Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for recent HIV infection
Final Report
February 2010
This final report was prepared by Dr Joanne Micallef and Professor John Kaldor, The University of New South Wales, under subcontract with Family Health International, funded by the Bill and Melinda Gates Foundation under the grant titled “Development of Assays for Acute HIV Infection and Estimation and HIV Incidence in Population”.
1 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Table of Contents
Table of Contents ...... 2
List of acronyms ...... 4
1 Introduction ...... 6
2 Methods ...... 7
2.1 Identification of potential studies and sample sets of relevance to the development and evaluation of assays for recent HIV infection ...... 7
2.1.1 Sources of sample sets ...... 7
2.1.2 Literature search ...... 8
2.2 Survey of study investigators ...... 9
2.2.1 Initial contact with study investigators ...... 9
2.2.2 Follow up of study investigators ...... 10
2.2.3 Questionnaire sent to study investigators ...... 10
2.2.4 Analysis of findings ...... 11
2.2.5 Data management ...... 12
3 Results and Discussion ...... 17
3.1 Literature search...... 17
3.1.1 Seronegative cohorts ...... 17
3.1.2 Acute cohorts ...... 19
3.2 Contact with study investigators ...... 20
3.2.1 Response to letter and questionnaire: Seronegative cohorts ...... 20
3.2.2 Response to letter and questionnaire: Acute cohorts ...... 22
3.3 Survey results: Seronegative cohorts ...... 23
3.3.1 Summary of study details ...... 23
3.3.2 Information about the biological specimens ...... 24
3.3.3 Availability of the specimens ...... 24
3.4 Survey results: Acute cohorts ...... 28
2 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
3.4.1 Summary of study details ...... 28
3.4.2 Information about the biological specimens ...... 28
3.4.3 Availability of the specimens ...... 29
3.4.4 Suitability of specimens identified to be included in sample panels ...... 33
4 Discussion ...... 37
Appendices ...... 40
References ...... 61
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List of acronyms
AIDS Acquired immune deficiency syndrome
ALIVE AIDS Linked to Intravenous Experience
ANRS French National Agency for Research on AIDS and Viral Hepatitis
BREC Biomedical Research Ethics Committee
CAPRISA Centre for the AIDS Programme of Research in South Africa
CDC Centers for Disease Control and Prevention
CRF Circulating Recombinant Forms
FRR False recent rate
FRSQ Fonds de la recherche en santé du Québec
HIV Human immunodeficiency virus
HIV-1 Human immunodeficiency virus subtype 1
HPTN HIV Prevention Trials Network
IAVI International AIDS Vaccine Initiative
IDU Injecting Drug Use
IRB Institutional Review Board
MSM Men who have sex with men
NCAIDS National Center for AIDS/STD Prevention and Control
PBMCs Peripheral Blood Mononuclear Cells
PHI Primary HIV Infection
RCT Randomised Clinical Trial
4 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
RIS la Red de Investigación en Sida (the Network of Investigation into AIDS)
RITA recent infection testing algorithm
US United States
WHO World Health Organisation
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1 Introduction
Reliable estimates of the incidence of HIV infection in populations are crucial for describing the status of HIV epidemics, monitoring transmission patterns, evaluating prevention programs and the planning and evaluation of intervention programs.
Assays for recent HIV infection are capable of distinguishing recent from non-recent HIV infections, and therefore able to measure HIV incidence in populations using cross-sectional study methods. Assays for recent HIV infection are based on the underlying principle that the immunologic response to HIV infection evolves for a number of months following infection and the capability to measure some aspect of this evolution. Several assays for recent infection have been developed since the first in 1998 and have been used to estimate incidence in a range of surveillance and research settings.
The use of current assays for recent infection to estimate HIV incidence is challenged by various obstacles such as: 1. The variability of the immune response among HIV-1 infected individuals, the impact of use of antiretroviral therapy and late stage immunosuppression, resulting in reduced sensitivity and specificity, 2. Mean recent infection testing algorithm (RITA) duration variability among various HIV-1 subtypes and populations, 3. Lack of standardization to calibrate and validate assays for recent infection, 4. Inconsistent commercial availability of HIV diagnostic assays which serve as the foundation for a number of assays for recent infection, 5. Complex laboratory methods and high cost of assays and 6. Inconsistent methodologies for the use of assays to estimate HIV infection.
An essential element of the development and evaluation process for the calibration and validation of assays for recent infection is the availability of relevant biological sample sets. The objective of this project was to catalogue studies that could potentially contribute specimens to specimen panels that could be used to develop and evaluate assays for recent HIV infection.
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2 Methods
The project was conducted over the period March 2009 to January 2010. It involved the following key steps in order to achieve the objective. Firstly, potential studies that may have specimens of relevance to the development and evaluation of assays for recent infection were identified by a literature search. Secondly, investigators of studies identified were contacted to determine whether they would be willing to potentially share specimens for the purpose of developing and evaluating assays for recent infection and asked to complete a questionnaire to obtain relevant information about the study, the biological specimens and sharing of specimens. Lastly, a database was created and information collected from completed forms was compiled into the database. Each of these three steps is described in detail below.
2.1 Identification of potential studies and sample sets of relevance to the development and evaluation of assays for recent HIV infection
2.1.1 Sources of sample sets
Categories and sources of sample panels were comprehensively reviewed in a presentation by Dr Michael Busch in May 2009 at the meeting of the WHO Technical Working Group on HIV Incidence Assays (Chapel Hill, 13-14 May 2009). The presentation was subsequently published in the Meeting report (Link to the Meeting Report: http://www.who.int/diagnostics_laboratory/links/hiv_incidence_assay/en/index.html ). Briefly, specimens for the development and evaluation of assays for recent infection can be sourced from two categories of individuals: recently HIV infected or HIV seroconverting individuals and long term HIV infected individuals.
Specimens from recently HIV infected or HIV seroconverting individuals are used to calibrate assays for recent infection by determining the sensitivity of the assay to detect recent infection and to obtain the mean RITA duration of the assay. Sources of these biological specimens include plasma donor seroconversion panels, interval HIV seroconvertors, high risk seroconvertor cohorts and acute HIV infection cohorts.
Specimens required to determine the specificity and false recent rate (FRR) of assays and algorithms are those from seropositive subjects who have been HIV infected for greater than approximately 1 year. Specimens from long term infected individuals who are long term non-progressors, patients with advanced stage acquired immune deficiency syndrome (AIDS), elite controllers and patients on antiretroviral therapy are also required.
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Reasonable access is available to specimens of long-term infected individuals, from natural history studies and prevention or vaccine trials. Specifically, specimens from plasma donor seroconversion panels and interval HIV seroconvertors are generally sourced from repeat blood donors, plasma donors, and serially tested clients and can be accessed from public health laboratories. In contrast, biological specimens from HIV seroconvertors and acute HIV infected individuals are extremely valuable to study investigators, making access difficult, and generally have limited volume of specimen available for contribution to sample panels. It is for this reason that this project focused on sourcing specimens from HIV seroconverting individuals and those with acute HIV infection.
2.1.2 Literature search
A literature search was conducted to identify clinical trials and epidemiological cohort studies that have collected biological specimens of potential value for assay development. The MEDLINE database was searched from January 2000 to March 2009 using the following search terms: [(HIV OR Human Immunodeficiency Virus OR HIV-1).ti] AND [(Inciden$) OR (early infection) OR (acute) OR “recent infection#” OR recent seroconversion# OR recently infected OR newly acquired OR primary adj2 infection]. Studies were restricted to the English language.
An additional search of the www.clinicaltrials.gov website was also performed to identify clinical trials or cohort studies. Search terms used in the search engine on the website included: (HIV and acute) OR (HIV and seroconversion) OR (HIV and primary infection) OR (HIV and incident).
