2020

Expiration Date: 04/15/2020 Due Dates for E.O. 12372: Due no later than 60 days after the application receipt date.

Required Application Instructions

**ELECTRONIC APPLICATION SUBMISSION VIA ASSIST IS PREFERRED**

It is recommended that applicants use ASSIST for the electronic preparation and submission of applications through Grants.gov to CDC. ASSIST is an alternative method to prepare and submit applications, and provides many features to facilitate the application submission process which improves data quality (e.g., pre-population of organization data, pre-submission validation of business rules, and preview of the application image used for review). Use of the Grants.gov downloadable Adobe application packages and submission process will still be supported.

It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide except where instructed to do otherwise in this NOFO. Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Note: The Research Strategy component of the Research Plan is limited to 25 pages.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Pages that exceed page limits described in this NOFO will be removed and not forwarded for peer review, potentially affecting an application's score.

Telecommunications for the Hearing Impaired: TTY 1-888-232-6348

Executive Summary http://grants.nih.gov/grants/funding/424/SF424_RR_Guide_General_VerC.pdf

Purpose: The purpose of this Notice of Funding Opportunity (NOFO) is to develop and implement protocols and recruitment strategies to evaluate the performance (sensitivity and specificity) of HIV tests under development, and/or newly available HIV tests, for use in point-of-care settings in the United States using fresh (unprocessed) specimens such as whole blood and oral fluid. Test sensitivity early in infection, when the antibody response is developing, and during conditions that might affect the detection of an analyte (HIV RNA, antigenic protein or antibody), is of particular interest; for example, determining test sensitivity in patients taking medications for antiretroviral therapy (ART) or HIV pre-exposure prophylaxis (PrEP). Therefore, protocols should address strategies for recruitment of patients with early HIV infection before they initiate ART, patients with HIV infection using ART, and HIV negative patients taking PrEP.

Mechanism of Support: U01 - Research Project - Cooperative Agreement.

Funds Available and Anticipated Number of Awards: The estimated total funding available, including direct and indirect costs, for the entire three (3)-year project period is $3,600,000. The number of awards will be up to three (3). Awards issued under this NOFO are contingent upon the availability of funds and receipt of a sufficient number of meritorious applications. Because the nature and scope of the proposed research will vary from application to application, it is also anticipated that the size and duration of each award may also vary. The total amount awarded, and the number of awards made, will depend upon the number, quality, duration and cost of the applications received.

Please note: All funds for the entire three (3)-year project period will be awarded in the first year; therefore, annual expenditures by the recipient may vary from year to year to complete project objectives but cannot exceed the total award amount. Although there will be no non-competing continuation application required on an annual basis, annual progress reports will be required.

Budget and Project Period: The estimated total funding (direct and indirect) will be $3,600,000 with individual awards ranging from $900,000 to $1,800,000. All funds for the project will be awarded in the first year; thus, the estimated total funding (direct and indirect) for the first year, and the entire project period, for all recipients combined will be $3,600,000. The project period is anticipated to run from 09/30/2020 to 09/29/2023.

Application Research Strategy Length: Page limits for the Research Strategy are clearly specified in Section IV. Application and Submission Information of this announcement.

Eligible Institutions/Organizations. Institutions/organizations listed in Section III of this announcement are eligible to apply.

Eligible Project Directors/Principal Investigators (PDs/PIs). Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/organization to develop an application for support. NOTE:

CDC does not make awards to individuals directly. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply.

Number of PDs/PIs. There will only be one PD/PI for each application.

Number of Applications. Only one application per institution (normally identified by having a unique DUNS number) is allowed.

Application Type. New.

Application Materials. See Section IV.1 for application materials. Please note that

Form E is to be used when completing the application package.

Part 2. Full Text Section I. Funding Opportunity Description

Statutory Authority Public Health Service Act, Sections 301(a) [42 USC 241] and 317(k)(2) [42 USC 247b], as amended.

1. Background and Purpose An estimated 38,000 new HIV infections occur each year in the United States (1). In 2016-2017, most new infections occurred among young black/African American and Hispanic/Latino men who have sex with men (MSM), and more than half of new HIV infections were reported in southern states and Washington, DC (2). The first few weeks after HIV infection, referred to as the acute HIV infection stage, comprise the stage when there is no detectable HIV-specific antibody response and HIV infection can only be detected by testing for HIV virus directly. The early detection of HIV infection, particularly during the acute stage, serves a public health need because those with acute infection have large amounts of circulating HIV virus and thereby have an increased risk of transmitting infection (3). Recent studies have shown that early initiation of antiretroviral treatment confers both clinical and public health benefits (4).

CDC recommends the use of point-of-care (POC) HIV tests whenever it is not feasible to do more sensitive laboratory-based testing. POC tests are useful in identifying HIV infections in hard to reach populations and have been widely used in a variety of venues such as mobile clinics, pride events, bars, clubs and bathhouses (6,7).