One reviewer (Joanne Micallef) reviewed the titles and abstracts of citations resulting from the literature search. Full articles for potentially relevant studies were retrieved if they met the following criteria: 1. Identified >10 seroconvertors or enrolled >10 patients with acute or newly acquired HIV infection, 2. Included patients from an original cohort (excluding individuals from another cohort identified); and 3. For seronegative cohorts, HIV serial testing of seronegative individuals occurred at least every 12 months and no greater.
Relevant studies were divided into two categories:
Category 1: Seronegative cohorts Studies which recruited people initially HIV negative and carried out serial HIV testing to identify seroconvertors during follow up.
Category 2: Acute cohorts
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Studies that recruited subjects with acute or primary HIV infection, diagnosed either on the basis of clinical symptoms and/or laboratory findings.
A Microsoft Office Access database was constructed to record data from cohort studies and clinical trials that were identified through the literature search. Separate databases were created for the two categories of studies, seroconvertor cohorts and acute cohorts. The databases included characteristics of each study population, such as cohort name, clinical trial study number (for clinical trials only), first author of publication (or Principal Investigator of unpublished clinical trial), year of publication, city/cities of study, country/countries of study and number of seroconvertors or acute HIV individuals in study. For seronegative cohorts, the HIV testing interval of seronegative subjects was recorded. For acute cohorts, the definition of acute HIV used in study and follow up schedule of enrolled participants was abstracted. In addition, contact details of the primary study investigator were recorded for each study. Generally, the corresponding author of the paper or the primary investigator of the clinical trial was the primary contact for the study.
2.2 Survey of study investigators
2.2.1 Initial contact with study investigators
Contact with study investigators occurred between September 2009 and January 2010. Study investigators of studies were contacted to determine whether they were willing to participate in a survey of clinical trials and cohort studies of relevance to the development of assays for recent HIV infection. If the primary study investigator was not the contact person for the cohort or trial, they were asked to refer an alternative investigator, who was subsequently contacted. Study investigators were sent a letter by email on behalf of Professor John Kaldor. The letter asked study investigators whether they would be willing to engage in a further round of correspondence by means of a survey to: 1. Provide additional information about the study and specimens collected; and 2. Provide an indication of their willingness to enter a discussion about making specimens available for the purpose of developing and validating assays for recent HIV infection. In addition to the letter, investigators were sent a protocol outlining the purpose and methodology of the survey. The letter sent to study investigators and the study protocol are appended to this report (Appendices 1a and 1b).
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2.2.2 Follow up of study investigators
If study investigators did not reply to the initial letter sent, they were sent an initial follow up email by Joanne Micallef, Jesus Maria Garcia Calleja or Michael Busch. A second follow up was sent by John Kaldor via email, if no response was received by mid-January.
2.2.3 Questionnaire sent to study investigators
The questionnaire entitled “Survey of clinical trials and cohort studies of relevance to the development of assays for recently acquired HIV infection” was prepared by Joanne Micallef and John Kaldor and reviewed by Steering Committee members of the WHO Technical Working Group on HIV Incidence Assays. Distinct forms were prepared for the seronegative cohorts and the acute cohorts. The questionnaires are appended to this report (Appendix 2 and Appendix 3).
The key sections and data collected in the seronegative cohort questionnaire were:
1. Contact details of study investigators
2. Details of the study – cohort or trial name, clinical trial number (for clinical trials), status of study (complete; ongoing; yet to begin), cities and countries of recruitment, included risk groups, HIV testing interval of seronegative subjects, number of HIV seroconvertors identified during the study period.
3. Information about the biological specimens – number of first HIV positive specimens stored, follow up of individuals after the first HIV positive visit, types of specimens stored (whole blood; serum/plasma).
4. Availability of the specimens – willingness to make stored specimens available for the purpose of developing and evaluating assays for recent infection, resources required for the specimens to be shared (funding, collaborative research agreement, other), volume of specimen aliquots available, HIV subtype distribution, location of stored specimens, ethical status for use of specimens for the purpose of developing and evaluating assays for recent infection, willingness to collect extra plasma if collection of specimens is ongoing.
The key sections and data collected in the acute cohort questionnaire were:
1. Contact details of study investigators
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2. Details of the study – cohort or trial name, clinical trial number (for clinical trials), status of study (complete; ongoing; yet to begin), cities and countries of recruitment, included risk groups, definition of acute HIV infection, number of acute HIV individuals enrolled in the study, follow up schedule after enrolment into the study.
3. Information about the biological specimens – number of pre-seroconversion specimens stored, number of stored specimens collected 0-3 months, 3-12 months and 1-10 years following seroconversion, types of specimens stored (whole blood; serum/plasma).
4. Availability of the specimens – data collected was the same as for the seronegative cohort questionnaire.
If a questionnaire was not completed and received by the requested date, study investigators were followed up by email by Joanne Micallef.
2.2.4 Analysis of findings
Analysis of the information compiled from the literature search, contact from study investigators and surveys was largely descriptive. Results of findings are in tables and described in the text.
Literature search. Analysis of the papers identified in the literature search was largely descriptive. Seronegative cohort studies were summarised in a table by reference, country of study, name of cohort, period of subject recruitment, follow up interval of seronegative participants and number of seroconvertors. Acute cohort studies were summarised in a table by reference, country of study, name of cohort, period of subject recruitment and number of acute HIV individuals enrolled into the study.
The distribution of studies by region was also summarised for the two categories of study.
Contact with study investigators. A descriptive analysis of study investigators who were contacted and the response of study investigators was undertaken.
Survey of cohort studies and clinical trials. A descriptive summary of results from completed seronegative cohort questionnaires and acute cohort questionnaires was presented in tables and within the text.
Studies for which the study investigators stated that they were willing to consider sharing specimens were evaluated for desirable characteristics of samples, against criteria discussed by the WHO
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Technical Working Group on HIV Incidence Assays (May 2009, see
(http://www.who.int/diagnostics_laboratory/links/hiv_incidence_assay/en/index.html ). Under this framework characteristics of specimens were categorized as ideal, satisfactory or inadequate, and presented in a table. The characteristics of sample panels include the following:
1. Panels should have an adequate number of serial specimens per subject in the year following infection with HIV a. Ideal: >3 specimens per subject b. Satisfactory: 1-3 specimens per subject c. Inadequate: No specimens 2. Adequate specimen volumes should be obtained from both archived specimens and prospective panels a. Ideal: >2 mL b. Satisfactory: 1-2 mL c. Inadequate: <1 mL 3. The HIV-1 subtype should be known or assumed with reason a. Ideal: HIV-1 subtype is known or reasonable assumed known b. Inadequate: HIV-1 subtype is unknown 4. For seronegative cohorts, the testing interval of seronegative individuals should be minimal a. Ideal: 1 month b. Satisfactory: >1 to 3 months c. Inadequate: >3 months
2.2.5 Data management
A Microsoft Office Access database was constructed to record information obtained from completed questionnaires. Distinct databases were built for the data from the seronegative cohort questionnaires (Figure 1-Figure 4) and acute cohort questionnaires (Figure 5-Figure 8).
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Figure 1. Seronegative cohort survey: Microsoft Access database data entry screen for information about study details
Figure 2. Seronegative cohort survey: Microsoft Access database data entry screen for study investigator contact details
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Figure 3. Seronegative cohort survey: Microsoft Access database data entry screen for information about biological specimens.
Figure 4. Seronegative cohort survey: Microsoft Access database data entry screen for information about the availability of specimens.