Use of the latest testing technologies can help identify HIV infections earlier, so that treatment and prevention is promptly offered and is more effective. Several new HIV tests have recently been approved (or will soon be approved) by the US Food and Drug Administration (FDA) to be used with unprocessed patient specimens (e.g., whole blood obtained via venipuncture or finger stick or oral fluid swabbed from the mouth). Some of the new tests can detect early infection by testing for the HIV virus itself, either using molecular techniques (molecular POC nucleic acid tests) or by direct detection of an antigenic component of the virus, such as p24 (POC antigen test). Other new tests can detect an early antibody response sooner than older HIV antibody tests.

Determining the relative sensitivity and specificity of available HIV tests during the earliest stages of infection, including the acute stage and during development of an antibody response, while also maximizing the number of persons with previously undiagnosed infection who are identified and linked to HIV medical care, will require an examination of new HIV testing technologies in populations (e.g., MSM) and geographic areas with high HIV incidence.

Although it has been known for some time that ART can affect the ability of tests to detect HIV antibodies, particularly in oral fluid specimens (8,9), recent data suggest that initiation of ART very early in infection, before a mature antibody response has been established (10), can lead to either undetectable or transiently detectable HIV antibodies. Further, patients using HIV PrEP, who nonetheless become HIV-infected, have been shown to also exhibit abnormal antibody response patterns as well as false-negative nucleic acid test (NAT) results. Because the goals of the HIV elimination strategy (2) rely on early ART initiation and expansion of PrEP coverage, issues with test performance in treated populations are expected to be observed more frequently.

Cohorts of patients currently taking ART or PrEP are needed to further evaluate characteristics of HIV test performance in these populations.

Novel HIV tests that purport to distinguish recent (e.g., within the past year) infection, from more long-term infections, are currently being used for HIV surveillance and to prioritize case finding in sub-Saharan Africa (11). These technologies could prove useful to focus attention on sources of ongoing HIV transmission to bring the epidemic to an end. However, novel POC tests that categorize the recency of infection have yet to be evaluated in clinical settings in the United States.

The purpose of this Notice of Funding Opportunity (NOFO) is to develop and implement protocols and recruitment strategies to evaluate the performance (sensitivity and specificity) of HIV tests under development, and/or newly available HIV tests, for use in point-of-care settings in the United States using fresh (unprocessed) specimens such as whole blood and oral fluid. Test sensitivity early in infection, when the antibody response is developing, and during conditions that might affect the detection of an analyte (HIV RNA, antigenic protein or antibody), is of particular interest; for example, determining test sensitivity in patients taking medications for antiretroviral therapy (ART) or HIV pre-exposure prophylaxis (PrEP). Therefore, protocols should address strategies for recruitment of patients with early HIV infection before they initiate ART, patients with HIV infection using ART, and HIV negative patients taking PrEP.

Research Objectives of the NOFO:

The overall project should address the following research objectives:

1. Develop and implement recruitment strategies and procedures to: (a) identify appropriate study participants to evaluate the differences in sensitivity (including acute HIV infection sensitivity) and specificity of the newest HIV tests in real time using fresh whole blood and oral fluid specimens; and (b) compare results to the currently recommended CDC laboratory algorithm (12). Patients with exposure to either early ART or PrEP should be oversampled in order to evaluate HIV test performance in these populations as well.

2. Evaluate the seroconversion sensitivity of the newest HIV tests through serial follow-up of study participants with discordant baseline test results.

3. Evaluate the diagnostic and clinical performance of nucleic acid (molecular) tests to determine the applicability of this technology for use in a variety of clinical and POC settings.

4. Collect matched demographic, behavioral and clinical data from participants to assess the impact of these factors on HIV test performance, including the use of behavioral and clinical data to categorize the timing of exposure for those with newly diagnosed infection.

5. Develop panels of specimens with accompanying demographic, clinical and behavioral data for evaluations of laboratory-based HIV tests.

References

1. Centers for Disease Control and Prevention. Estimated HIV incidence and prevalence in the United States, 2010?2016. HIV Surveillance Supplemental Report 2019; 24(No. 1).

http://www.cdc.gov/hiv/library/reports/hiv-surveillance.html. Published February 2019.

Accessed May 8, 2019.

2. Fauci AS, Redfield RR, Sigounas G, Weahkee MD, Giroir BP. Ending the HIV Epidemic:

A Plan for the United States. JAMA. 2019;321(9):844-845. doi:10.1001/jama.2019.1343

3. Miller WC, Rosenberg NE, Rutstein SE, Powers KA. Role of acute and early HIV infection in the sexual transmission of HIV. Curr Opin HIV AIDS. 2010 Jul;5(4):277-82.

Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130067/

4. Cohen MS, Smith MK, Muessig KE, Hallett TB, Powers KA, Kashuba AD. Antiretroviral treatment of HIV-1 prevents transmission of HIV-1: where do we go from here? Lancet.

2013 Nov 2;382(9903):1515-24. Available from: http://www.ncbi.nlm.nih.gov/pmc/artic les/PMC3880570/

5. Centers for Disease Control and Prevention. Implementing HIV Testing in Nonclinical Settings: A Guide for HIV Testing Providers. 2016. Available from: https://www.cdc.gov /hiv/pdf/testing/CDC_HIV_Implementing_HIV_Testing_in_Nonclinical_Settings.pdf

6. Spielberg F, Branson BM, Goldbaum GM, Kurth A, Wood RW. Designing an HIV counseling and testing program for bathhouses: the Seattle experience with strategies to improve acceptability. J Homosex 2003;44(3-4):203-20 doi: 10.1300/J082v44n03_09.

7. Keenan PA, Keenan JM, Branson BM. Rapid HIV testing. Wait time reduced from days to minutes. Postgrad Med 2005;117(3):47-52.

8. Delaney KP, Branson BM, Uniyal A, Phillips S, Candal D, Owen SM, Kerndt PR. Evalu ation of the performance characteristics of 6 rapid HIV antibody tests. Clin Infect Dis.

2011 Jan 15;52(2):257-63.

9. O'Connell, R. J., T. M. Merritt, J. A. Malia, T. C. VanCott, M. J. Dolan, H. Zahwa, W. P.

Bradley, B. M. Branson, N. L. Michael, and C. C. DeWitt. 2003. Performance of the OraQuick Rapid Antibody Test for diagnosis of human immunodeficiency virus type 1 infection in patients with various levels of exposure to highly active antiretroviral therapy.

J. Clin. Microbiol. 41:2153-2155.

10. de Souza MS, Pinyakorn S, Akapirat S, Pattanachaiwit S, Fletcher JL, Chomchey N, Kroon ED, Ubolyam S, Michael NL, Robb ML, Phanuphak P, Kim JH, Phanuphak N, Ananworanich J; RV254/SEARCH010 Study Group. Initiation of antiretroviral therapy during acute HIV-1 infection leads to a high rate of nonreactive HIV serology. Clin Infect Dis. 2016 Aug 15;63(4):555-61. doi: 10.1093/cid/ciw365. Epub 2016 Jun 17.

11. Kim AA, Behel S, Northbrook S, Parekh BS. Tracking with recency assays to control the epidemic: real-time HIV surveillance and public health response. AIDS. 2019 Apr 22. doi:

10.1097/QAD.0000000000002239

12. Centers for Disease Control and Prevention. HIV Laboratory Testing Guidance. Available from: https://www.cdc.gov/hiv/testing/laboratorytests.html

Health Equity:

The program supports efforts to improve the health of populations disproportionately affected by HIV/AIDS, viral hepatitis, sexually transmitted diseases (STDs) and TB by maximizing the http://www.cdc.gov/hiv/library/reports/hiv-surveillance.html http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130067/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880570/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880570/ https://www.cdc.gov/hiv/pdf/testing/CDC_HIV_Implementing_HIV_Testing_in_Nonclinical_Settings.pdf https://www.cdc.gov/hiv/pdf/testing/CDC_HIV_Implementing_HIV_Testing_in_Nonclinical_Settings.pdf https://www.ncbi.nlm.nih.gov/pubmed/21288853 https://www.ncbi.nlm.nih.gov/pubmed/21288853 https://www.cdc.gov/hiv/testing/laboratorytests.html health impact of public health services, reducing disease prevalence, and promoting health equity consistent with the National HIV/AIDS Strategy available at https://www.whitehouse.gov/admin istration/eop/onap/nhas.

Health disparity is a particular type of health difference that is closely linked with social or economic disadvantage based on racial or ethnic group, religion, socioeconomic status, gender, mental health, cognitive, sensory, or physical disability, sexual orientation, geographic location, or other characteristics historically linked to discrimination or exclusion [HP 2020 - http://www .healthypeople.gov/2010/hp2020/advisory/PhaseI/glossary.htm]. Health disparities in HIV, viral hepatitis, STDs, and TB are inextricably linked to a complex blend of social determinants that influence which populations are most severely affected by these diseases.

Social determinants are the economic and social conditions that influence the health of individuals, communities and jurisdictions and include conditions for early childhood development; education, employment, and work; food security, health services, housing, income, and social exclusion.

Health equity is a desirable goal that entails special efforts to improve the health of those who have experienced social or economic disadvantage. It requires:

Continuous efforts focused on elimination of health disparities, including disparities in health and in the living and working conditions that influence health, and

Continuous efforts to maintain a desired state of equity after particular health disparities are eliminated.