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Figure 5. Acute cohort survey: Microsoft Access database data entry screen for information about study details
Figure 6. Acute cohort survey: Microsoft Access database data entry screen for study investigator contact details
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Figure 7. Acute cohort survey: Microsoft Access database data entry screen for information about biological specimens.
Figure 8. Acute cohort survey: Microsoft Access database data entry screen for information about the availability of specimens.
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3 Results and Discussion
3.1 Literature search
A total of 5,268 articles from MEDLINE and more than 250 clinical trials were retrieved. After excluding irrelevant studies and studies not meeting the inclusion criteria, data from 42 seronegative cohorts [1-42] and 16 acute cohorts were extracted [43-58] (see Appendix 4 and Appendix 5).
3.1.1 Seronegative cohorts
Seronegative cohorts recruited individuals from a wide array of world regions (Figure 9). The most represented regions were Eastern Africa (n=14 studies), Northern America (n=8) and Southern and Western Africa (n=5 each).
The HIV testing interval of seronegative individuals ranged between 1 month and 12 months. The most common HIV testing intervals were six months (n=19 cohorts), three months (n=8) and one month (n=7) (Figure 10). Yearly testing was required in three cohorts [20, 37, 59], and one study involved testing every four months [12]. Four studies had HIV testing intervals of varying length, with three conducting HIV testing at clinic visits [1, 4, 9] and one at months 3, 12 and 21 following enrolment into the study [19]. The number of seroconvertors identified in each study ranged between 11 [11, 18] and 436 [33] (mean number of seroconvertors overall = 103; data missing from one cohort).
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Figure 9. Recruitment of seronegative cohorts occurred in various regions of the world. The most common regions where the seronegative cohorts were carried out were Eastern Africa, Northern America, Southern and Western Africa. The total number of regions represented in this map exceeds the number of studies as one study recruited in 3 regions [41]. World map, courtesy of www.psdgraphics.com
20 18 16 14 12 10 8
Number of Numberof cohorts 6 4 2 0 1 3 4 6 12 various HIV testing interval of seronegative subjects (months)
Figure 10. HIV testing interval of seronegative subjects within the cohort ranged between 1 month and 12 months.
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3.1.2 Acute cohorts
Acute cohorts (n=16) were recruited in fewer regions of the world, compared with seronegative studies (Figure 11). The most represented region was Northern America (n=9). Acute cohorts also enrolled patients from Northern Europe, Southern Europe, Western Europe, Southern Africa, Eastern Africa and Oceania.
The number of acute HIV subjects enrolled ranged between 18 [49] and 495 [51] (mean number of acute HIV subjects = 135; data missing from one cohort).
Figure 11. Enrolment of acute HIV subjects occurred in five regions of the world, the most common being Northern America N=9). The total number of regions represented in this map exceeds the number of studies as one study recruited in 5 regions [58]. World map, courtesy of www.psdgraphics.com
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3.2 Contact with study investigators
3.2.1 Response to letter and questionnaire: Seronegative cohorts
A total of 38 study investigators responsible for seronegative cohorts were sent a letter asking if they were willing to engage in a further round of correspondence by means of a questionnaire (Appendix 6). The study investigators were responsible for 46 seronegative cohorts. For one cohort [40], a study investigator was contacted for each of the three study sites that identified seroconvertors (Kampala, Uganda; Durban, South Africa; Cotonou, Benin). Each of these three sites was considered as a separate cohort. Two additional sites (Bangalore, India; Chennai, India) did not identify any seroconvertors during the study period. Seven seronegative cohorts (Prospective cohort of MSM in Beijing, IAVI HIV Incidence Cohorts, HPTN052-India, NIMH C-POL HIV/STD Prevention Trial-India, Study of FSW-Benin, Vaccine Trial with ALVAC and AIDSVAX-Thailand and HIVNET011) were not identified through the literature search but through referral from a colleague or referral via the questionnaire (see Appendix 6).
No reply to the initial letter or subsequent follow up emails was received (to date, 26 February 2010) from study investigators responsible for 14 seronegative cohorts (Figure 12). Of the remaining 32 seronegative cohorts, study investigators of 8 cohorts did not agree to complete the questionnaire for various reasons: investigators would like to access specimens for their own future research (n=2), specimens were destroyed at completion of the study as there was no permission for long term storage of specimens (n=1), limited or no specimens remain after the study (n=2), permission not received for further use of specimens (n=1), specimens have been inappropriately stored and not suitable for further research (n=1) and study investigator cannot complete questionnaire and grant permission on behalf of CDC (n=1).
Study investigators from 24 cohorts agreed to complete a questionnaire, however questionnaires from 14 study investigators were not returned, despite sending up to two follow up emails. Ten study investigators of seronegative cohorts were received (Figure 12).
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38 study investigators sent initial letter Total seronegative cohorts = 46
No reply from study Reply received from investigator to initial initial letter or follow up letter or subsequent email follow up emails 32 seronegative cohorts 14 seronegative cohorts
Did not agree to complete Agreed to complete survey Completed survey survey but survey not returned received 8 seronegative cohorts 14 seronegative cohorts 10 seronegative cohorts
Figure 12. Response to initial letter to study investigators of seronegative cohorts asking for participation in the survey. No reply was received from study investigators of 14 seronegative cohorts. Of those who replied, study investigators did not agree to complete the questionnaire (n=8 cohorts), agreed to complete the questionnaire but did not return the questionnaire (n=14 cohorts) and returned the completed questionnaire (10 cohorts).
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3.2.2 Response to letter and questionnaire: Acute cohorts
A total of 16 study investigators responsible for 18 acute cohorts were sent a letter asking if they were willing to engage in a further round of correspondence by means of a questionnaire (Appendix 7). Three acute cohorts (Cohort of RIS, CAPRISA 050 Acute Infection Study and SPARTAC) were not identified through the literature search. Instead, they were referred by a colleague or, after contacting study investigators were proffered as potential studies with relevant specimens.
No reply to the initial letter or subsequent follow up emails was received from study investigators responsible for eight acute cohorts (to date, 26 February 2010) (Figure 13). Of the remaining ten acute HIV cohorts, the study investigators of three cohorts did not agree to complete the questionnaire as specimens were discarded following complete of the study or extremely limited volumes remained.
Study investigators from seven acute HIV cohorts agreed to complete a questionnaire. However, questionnaires from two cohorts were not returned. Questionnaires from five acute cohorts were received (Figure 13).
16 study investigators sent initial letter Total acute cohorts = 18
No reply from study Reply received from investigator to initial initial letter or follow up letter or subsequent email follow up emails 10 acute cohorts 8 acute cohorts
Did not agree to complete Agreed to complete survey Completed survey survey but survey not returned received 3 acute cohorts 2 acute cohorts 5 acute cohorts
Figure 13. Response to initial letter to study investigators of acute cohorts asking for participation in the survey. No reply was received from study investigators of 8 acute cohorts. Of those who replied, study investigators did not agree to complete the questionnaire (n=3 cohorts), agreed to complete the questionnaire but did not return the questionnaire (n=2 cohorts) and returned the questionnaire (n=5 cohorts).
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3.3 Survey results: Seronegative cohorts
3.3.1 Summary of study details
Questionnaires were completed for 10 seronegative cohorts. A summary of the cohorts is presented in Table 1.
Seven seronegative cohorts have completed recruitment of subjects. The last year of recruitment ranged between 2002 and 2008 and was distributed as follows: 2008 (n=1), 2007 (n=2), 2004 (n=1), 2003 (n=1) and 2002 (n=2). Three seronegative cohorts are ongoing (IAVI Early Infection Cohort, HPTN052-India and ALIVE).