Programs should use data, including social determinants data, to identify communities within their jurisdiction that are disproportionately affected by HIV, viral hepatitis, STDs and TB and related diseases and conditions, and plan activities to help eliminate health disparities. In collaboration with partners and appropriate sectors of the community, programs should consider social determinants of health in the development, implementation, and evaluation of program specific efforts and use culturally appropriate interventions that are tailored for the communities for which they are intended.

Healthy People 2020 and other National Strategic Priorities Healthy People 2020 For additional details on the Healthy People 2020 goals listed above, visit http://www.healthypeo ple.gov/2020/topicsobjectives2020/objectiveslist.aspx?topicId=22 This project is designed to: (1) evaluate the tests under study using unprocessed specimens and

(2) evaluate the seroconversion sensitivity of new HIV tests through serial follow-up; it specifically addresses, or contributes to, the following Healthy People 2020 goals:

HIV-2: (Measurable) Reduce the number of new HIV infections among adolescents and adults.

HIV-19: (Measurable) Increase the percentage of persons with newly diagnosed HIV infection linked to HIV medical care (had a routine HIV medical visit) within one month of their HIV diagnosis.

HIV-20: (Measurable) Increase the percentage of newly diagnosed persons with diagnosed https://www.whitehouse.gov/administration/eop/onap/nhas https://www.whitehouse.gov/administration/eop/onap/nhas http://www.healthypeople.gov/2010/hp2020/advisory/PhaseI/glossary.htm http://www.healthypeople.gov/2010/hp2020/advisory/PhaseI/glossary.htm http://www.healthypeople.gov/2020/topicsobjectives2020/objectiveslist.aspx?topicId=22

HIV infection who are retained in continuous HIV medical care.

HIV-22: (Measurable) Increase the percentage of persons with diagnosed HIV infection who are virally suppressed.

o HIV-22.1:(Measurable) Increase the percentage of persons aged 13 years and older with diagnosed HIV infection who are virally suppressed.

o HIV-22.2: (Measurable) Increase the percentage of youth with diagnosed HIV infection who are virally suppressed.

o HIV-22.3: (Measurable) Increase the percentage of persons who inject drugs

(PWID) with diagnosed HIV infection who are virally suppressed.

HIV-23: (Developmental) Reduce the proportion of persons with an HIV diagnosis receiving HIV services who were homeless or unstably housed in the 12-month measurement period.

For additional details on the Healthy People 2020 goals listed above, visit http://www.healthypeo ple.gov/2020/topicsobjectives2020/objectiveslist.aspx?topicId=22 Other Strategic Priorities

CDC's Division of HIV/AIDS Prevention No New HIV Infections Concept by (1) Preventing New HIV Infections with PrEP and by (2) Reducing Transmission of HIV with improved viral suppression.

The White House national initiative "Ending the HIV Epidemic: A Plan for America", particularly the DIAGNOSE strategy: Diagnose all individuals with HIV as early as possible after infection.

Public Health Impact CDC provides guidelines for HIV testing and diagnosis in the United States, as well as programmatic technical guidance for its partners. Because of the critical importance of detecting HIV infection as early as possible, CDC monitors and updates these guidance documents to reflect advancements in HIV testing technology and the availability of new tests. Although manufacturers seeking approval of HIV tests conduct studies to demonstrate device safety and effectiveness, clinical trials are not designed to evaluate important aspects that determine the public health impact of these tests. Moreover, they do not evaluate multiple tests head-to-head to yield relative performance data that is helpful in guiding testing strategies. Therefore, this NOFO will support test evaluations to understand the differences in sensitivity and specificity of the newest HIV serologic tests, using unprocessed specimens collected from infected individuals who are in the acute or early stages of disease.

This research NOFO is to assess the relative performance of these new POC HIV tests, particularly among persons who: (a) present diagnostic challenges, including those exposed to HIV PrEP; (b) those with very recent HIV infection (before the development of a mature antibody response); and (c) those achieving viral suppression before developing an antibody response, among others.

Test performance and questionnaire data will be used to inform HIV testing guidelines and provide information to HIV test providers about the appropriate use of different HIV testing technologies in different settings, and for different populations (e.g., for highest risk persons as well as the general population). Diagnosing HIV infection as early as possible, and using appropriate HIV tests to monitor those using PrEP or ART to optimize the preventive effects of these interventions, are key components of the HIV elimination strategy. Test performance data will help inform the choice of test technology and allow these technologies to be tailored to the strategies needed to end the HIV epidemic.