Countries from which seronegative cohorts were recruited include Canada, the United States, Benin and South Africa (1 cohort within each country). Three studies were conducted in China and two studies in India. One study (IAVI Early Infection cohort) recruited HIV seronegative participants from nine cities in five countries: Rwanda, Uganda, Kenya, Zambia and South Africa.
All but one seronegative cohort recruited patients from a single risk group. Risk groups from which cohorts were recruited include injecting drug users (n=3 cohorts), men who have sex with men (n=2 cohorts), women at risk (n=1 cohort), HIV discordant couples (n=1 cohort), young men aged 18-24 years (n=1 cohort) and wine shop patrons (n=1 cohort). The IAVI Early Infection cohort included individuals from multiple risk groups, such as sex workers, MSM, women at risk, HIV discordant couples and miners.
Seronegative subjects were tested for HIV every 3 months in two cohorts, every 6 months in five cohorts and 12 months in one cohort. The IAVI Early Infection cohort followed up seronegative cohorts every 1-3 months whilst the ANRS1265 Trial followed subjects at 3 months, 9 months and 21 months after enrolment into the study.
Cohort studies identified between two and 487 seroconvertors during prospective follow up of seronegative individuals. HPTN052 (India), which identified two seroconvertors, is ongoing, as is the IAVI Early Infection cohort (n=487 seroconvertors) and ALIVE cohort (n=335 seroconvertors). Five cohorts (including HPTN052) identified less than 20 seroconvertors.
Although the inclusion criteria for the literature search included studies with greater than 10 seroconvertors, three cohorts included in the survey identified less than 10 seroconvertors. The CS Trial-Benin identified 9 seroconvertors but was one of a collection of clinical trial study sites, thus was included. Two Indian cohorts had two or four seroconvertors but were included as the
23 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report specimens collected from both cohorts are stored at the same location and one of the studies (HPTN052) is ongoing so may identify more seroconvertors in time.
3.3.2 Information about the biological specimens
The first HIV positive specimens of seronegative subjects from all ten studies were stored. However, stored specimens are not available for all identified seroconvertors. Six studies followed up seroconvertors after their first HIV positive visit. Follow up occurred every 3 months in two studies (Cellulose Sulfate Trial-Benin and HPTN052-India), every 6 months in one study (ALIVE) and at 12 months in one study (NIMH C-POL HIV/STD Prevention Trial -India). The ANRS1265 Trial followed up seroconvertors at the same time points as the trial and depending at which time point the first HIV positive visit occurred (3, 9 or 21 months after initial enrolment). The IAVI Early Infection cohort followed seroconvertors monthly for the first 3 months, quarterly until 2 years and every 6 months subsequently.
Specimens stored for all cohorts were either serum or plasma. The IAVI Early Infection cohort also stored whole blood and PBMCs.
3.3.3 Availability of the specimens
Study investigators of all ten seronegative cohorts were willing to make specimens available for the purpose of developing and evaluating assays for recent infection. All cohorts required funding for specimens to be shared, although not all study investigators could provide a cost estimate. The three cohorts in China (HPTN033, Prospective Cohort of IDUs in China and Prospective Cohort of MSM in China) would each require approximately $3000 for shipping costs and reagents, whilst the ALIVE study would require US$10 per specimen. The study investigators of the remaining cohorts communicated that cost would need to be discussed, or, identified that costs would be necessary for shipping, identifying specimens and preparing specimens for shipping but did not provide an indication of cost.
In addition to funding, nine cohorts required collaborative research agreements to be in place for the specimens to be shared. One study investigator added that a technology transfer would be required, where applicable. It was requested that specimens from China be tested within the country due to in-country regulations.
HIV-1 subtyping of specimens was performed in four seronegative cohorts (HPTN033-China, IAVI Early Infection Cohort, Prospective Cohort of IDUs in China and Prospective Cohort of MSM in China). An additional three studies did not carry out subtyping on specimens from seroconvertors,
24 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report but could assume genotype distribution from previous studies in a similar population or known country HIV-1 subtype distribution (Cellulose Sulfate Trial – Benin, Omega Cohort and ANRS1265 Trial).
Biological specimens from each seronegative cohort were generally stored in the country which subjects were recruited from. The exception was the IAVI Early Infection cohort, where the study team at each recruitment site kept 30% of all samples collected and shipped the remaining 70% of samples to the London-based IAVI Human Immunology Laboratory.
For six seronegative cohorts, the existing ethics approval was considered adequate for the use of the biological specimens for the purpose of developing and evaluating assays for recent infection. For both the Prospective Cohort of MSM in China and the Prospective cohort of IDUs in China, further approval needs to be sought from NCAIDS IRB. Specimens from the ANRS1265 Trial can be tested onsite, but cannot be shipped per international review board (IRB) regulations.
Of the three studies that are ongoing, study investigators from HPTN052 (India) and ALIVE cohorts were open to collecting extra plasma for the purpose of developing and evaluating assays for recent infection. Study investigators from the IAVI Early Infection Cohort are open to discuss the possibility of collecting extra plasma, however, the current blood draw is already quite large.
25 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Table 1. Summary of the 10 seronegative cohorts for which a questionnaire was completed. The cohort name, details of the primary contact for the study, recruitment period of seronegative individuals, cities and countries of recruitment, population groups represented in cohort, follow up time interval of HIV seronegative subjects and the number of HIV seroconvertors identified for each cohort is summarised. Cohort or trial name Primary contact for study Study City and Country of Population groups Follow up time Number of HIV period recruitment included interval of HIV seroconvertor s seronegative identified subjects
Cellulose Sulfate Trial - Dr Michel Alary 2005-2007 Cotonou, Benin women at risk 3 months 9 Benin site Centre hospitalier affilié universitaire de Québec, Canada Omega Cohort Dr Michel Alary 1996-2003 Montreal, Canada MSM 6 months 32 Centre hospitalier affilié universitaire de Québec, Canada HPTN033 (China) Dr Yiming Shao 2002-2002 Xinjiang, China IDU 6 months 42 Chinese Center for Disease Control and Prevention IAVI Early Infection Dr Pauli Amornkul 2005- Kigali, Rwanda; Masaka and MSM, women at risk, 1-3 months 487* (to date) Cohort International AIDS Vaccine ongoing Entebbe, Uganda; Nairobi and sex workers, Initiative Kilifi, Kenya; Ndola and heterosexual HIV Lusaka, Zambia; Rustenburg discordant couples, and Cape Town, South Africa mining community ANRS1265 Trial Agnes Fiamma 2002-2004 Orange Farm, South Africa Young men, aged 18- Followed up at 69 UCLA Program in Global Health, 24 years 3, 9 and 21 Division of Infectious Diseases months Africa and Asia Regional Office HPTN052 (India site) Professor Suniti Solomon 2005- Chennai, India HIV discordant 3 months 2* (to date) YR Gaitonde Centre for AIDS ongoing couples Research and Education, Chennai, India NIMH C-POL HIV/STD Professor Suniti Solomon 2002-2008 Chennai, India sex workers, wine 12 months 4 Prevention Trial - YR Gaitonde Centre for AIDS shop patrons Multicentric study Research and Education, (India) Chennai, India ALIVE - AIDS Linked to Dr Shruti Mehta 1998- Baltimore, US IDU 6 months 335* (to date) the IntraVenous Johns Hopkins School of Public ongoing Experience Health, Baltimore, US
26 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Prospective cohort of Dr Yiming Shao 2002-2002 Xichang County of Sichuan IDU 6 months 16 IDUs in China Chinese Center for Disease Province, China Control and Prevention Prospective cohort of Dr Yiming Shao 2006-2007 Beijing, China MSM 6 months 11 MSM in China Chinese Center for Disease Control and Prevention * Studies are ongoing. Number of seroconvertors identified at January 2010.
27 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
3.4 Survey results: Acute cohorts
3.4.1 Summary of study details
Questionnaires were returned for five acute cohorts. A summary of the cohorts is presented in Table 2. One questionnaire (Cohort of RIS) is incomplete at present (February 2010) as study investigators are awaiting responses from laboratory personnel regarding details of specimens stored and accurate numbers of enrolled acute HIV subjects. As this questionnaire is incomplete, the results will not be included in the survey results below. The investigators will return the completed questionnaire by mid-March 2010.
Two acute cohort studies have completed recruitment of subjects with the last year of recruitment being 2005 (CAPRISA002 Acute HIV Infection Study) and 2007 (Quebec PHI Cohort). The remaining two studies (Acute and Early Cohort of HIV-Infected Individuals-Boston, US and Primary Acute HIV Patients in Modena, Italy) are still enrolling acute HIV participants. The four acute cohorts enrolled participants from the United States, South Africa, Italy and Canada.
Each of the four acute cohorts enrolled patients from diverse risk groups. The Acute and Early Cohort of HIV-Infected Individuals (US) enrolled patients representing seven risk groups: general population (women and men), MSM, IDU, women at risk, transmission from infected blood products and needle stick injuries. The CAPRISA002 Acute HIV Infection Study enrolled sex workers and women at risk whilst participants in the Primary Acute HIV Patients in Modena, Italy study and the Quebec PHI Cohort were MSM and IDU.
The ongoing cohort of the Acute and Early Cohort of HIV-Infected Individuals (Boston, US) has enrolled 258 acute and early HIV—infected individuals to date (January 2010). Study participants are followed up at 1, 2, 3, 6, 9 and 12 months following enrolment into the study, and then every 3 months. Sixteen individuals have been enrolled into the ongoing Primary Acute HIV patients in Modena, Italy cohort to date (January 2010) and are followed up at 1, 3, 6 and 12 months. CAPRISA002 Acute HIV Infection Study identified 62 individuals who were subsequently followed up weekly for 3 weeks, fortnightly until 3 months, monthly until 1 year and then every 3 months. Lastly, the Quebec PHI Cohort identified 249 individuals with primary HIV infection who were followed up at 14 time points over two years.
3.4.2 Information about the biological specimens
All four acute cohorts have serum or plasma specimens stored at various time points during follow up. Storage of pre-seroconversion specimens (HIV RNA positive and anti-HIV antibody negative)
28 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report was minimal or unavailable for three studies. The CAPRISA002 Acute HIV Infection Study, however, had pre-seroconversion specimens from 35 acutely HIV infected individuals.
3.4.3 Availability of the specimens
Study investigators of all four acute cohorts were willing to make specimens available for the purpose of developing and evaluating assays for recent infection. Two cohorts (The Acute and Early Cohort of HIV-Infected Individuals and CAPRISA002 Acute HIV Infection Study) did not indicate whether funding was required in order for specimens to be shared. Both the remaining two cohorts would require funding for shipping costs, however could not provide an estimate for these costs.
Two acute cohorts indicated an interest for a Collaborative Research Agreement for sharing of specimens to take place. Additionally, the Acute and Early Cohort of HIV-Infected Individuals requires both a coded tissue agreement in place prior to the sharing of specimens and a concept sheet to be submitted. The investigators of the CAPRISA002 Acute HIV Infection study requested active participation in all stages of the sharing and testing of specimens. Lastly, the sharing of specimens obtained from the Quebec PHI Cohort must be approved by the Fonds de la recherche en santé du Québec (FRSQ) Reseau Committee.
Subtyping of specimens was performed in two acute cohorts. Specimens from the CAPRISA002 study are all subtype C and specimens from the Quebec PHI Cohort are subtype B. An additional study, the Acute and Early Cohort of HIV-Infected Individuals, did not carry out subtyping on specimens, but assumed genotype distribution from known HIV-1 subtype distribution within the greater Boston area, which is primarily subtype B. HIV positive specimens from the Primary Acute HIV Patients in Modena, Italy study were not subtyped.
Biological specimens from each acute cohort were stored in the country which subjects were enrolled. Available volumes of specimens ranged from 0.5 mL (CAPRISA002 Acute HIV Infection study) to 2-5 mL for the US and Italian cohorts. Volume of specimens from the Quebec PHI Cohort was thought to be limited.
The existing ethics approval of specimens from the Quebec PHI Cohort and the Primary Acute HIV Patients in Modena, Italy cohort is adequate for the use of the biological specimens from the cohort for the development and evaluation of assays for recent infection. Approval of the sharing of specimens from the CAPRISA002 Acute HIV Infection Study would be required from the Biomedical Research Ethics Committee (BREC) of the University of KwaZulu Natal.
29 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Collection of additional plasma from individuals in the ongoing Acute and Early Cohort of HIV- Infected Individuals is not possible due to IRB restriction on the volume of blood permitted to be drawn at a single research visit. Study investigators from the second ongoing cohort (Primary Acute HIV Patients in Modena, Italy cohort) are open to discuss the collection of additional plasma for the purpose of developing and evaluating assays for recent infection.
30 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Table 2. Summary of the four acute cohorts for which a questionnaire was completed. The cohort name, details of the primary contact for the study, recruitment period of acute HIV individuals, cities and countries of recruitment, population groups represented in cohort, definition of acute HIV infection, number of acute HIV individuals enrolled and follow up schedule of acute HIV subjects. Cohort or trial Primary contact for Study period City and coun try Population Definition of acute HIV infection Number of Follow up of acute name study groups included acute HIV HIV subjects of recruitment individuals enrolled The Acute and Karen Axten 1996 -ongoing Boston, United general population Acute HIV infection: 258* 1,2,3,6,9 and 12 Early Cohort of The Regon Institute of States -males and females, Signs/symptoms of acute retroviral syndrome with months , every 3 HIV -Infected MGH, MIT and MSM, IDU, women either a negative antibody response with a positive p24 months thereafter Individuals Harvard , United States at risk, blood antigen or HIV-1 proviral DNA PCR or positive HIV-1 RNA; or product recipients A negative or evolving antibody response with a and needlestick positive p24 antigen or HIV-1 proviral DNA PCR or injuries positive HIV-1 RNA.
Early HIV infection: A positive antibody response with a documented negative serological test or plasma HIV-1 RNA within the past 12 months; or A positive ELISA and a negative de-tuned ELISA within 30 days of the positive ELISA specimen in an untreated person with no clinical or immunological evidence of advanced HIV disease. CAPRISA 002 Dr Koleka Mlisana 2004 -2005 Durban, South sex workers, Positive HIV-1 RNA, negative anti-HIV 62 Weekly for 3 weeks, Acute HIV CAPRISA, Doris Duke Africa women at risk antibody test OR detection of anti-HIV fortnightly until 3 Infection Study Medical Research antibodies within 3 months of previous months, mont hly Institute, University of negative test until 1 year, every 3 KwaZulu -Natal months thereafter Primary Acute Professor Andrea 1995-ongoing Modena, Italy MSM, IDU HIV associated clinical symptoms, anti-HIV 16* 1,3,6,12 months HIV patients in Cossarizza antibody negative, HIV DNA positive Modena, Italy University of Modena and Reggio Emilia, Modena , Italy Quebec PHI Dr Bluma Brenner 1997 -2007 Quebec, Canada MSM, IDU Primary HIV infection defined as <6 months 249 14 time points over Cohort McGill AIDS Centre, following HIV seroconversion 2 years Jewish General Hospital, Montreal, Canada
31 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Cohort of RIS Beatriz Hernández - 2004 -ongoing 17 cities, Spain unknown Previous known HIV negative test prior to HIV Unknown* unknown Novoa positive test. Various intervals between the Hospital Ramón y two tests are used Cajal, Madrid, Spain *Cohort still enrolling acute HIV subjects
32 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
3.4.4 Suitability of specimens identified to be included in sample panels
Data collected in the seronegative and acute cohort questionnaires were evaluated to determine whether the specimens collected and stored comprise the desired characteristics of specimens of required samples panels (Table 3 and Table 4). Two seronegative cohorts (Cellulose Sulfate Trial: Benin and IAVI Early Infection Cohort) had greater than 3 specimens per subject in the year following infection with HIV, which is ideal. Between 1 and 3 specimens per subject in the year following HIV infection are available for four seronegative cohorts (ANRS1265 Trial, HPTN052 (India), NIMH C-POL HIV/STD Prevention Trial and ALIVE). The remaining four seronegative cohorts did not have further follow up specimens from seroconvertors available. All four acute cohorts also had greater than 3 specimens per subject in the year following infection with HIV.