Relevant Work

1. Time From HIV Infection to Earliest Detection for 4 FDA-Approved Point-Of-Care Tests, CROI 2018: http://www.croiconference.org/sessions/time-hiv-infection-earliest-detection- 4-fda-approved-point-care-tests

2. Evaluation of New HIV Testing Technologies in a Clinical Setting with High Incidence:

Rationale, Study Design and Preliminary Results from Project DETECT, 2016 HIV Diagnostics Conference: https://custom.cvent.com/BEED90636AE44DD0A76741F3C CF3692C/files/4ed4a58483b64239b05bf4edc3532f6a.pdf

3. Performance Evaluation of Four Point-of-Care HIV Tests Using Unprocessed Specimens:

Baseline Data from Project DETECT, 2019 HIV Diagnostics Conference: http://hivtesting conference.org/wp-content/uploads/2019/04/35_Chavez.pdf

4. Delaney KP, Branson BM, Uniyal A, Phillips S, Candal D, Owen SM, Kerndt PR.

Evaluation of the performance characteristics of 6 rapid HIV antibody tests. Clin Infect Dis. 2011 Jan 15;52(2):257-63. https://www.ncbi.nlm.nih.gov/pubmed/21288853

5. Keenan PA, Keenan JM, Branson BM. Rapid HIV testing. Wait time reduced from days to minutes. Postgrad Med 2005;117(3):47-52

6. Delaney KP, Branson BM, Uniyal A, Kerndt PR, Keenan PA, Jafa K, Gardner AD, Jamieson DJ, Bulterys M. Performance of an oral fluid rapid HIV-1/2 test: experience from four CDC studies. AIDS. 2006 Aug 1;20(12):1655-60. https://www.ncbi.nlm.nih .gov/pubmed/16868447

7. Chavez P, Wesolowski L, Patel P, Delaney K, Owen SM. Evaluation of the performance of the Abbott ARCHITECT HIV Ag/Ab Combo Assay. J Clin Virol. 2011 Dec;52 Suppl 1:S51-5. https://www.ncbi.nlm.nih.gov/pubmed/21983253

8. Ethridge SF, Wesolowski LG, Nasrullah M, Kennedy MS, Delaney KP, Candal D, Owen SM. Comparative evaluation of Aptima HIV-1 Qualitative RNA assay performance using plasma and serum specimens from persons with established HIV-1 infection. J Clin Virol.

2011 Dec; 52 Suppl 1:S63-6. https://www.ncbi.nlm.nih.gov/pubmed/21995932

9. Delaney KP, Heffelfinger JD, Wesolowski LG, Owen SM, Meyer WA 3rd, Kennedy S, Uniyal A, Kerndt PR, Branson BM. Performance of an alternative laboratory-based algorithm for HIV diagnosis in a high-risk population. J Clin Virol. 2011 Dec;52 Suppl 1:S5-10. https://www.ncbi.nlm.nih.gov/pubmed/22019251

2. Approach CDC updates HIV testing guidance on an ongoing basis to reflect advancements in HIV testing technology and is committed to independent evaluations of the performance of new HIV tests in head-to-head comparisons with existing technology to inform this guidance. For point-of-care tests, test performance should be evaluated in settings where they are intended to be used, http://www.croiconference.org/sessions/time-hiv-infection-earliest-detection-4-fda-approved-point-care-tests http://www.croiconference.org/sessions/time-hiv-infection-earliest-detection-4-fda-approved-point-care-tests https://custom.cvent.com/BEED90636AE44DD0A76741F3CCF3692C/files/4ed4a58483b64239b05bf4edc3532f6a.pdf https://custom.cvent.com/BEED90636AE44DD0A76741F3CCF3692C/files/4ed4a58483b64239b05bf4edc3532f6a.pdf http://hivtestingconference.org/wp-content/uploads/2019/04/35_Chavez.pdf http://hivtestingconference.org/wp-content/uploads/2019/04/35_Chavez.pdf https://www.ncbi.nlm.nih.gov/pubmed/21288853 https://www.ncbi.nlm.nih.gov/pubmed/16868447 https://www.ncbi.nlm.nih.gov/pubmed/16868447 https://www.ncbi.nlm.nih.gov/pubmed/21983253 https://www.ncbi.nlm.nih.gov/pubmed/21995932 https://www.ncbi.nlm.nih.gov/pubmed/22019251 employing a variety of unprocessed specimens and with patients representing the likely population of persons seeking HIV testing (including those at high-risk of recent infection), or undergoing ongoing monitoring while receiving HIV ART or PrEP. This NOFO aims to support the evaluation of HIV tests when conducted in clinical settings with high HIV incidence, and with large populations of patients receiving both PrEP and ART care. Under this cooperative agreement, protocols should be developed with technical assistance and consultation from CDC scientists and other partners (e.g., local health departments, local laboratories).