The most favorable volume of stored specimens available for sample panels is greater than 2 mL. Only one acute cohort, the Acute and Early Cohort of HIV-Infected Individuals, had the preferred volume of greater than 2 mL. No seronegative cohorts had specimens available in volumes greater than 2 mL. There were, however, 4 cohorts (IAVI Early Infection cohort, HPTN052, ALIVE and Primary Acute HIV patients in Modena, Italy) that would be open to discuss the collection of extra plasma for the purpose of developing and evaluating assays for recent infection.
Most preferred specimens for sample panels are those with known HIV-1 subtype or HIV-1 subtype assumed with reason. Specimens from seven seronegative cohorts and three acute cohorts were subtyped or the HIV-1 subtype was assumed. The subtypes observed in these cohorts include A, B, C, D and many unique and circulating recombinant forms.
For seronegative cohorts, short (1 month) follow up time intervals of seronegative individuals is ideal. Only one seronegative cohort (IAVI Early Infection Cohort) had short follow up of seronegative individuals. Two additional seronegative cohorts (Cellulose Sulfate Trial - Benin and HPTN052- India) followed up seronegative individuals every three months.
Overall, specimens from the Acute and Early Cohort of HIV-Infected Individuals (US) fulfilled the “ideal” category for each of the three desired characteristics for acute cohorts: >3 specimens per subject in the year following HIV infection, >2 mL specimen volume available and the HIV-1 subtype assumed with reason. In addition, this cohort has a large number of acute and early HIV patients enrolled (n=258) and is still recruiting.
Similarly, specimens from the IAVI Early Infection Cohort were also favorable, meeting three of the four desirable characteristics for seroconvertor specimens required for sample panels: 1 month
33 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report follow up interval of seronegative individuals, >3 specimens per subject in the year following HIV infection, and the specimens subtyped. Although the volume of specimen available was only “satisfactory” (1-2 mL), the study investigators are open to discuss the possibility of collecting extra plasma.
34 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Table 3. Evaluation of specimens available from seronegative cohorts for having desired characteristics of specimens for sample panels for the purpose of developing and evaluating assays for recent infection. Each characteristic was categorised as either inadequate (shaded yellow), satisfactory (blue) or ideal (green).
Seronegative Number of first HIV Follow up interval for Specimens per subject in Specimen volume Specimens subtyped? Subtypes cohort positive specimens seronegative subjects the year following HIV available (mL) observed available (months) infection >3-12 >1-3 1 Nil 1-3 >3 <1 1-2 >2-5 >5 No Assumed Yes Cellulose Sulfate 9 Numerous Trial – Benin site 1 subtypes 3 Omega Cohort 32 B HPTN033 (China) 42 CRF07_BC, CRF08_BC IAVI Early 487 2 A, C, D, other Infection Cohort CRFs 4 ANRS Trial 69 C HPTN052 (India) 22 NIMH C-POL 4 HIV/STD Prevention Trial (India) ALIVE 335 2 Prospective cohort 16 CRF_07BC of IDUs in China Prospective cohort 11 Not provided of MSM in China 1 Serial specimens available for only 3 or 4 subjects 2 Study ongoing, number of seroconvertors to date (January 2010) 3 Assumed from the distribution of a similar study: CRF02_AG 68.4%, G 14.3%, CRF06 4.1%, AE-K and AG-G at 3.1% each; subtypes A, K, A-AE, AG-AE, A-AG, G-AG and H-J at 1% each 4 Zambia and South Africa specimens are exclusively HIV-1 subtype C (100%). East African specimens include subtype A (60%), subtype D (25%), subtype C (10%) and unique and circulating recombinant forms (5%)
35 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Table 4. Evaluation of specimens available from acute HIV cohorts for having desired characteristics of specimens for sample panels for the purpose of developing and evaluating assays for recent infection. Each characteristic was categorised as either inadequate (shaded yellow), satisfactory (blue) or ideal (green).
Seronegative cohort Number of acute HIV Specimens per subject in the Specimen volume available Specimens subtyped? Subtypes individuals enrolled in study year following HIV infection (mL) observed
Nil 1-3 >3 <1 1-2 >2-5 >5 No Assumed Yes The Acute and Early Cohort 258 1 B of HIV -Infected Individuals CAPRISA 002 Acute HIV 62 C Infection Study Primary Acute HIV patients 16 1 in Modena, Italy Quebec PHI Cohort 249 B 1 Study ongoing, number of acute HIV individuals enrolled to date (January 2010)
36 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
4 Discussion
Accessibility of relevant biological sample panels is essential for the process of developing and evaluating assays for recent HIV infection. The aim of this project was to identify and catalogue cohort studies and clinical trials that could potentially contribute specimens to sample panels for future use in the calibration and validation of assays for recent HIV infection.
Completed questionnaires were received from study investigators responsible for 10 seronegative cohorts and 4 acute HIV cohorts. One questionnaire from an acute HIV cohort was returned incomplete and the study investigators intend on returning the completed questionnaire by mid- March 2010. The available data from this incomplete questionnaire was not included in analyses within this report.
Risk groups represented in the 14 cohorts were diverse (IDU, MSM, women at risk, sex workers, discordant couples, general population) as were the HIV-1 subtypes of specimens collected (A, B, C, D, and other unique and circulating CRFs). The surveys included seronegative and acute HIV cohorts from 12 different countries. The specimens collected as part of these 14 cohorts represent a varied assortment, valuable for sample panels which are required to be comprised of specimens from various populations and HIV-1 subtypes.
Although all study investigators were willing to contribute biological specimens for the purpose of developing and evaluating assays for recent HIV infection, the volume of specimen aliquots available was less than 2 mL for the majority of cohorts. The small volumes available are not ideal for contribution to sample panels, however, study investigators responsible for three ongoing seronegative cohorts and one ongoing acute HIV cohort were open to discuss the possibility of collecting extra plasma for the purpose of developing and evaluating assays for recent HIV infection. Although the ongoing cohorts of HPTN052 (India) and Primary Acute HIV Patients in Modena, Italy had recruited a small number of seroconvertors and acute HIV patients (n=2 and n=16, respectively, at January 2010), the remaining two ongoing studies identified greater numbers of seroconvertors (IAVI Early Infection Cohort, n=335; and ALIVE, n=487). The identification of ongoing studies that are willing to discuss collecting extra plasma is a significant finding of this project as prospective specimens of larger volumes are of greater value than archived specimens with limited available volume.
The central obstacle in achieving success in this project was obtaining an initial response to the letter sent to study investigators. No response was received from study investigators responsible
37 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report for almost a third of seronegative cohorts and 44% of acute cohorts, despite several follow up emails by various individuals. Furthermore, when a study investigator agreed to complete a questionnaire, a large number of questionnaires were not received. Again, this was despite several follow up emails to study investigators.
The focus of the project was intentionally limited to the identification of biological specimens from HIV seronegative cohorts and acute HIV cohorts. Access to such cohorts is generally difficult due to the value of the specimens to the study investigators and limited volume of specimen remaining. This point was maintained in the response of study investigators who replied to the initial contact letter, where stored specimens were preferred to be used for the study investigator’s own research for two seronegative cohorts and no stored specimens remained after the study for one seronegative cohort. Other barriers to sharing specimens collected from cohort studies or clinical trials included no permission for long term storage of specimens leading to specimens being discarded following completion of the study, no permission available for use of specimens beyond the original study purpose and specimens being inappropriately stored and therefore not suitable for further research.
Additional to the above, there were further obstacles to the sharing of specimens raised by study investigators who completed questionnaires. This included difficulties in obtaining permission to ship specimens out of specific countries and the need for further approval for the sharing of biological specimens by institutional review boards. Funding would be essential for the majority of cohorts to prepare biological specimens for transport and for shipping specimen from laboratories. Many cohorts would also require collaborative research agreements.
The abovementioned obstacles, identified through contact with study investigators and from completed questionnaires, need to be considered when building a central specimen repository. Specific considerations include: careful budget planning of costing required to build a central repository; location of specimen repositories; realistic time lines for the acquisition of specimens and therefore the development of central specimen repositories; preparation of separate protocols for obtaining specimens from specific countries and; establishment of collaborative research agreements for study investigators and their respective research teams.
Several other sources in additional to seronegative cohorts and acute HIV cohorts exist for the acquisition of specimens of use in the development and evaluation of assays for recent infection. Future efforts in obtaining specimens for the development and evaluation of assays for recent HIV infection may be expanded to include plasma donor seroconversion panels and interval HIV
38 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report seroconvertors, and specimens from long term infected individuals, including those who are long term non-progressors, patients with advanced stage acquired immune deficiency syndrome (AIDS), elite controllers and patients on antiretroviral therapy. Possible sources of these specimens were identified at the meeting of the WHO Technical Working Group on HIV Incidence Assays (Chapel Hill, 13-14 May 2009) and subsequently published in the Meeting report (Link to the Meeting
Report: http://www.who.int/diagnostics_laboratory/links/hiv_incidence_assay/en/index.html ; page 37).
To conclude, difficulties in obtaining responses from initial contact with study investigators and receiving completed questionnaires were the key obstacles for the implementation of this project. However, specimens from cohorts identified through this project are a good foundation for future work in establishing a central HIV specimen repository for the purpose of developing and evaluating assays for recent infection. Specimens identified will be of value to the assembly of sample panels for the development and evaluation of assays for recent infection. In addition, the completed questionnaires for 14 cohorts and the responses from study investigators to the initial contact letter, shed light on potential obstacles for the building of a central specimen repository, which is a valuable next step in the development of new assays for recent infection and the evaluation of both current and new assays.
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Appendices
Appendix 1a. Letter sent to study investigators
Appendix 1b. Survey protocol sent to study investigators
Appendix 2. Seronegative cohorts questionnaire
Appendix 3. Acute cohorts questionnaire
Appendix 4. Seronegative cohort studies and clinical trials identified through the literature search
Appendix 5. Acute cohort studies and clinical trials identified through the literature search
Appendix 6. Seronegative cohorts: List of study investigators who were contacted and the studies for which each investigator was responsible for
Appendix 7. Acute cohorts: List of study investigators who were contacted and the studies for which each investigator was responsible for
40 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Appendix 1a. Letter sent to study investigators
41 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Appendix 1b. Survey protocol (page 1) sent to study investigators
42 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Appendix 1b. Survey protocol (page 2) sent to study investigators
43 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Appendix 2. Seronegative cohorts questionnaire (page 1)
44 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Appendix 2 (continued). Seronegative cohorts questionnaire (page 2)
45 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Appendix 2 (continued). Seronegative cohorts questionnaire (page 3)
46 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Appendix 2 (continued). Seronegative cohorts questionnaire (page 4)
47 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Appendix 3. Acute cohorts questionnaire (page 1)
48 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Appendix 3 (continued). Acute cohorts questionnaire (page 2)
49 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Appendix 3 (continued). Acute cohorts questionnaire (page 3)
50 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Appendix 3 (continued). Acute cohorts questionnaire (page 4)
51 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Appendix 4. Seronegative cohort studies and clinical trials identified through the literature search
Reference Country Name of Cohort/Study Year of Recruitment Testing interval Number of of seronegative seroconvertors subjects Batra et al 2000 [2, 60] Zimbabwe Zimbabwe AIDS Prevention Project (ZAPP) 1993-1997 6 months 124 Carneiro et al 2000 [3] Brazil Project Horizonte 1994-1999 6 months 18 Hubert et al 2000 [4] France SEROCO Study 1988 - ongoing Various; median 7 330 months Ryder et al 2000 [5] Democratic Republic HIV incidence among HIV discordant couples in the 1987 6 months 16 of the Congo Democratic Republic of the Congo Bakari et al 2000 [1] Tanzania HIV incidence in a cohort of police officers in Dar es 1994-1996 At clinic visits- 58 Salaam, Tanzania various Steffen et al 2001 [11] Switzerland HIV infections among IDUs 1994-1996 6 months 11 MacDonald et al 2001 [8] Kenya HIV seroconversion among Kenyan men with genital 1993-1997 3 months 38 ulcers Kumwenda et al 2001 [7] Malawi HIV incidence among male workers at a sugar estate 1994, 1998 6 months 216 Ghys et al 2001 [6] Cote d'Ivoire Cohort study among female sex workers in Abidjan, 1994-1997 6 months 26 Cote d'Ivoire Seage et al 2001 [10] US HIVNET preparedness study 1995 6 months 90 Sabbatini et al 2001 [9] Italy Northern Italy Seronegative Drug Addicts (NISDA) 1993-1999 At clinic visits- 135 various Nelson et al 2002 [13] US ALIVE (AIDS Linked to the IntraVenous Experience) 1988-2008 6 months 277 Choopanya et al 2002 [12] Thailand Longitudinal cohort study among IDUs in Bangkok 1995-1996 4 months 133 Van Damme et al 2002 [14] South Africa COL-1492 Study 1996-2000 1 month 104 Deren et al 2004 [15] US HIV incidence among high risk Puerto Rican drug 1998-1999 6 months 32 users Kaul et al 2004 [16] Kenya Monthly antibiotic chemoprophylaxis and incidence of 1998 3 months 35 STIs and HIV-1 infection in Kenyan sex workers: RCT Schechter et al 2004 [18] Brazil Projecto Praca Onze 1998-2001 12 months 11 Koblin et al 2004 [17] US EXPLORE 1999-2001 6 months 259 Ramjee et al 2005 [21] South Africa HIV incidence among commercial sex workers in 1996-1997 1 month 21 South Africa Ruan et al 2005[22] China Prospective cohort of IDUs in China 2002 6 months 16 Gray et al 2005 [20] Uganda Rakai Community Cohort Study 1994-1999 10-12 months 23