In this study, the recipient should identify and recruit participants in specific target populations and conduct multiple POC tests using unprocessed specimens, including oral fluid and finger stick blood, as well as anticoagulated whole blood from venipuncture. The recipient should also collect blood for laboratory-based comparator tests against which POC tests will be evaluated. If individual POC test results are not concordant (i.e., not all positive or all negative), the recipient will enroll participants with discrepant results in follow-up testing until these discrepant results are resolved. Finally, in order to provide detailed and standardized risk behavior data for each study participant, CDC will provide technical assistance to implement an approved questionnaire that will be administered by the recipient(s). Data collected via this questionnaire will be used to quantify the HIV risk behaviors that participants engage in around the time of infection and describe changes in risk behavior associated with diagnosis.

The application should describe the approach for meeting the research objectives, including the identification of study clinical sites, the recruitment of participants into the study, the process for conducting point-of-care (POC) and laboratory testing, any additional follow-up clinic visits for evaluating the performance of new testing technologies, and the procedures for data and specimen collection, including the following activities:

Study sites

Describe the clinical site(s) where the HIV tests under evaluation will be conducted as well as potential partner sites from which participants will be referred for study enrollment at the clinic site.

Describe any prior experience with evaluations of HIV tests at potential study sites.

Consider the current standard of care for HIV testing, and describe how this standard will be modified, if necessary, so that the comparator for evaluations of POC tests will include the CDC laboratory algorithm, including an antigen/antibody screening test and, when indicated, an HIV-1/HIV-2 differentiation test and an HIV-1 nucleic acid test (12).

Describe the current standard of care for monitoring patients receiving either ART or PrEP, and the type of viral load test used for monitoring HIV-infected patients; these tests will serve as the gold standard for any evaluations of qualitative, quantitative or semi-quantitative POC NATs.

Recruitment procedures for one or more of the following groups of patients Note that here, and elsewhere, the proposed sample sizes are per recipient, per year (i.e., if there are two awards, the total sample for the entire project for each year would be expected to double relative to the numbers listed below; and, for a given recipient, the sample size projection for the total five (5)-year project period would be expected to be five times greater than what is listed below).

1. The application should describe strategies to recruit HIV infected participants for the evaluation of the sensitivity of the tests under investigation. In each study year, at least 200 participants known to be infected with HIV should be recruited including:

(a) Newly diagnosed (within the prior 90 days) patients who have and have not started ART.

(b) Patients not currently taking ART (who have not taken even one dose in the past 30 days).

(c) Patients taking ART who have not yet achieved viral suppression, based on the CDC definition of a viral load <200 copies/ml.

(d) Patients taking ART who are considered to have achieved viral suppression, based on the CDC definition of a viral load <200 copies/ml.

The target for the mix of populations (a. through d. above) will be determined each year by the recipient in consultation with CDC.

2. The application should also describe recruitment strategies for the evaluation of test specificity, including prioritizing participants currently taking or initiating PrEP. The application should describe how, in each study year, a sample of at least 500 participants not known to be HIV-infected (e.g., those seeking HIV testing, or with a possible exposure to HIV since their last documented HIV-negative test result) will be recruited, including at least 50 patients initiating or taking HIV PrEP. Participants in this group should be allowed to re-enroll no more than every 90 days, and repeat enrollments should be documented such that all study visits for a participant can be linked at the end of the study.

Testing with novel HIV testing technologies at each study visit

The application should describe how clinic clients, who consent to participate in the study, will have anti-coagulated (EDTA) whole blood, oral fluid and dried-blood spot specimens collected for the evaluation of the new HIV screening and diagnostic tests.

The application should describe how staff will operationalize a protocol to perform multiple POC HIV tests, including those still under investigation for FDA approval, on unprocessed specimens, in real time.

The application should describe the investigator's ability to change the tests under evaluation, depending on the performance of the tests during the study, and the availability of new tests over time. The tests being used may change as frequently as annually over the period of performance of the award as long as the objectives and specific aims remain within the scope of activities originally proposed.

The application should describe the process for providing a baseline behavioral survey, developed with technical assistance from CDC, that will supply detailed and standardized risk behavior data. Data collected via this survey will be used to quantify the HIV risk behaviors that participants engage in around the time of infection, and describe changes in risk behavior associated with diagnosis.

Specimen collection at each study clinic visit

The application should describe the ability of clinic staff and partner laboratories to collect, process, and store specimens (e.g., dried-blood spots, oral fluid, and/or EDTA plasma processed from whole blood specimens) until they can be used in evaluations of laboratory-based HIV tests.

At a minimum, each recipient should aim to collect and store specimens from 800 HIV-infected participants with positive HIV test results on all screening tests, as well as 1500 specimens from participants with negative HIV test results on all screening tests during the five (5)-year period of performance.

Serial follow-up visits after the first study clinic visit The application should describe how participants with at least one reactive HIV screening test result, and at least one non-reactive HIV screening test result (i.e., discordant screening result), will be invited to continue with follow-up visits to resolve test discrepancies and to assess seroconversion sensitivity for all tests. It is expected that study participants with discordant test results at their first study visit will comprise a mix of: (a) those having falsely reactive HIV test results, (b) those in the process of seroconverting after the acute stage of infection, and (c) possibly those in the process of achieving viral suppression. The application should provide estimates of the expected number of participants with discordant results that could be identified in each study year, based either on past studies conducted in the potential clinic population, or information about test results from the past two years of data at the proposed study clinics.

The application should describe the proposed follow-up schedule for each category of discordant test results and the consent and enrollment plan for serial follow-up. For example, study participants in the process of seroconversion might require several closely spaced study visits in the first 30 to 60 days after enrollment. The application should also describe a plan for re-contacting participants who fail to return for a scheduled follow-up visit, and how investigators will document how the plan was implemented when necessary.

The application should describe the testing and specimen collection procedures at each follow-up visit. At a minimum, the recipient will collect specimens appropriate to run the POC tests currently under evaluation; remnant specimens (i.e., EDTA plasma) may be processed, aliquoted, and stored for shipment to CDC for further test evaluations, as warranted.

The application should demonstrate the recipient's prior experience with: (a) research studies involving clinical follow-up in their clinic population; and (b) electronic information management systems which either already collect, or which can be modified to collect, the clinical and risk information required to fulfill the objectives of the NOFO.

The application should also describe how a behavioral survey, created with technical assistance from CDC, will be administered during follow-up. At a minimum, when all tests become concordant (i.e., at the last serial follow-up visit), participants should complete a final behavioral survey to identify any behavioral changes during their time of follow-up. This survey should contain the same domains as the baseline survey administered to participants in the first study visit, with additional questions about disclosure of study HIV test results to recent sex partners, and risk behaviors during the follow-up period.

Laboratory testing for comparison to POC tests under study Laboratory-based HIV testing using the CDC recommended algorithm and, for those participants with at least one reactive HIV test, a quantitative HIV-1 viral load, should serve as the gold standard comparison for HIV test performance in this study. As indicated in the site selection criteria, an ideal study clinical site should already be performing these tests routinely for patients seeking HIV testing and for those receiving ongoing HIV or PrEP care. If the study clinical site(s) do not routinely offer this laboratory testing, the recipient should identify a partner laboratory that conducts either an algorithm that includes an antigen/antibody laboratory immunoassay, an HIV- 1/HIV-2 differentiation test, and a nucleic acid test, or pooled nucleic acid testing of all persons who screen HIV-negative on site. The identified partner should be able to run these tests on the entire study population, with negative test results on all tests under evaluation as the reference standard for the evaluation of the new test technologies. This, or another partner laboratory, should be able to perform a quantitative HIV-1 viral load test for all study participants identified, with a reactive result on at least one (1) test under evaluation, indicating possible HIV infection.

The application should describe the process for specimen handling, timeline from specimen collection to receipt of these gold standard test results, and the proposed process for notifying study participants of any discrepancies between laboratory test results and those from the POC tests.

Transmitting collected data

The application should describe how investigators will collect, clean, and store all study data including:

o POC test results for the tests under evaluation.

o Laboratory test results for comparison to the POC tests.

o Behavioral data collected via questionnaires created with CDC technical assistance.

o A process for linking data collected at the first study visit to all follow-up study visits (for those enrolled for follow-up of discordant test results, and those not known to be infected with HIV, who participate in the study more than once).

The recipient should work with CDC to develop procedures for data quality control and secure storage, reporting, and transmittal of data.

The application should describe the procedures to ensure completeness of the data. At a minimum, the recipient should ensure all consent information is 100% complete, survey data are 80% complete, and all performance data on test results is 100% complete prior to submission to CDC.

The recipient will work with CDC to ensure that data are available for public use according to the requirements for sharing public health data.

Patient specimen processing, storage and shipment procedures Applications should describe standard operating procedures for collection, labeling, processing, storage and shipment of all specimens to be collected during the first study visit and the serial follow-up visits. The description should include plans for: a) collection and labeling of fresh unprocessed specimens (oral fluid and EDTA whole blood) used for the point-of-care screening tests at the clinical site; b) labeling, processing and shipping, when required, of specimens for testing with the laboratory test(s) described above as the reference standard for the evaluation of the new test technology; and c) labeling, processing and shipping, when required, of specimens for which any other HIV test was reactive so that these specimens can be tested with a quantitative HIV-1 viral load test. The application should include descriptions of how remnant specimens may be aliquoted, stored and shipped to CDC, as warranted (not to exceed quarterly).

CDC and the recipient will work together to develop consent forms to cover the collection and storage of biologic specimens for this project. Consent forms will contain the following language, or some variation of the following language, with the same intent: "This research study is part of a cooperative agreement with the U.S. Centers for Disease Control and Prevention. Remnants from patient specimens collected as part of this study may be sent to CDC and possibly to other institutions for additional testing. These research tests include, but are not limited to, the development or evaluation of tests to detect HIV infection and other tests for research purposes only. The research tests will not be those that test for genetic problems and the blood will not be used for cloning or commercial purposes. You may choose not to have your blood stored for future research and still be part of the study. Your name and/or other directly identifiable information will not be shared outside of the research study site. All links to your name and other directly identifiable information will be removed before the specimens are transferred to the CDC. Since all tests on remnant specimens are for research purposes only and will be conducted after the link to your identifying information has been removed, no individual results will be given back to you or go into your medical record."

Objectives/Outcomes The overall project should address the following research objectives:

1. Develop and implement recruitment strategies and procedures to: (a) evaluate the differences in sensitivity (including acute HIV infection sensitivity) and specificity of the newest HIV tests in real time, using fresh whole blood and oral fluid specimens and (b) compare to the recommended CDC laboratory algorithm. Patients with exposure to either early ART or PrEP should be oversampled in order to evaluate HIV test performance in these populations as well.

2. Evaluate the seroconversion sensitivity of the newest HIV tests through serial follow-up of study participants with discordant baseline test results.

3. Evaluate the diagnostic and clinical performance of nucleic acid (molecular) tests to determine the applicability of this technology for use in a variety of clinical and POC settings.

4. Collect matched demographic, behavioral and clinical data from participants to assess the impact of these factors on HIV test performance, including the use of behavioral and clinical data to categorize the timing of exposure for those with newly diagnosed infection.

5. Develop panels of specimens with accompanying demographic, clinical and behavioral data for evaluations of laboratory-based HIV tests.

Primary study outcomes are:

Assess sensitivity of POC tests under study in at least 200 participants known to be infected with HIV in each study year.

Assess specificity of POC tests under study in at least 500 participants not known to be infected with HIV in each study year.

Assess performance (concordance with a reference standard viral load) of POC NAT tests.

Increase the number of (oral fluid, plasma, dried-blood spot, etc.) specimens in storage for evaluations of new laboratory-based HIV tests.

Secondary study outcomes are:

Increase the number of well-characterized panels of specimens with POC test results and behavioral data that can be used to evaluate the seroconversion sensitivity of the newest HIV tests through serial follow-up of study participants with discordant baseline test results.

Evaluate the performance of tests under evaluation (in terms of sensitivity and specificity) in specific populations including persons who initiate ART early in infection and those taking PrEP.

Target Population The following groups should be approached for participation through convenience sampling if they are 18 years of age or older, able to consent to study participation, and able to complete the computer-assisted self-interview in English or Spanish:

Newly diagnosed (within the prior 90 days) patients who have and have not started ART.

Patients not currently taking ART (who have not taken even one dose in the past 30 days).

Patients taking ART who have not yet achieved viral suppression based on the CDC definition of a viral load of <200 copies/ml.

Patients taking ART who are considered to have achieved viral suppression based on the

CDC definition of a viral load of <200 copies/ml.

Patients not known to be HIV-infected (e.g., those seeking HIV testing or with a possible exposure to HIV since their last documented HIV-negative test result). Participants in this group should be allowed to re-enroll no more than every 90 days.

Collaboration/Partnerships The recipient should work collaboratively with other project partners to develop and implement the study through consultation and by gathering technical assistance. These partners may include other clinics, non-clinical HIV test providers, clinical or commercial laboratories, and the relevant State or local health department.

Recipients should collaborate with a sufficient number of clinical (e.g., large HIV clinics, and/or PrEP clinics) and non-clinical (e.g., community-based organizations offering HIV testing) partners to obtain study referrals and recruitment to achieve the study sample size. Recipients should include in their application a description of how the partner sites were selected, including a description of the minimum criteria to participate (e.g., provide a minimum number of referrals to the study per month).

If the study clinical site(s) do not routinely offer laboratory testing, the recipient should identify a partner laboratory that conducts either: (a) an algorithm that includes an antigen/antibody laboratory immunoassay, an HIV-1/HIV-2 differentiation test and a nucleic acid test; or (b) pooled nucleic acid testing of all those who screen HIV-negative on site. The partner laboratory should be able to run these tests on the entire study population using negative test results on all tests under evaluation as the reference standard for the evaluation of the new test technologies.

This or another partner laboratory should be able to perform a quantitative HIV-1 viral load test for all study participants identified with a reactive result on at least one test under evaluation, indicating possible HIV infection. Finally, the recipient should identify a partner laboratory able to properly process, aliquot, store and ship frozen biologic materials from this study on dry ice for testing.

Letters of Support The application should include Letters of Support from each non-federal partner that will collaborate in the study. The letters should include estimates of the total number of participants from each of the proposed target populations that the partner site can refer annually. The recipient and proposed project partners should establish policies to confidentially share data during the study. Examples of the types of data that may need to be shared include prior HIV test results and information about referred patients' exposure to ART and/or PrEP.