52 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Auvert et al 2005 [19] South Africa ANRS 1265 Trial 2002-2004 3 visits-months 3, 69 12 and 21 Kerr et al 2006 [24] Canada VIDUS (Vancouver Injection Drug Users Study) 1996-2003 3 months 125 Kozlov et al 2006 [25] Russia Cohort study of injection drug users in St Petersburg, 2002 6 months 20 Russia McClelland et al 2006 [26] Kenya Seronegative cohort of female sex workers in 1993-2004 1 month 265 Mombasa, Kenya Bartholow et al 2006 [23] US VAX004 clinical trial 1998-1999 6 months 360 Peterson et al 2007 [32] Ghana SAVVY Trial – Ghana 2004-2006 1 month 17 Kapiga et al 2007 [30] Tanzania HIV-1 among high risk women in Northern Tanzania 2002-2003 3 months 32 Brown et al 2007 [28] Uganda Hormonal Contraception and HIV (HC-HIV) study 1999-2004 3 months 211 Paxton et al 2007 [42] Botswana Botswana TDF/FTC Oral HIV Prophylaxis Trial 2007 - ongoing 1 month Unknown 1 Mehendale et al 2007 [31] India HIV incidence among patients attending STI clinics in 1993-2002 3 months 274 Pune Zhang et al 2007 [34] China HPTN 033 (China) 2002 6 months 42 Plankey et al 2007 [33] US MACS - Multicenter AIDS Cohort Study 1984-1985, 1987- 3 months 436 1991, 2001-2003 Bailey et al 2007 [27] Kenya Male circumcision for HIV prevention - Kenya 2002-2005 6 months 69 Gray et al 2007 [29] Uganda Male circumcision for HIV prevention in men in 6 months 67 Rakai, Uganda: a randomised trial Watson-Jones et al 2008 Tanzania Incidence of HIV among Women in Tanzania 2004-2006 6 months 55 [41] Halpern et al 2008 [36] Nigeria Cellulose Sulfate Vaginal Gel Phase III Trial 2004-2007 6 months 23 Kumwenda et al 2008 [38] Malawi HIV-1 infection among reproductive age women 2003-2005 3 months 31 Jin et al 2008 [37] Australia Health in Men (HIM) Study 2001-2004 12 months 52 Lavoie et al 2008 [39] US Omega Cohort 1996-2003 6 months 32 Van Damme et al 2008 [40] Uganda, South RCT of 6% Cellulose Sulfate Gel and the Effect on 2005-2007 1 month 41 Africa, Benin, India Vaginal HIV Transmission Feldblum et al 2008 [35] Nigeria SAVVY trial 2004-2006 1 month 33 1 Year of recruitment, testing interval of seronegative subjects or number of seroconvertors are not known from the reference
53 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Appendix 5. Acute HIV cohort studies and clinical trials identified through the literature search Reference Country Name of Cohort/Study Year of recruitment Number of acute HIV subjects Cao et al 2003 [45, 61] US Clinical and epidemiologic features of primary HIV infection 1993-1995 46 Lindback et al 2000 [54] Sweden Prospective cohort of patients with Primary HIV infection 1987-1997 38 Connick et al 2001 [48] US Relationship between HIV-1–specific memory cytotoxic T lymphocytes and 1994-1997 32 virus load after recent HIV-1 seroconversion del Amo et al 2002 [50] Spain Seroconvertors of the Community of Madrid 1985-ongoing 226 Cao et al 2003 [46] US Longitudinal cohort of patients with newly diagnosed HIV-1 infection 1993-1996 21 followed at University of Washington Primary Infection Clinic Cossarizza et al 2004 [49] Italy Primary Acute HIV patients in Modena, Italy 1995-ongoing 18 Casula et al 2005 [47] The Netherlands Amsterdam Cohort Study 1984-1986 36 Walker et al 2005 [57] US Treatment of Acute HIV Infection to Preserve Immune Function 1999-2004 Unknown 1 Hecht et al 2006 [51] US and Canada AIEDRP 495 Kassutto et al 2006 [52] US Longitudinal analysis of clinical markers following antiretroviral therapy 1996-2003 102 initiated during acute or early HIV-1 infection Kelley et al 2007 [53] US UCSF Options Project 177 Brenner et al 2008 [43] Canada Quebec PHI Cohort 1997-2007 249 Mlisana et al 2008 [55] South Africa CAPRISA 002 Acute Infection Study 2004-2005 62 Brumme et al 2008 [44] Germany HIV seroconvertor cohort in Berlin, Germany Unknown 1 61 Duda et al 2009 [58] UK, Ireland, Short Pulse Anti Retroviral Therapy at HIV Seroconversion (SPARTAC) 2004-2007 371 Australia, Italy, South Africa, Uganda, Spain Valentine et al [56] US, Canada Immunopathogenesis of acute and early HIV infection 2005-ongoing 92 1 Year of recruitment or number of acute HIV subjects are not known from reference
54 Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Appendix 6. Seronegative cohorts: List of study investigators who were contacted and the studies for which each investigator is responsible for. The response to the initial letter is given as either “no response received to date,” “willing to complete questionnaire” or “questionnaire will not be completed: reason given.” For studies which the study investigators committed to completing a questionnaire, an additional column indicates if the questionnaire has been received to date.
Name of Seronegative Cohort/Study Country/countries Study investigator/s Institution Response to letter Questionnaire [reference] of study contacted received to date (26 February 2010) EXPLORE [17] US A/Prof Beryl Koblin New York Blood Center Questionnaire will not be completed: Limited volume of specimens remain Cohort study of injection drug users Russia Andrei Kozlov The Biomedical Center, St No response received to date ( 26 February in St Petersburg, Russia [25] Petersburg 2010) ANRS 1265 Trial [19] South Africa Bertran Auvert Hopital Anbroise -Pare Willing to complete questionnaire Yes Agnes Fiamma Africa regional office, UCLA HIVNET 011 1 Zimbabwe, Malawi, David Katzenstein Stanford University Willing to complete questionnaire No South Africa Dr Carolyn Williamson Zimbabwe AIDS Prevention Project Zimbabwe David Katzenstein Stanford University Willing to complete questionnaire No (ZAPP) [2, 60] Dr Guanzura Project Horizonte [3] Brazil Dirceu Greco Universidade Federal de Minas No response received to date ( 26 February Gerais 2010) Northern Italy Seronegative Drug Italy Dr Alfredo Nicolosi Institute of Biomedical No response received to date ( 26 February Addicts (NISDA)[9] Technologies 2010)
VAX004 clinical trial [23] US, Canada and Dr Bradford Division of HIV/AIDS No response received to date ( 26 February Netherlands Bartholow Prevention, Center for HIV, STD 2010) and TB Prevention Incidence of HIV among Women in Tanzania Dr Deborah Watson - Department of Infectious and Willing to complete questionnaire No Tanzania: A randomized, double- Jones Tropical Diseases blind, placebo-controlled trial [41]
HIVNET preparedness study [10] US Dr George Seage III Department of Epidemiology, No response received to date ( 26 February Harvard School of Public Health 2010) SAVVY trial [32] Ghana Dr Kavita Nanda Family Health International Questionnaire will not be completed: No specimens remaining ALIVE ( AIDS Linked to the US Dr Kenrad Nelson Johns Hopkins Bloomberg Willing to complete questionnaire Yes IntraVenous Experience) [13] School of Public Health
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Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
COL -1492 Study [14] South Africa, Dr Lut van Damme Family Health International Questionnaire will not be completed: Thailand, Cote Permission not received for further use of d'Ivoire specimens Cohort study among female sex Cote d'Ivoire Dr Marie Laga Prince Leopold Institute of No response received to date ( 26 February workers in Abidjan, Cote d'Ivoire [6] Tropical Medicine 2010) Projecto Praca Onze [18] Brazil Dr Mauro Schechter Universidade Fed eral do Rio de Willing to complete questionnaire No Janeiro MACS - Multicenter AIDS Cohort US Dr Michael Plankey Georgetown University Medical No response received to date ( 26 February Study [33] Center 2010) Study of FSW in Benin 1 Benin Dr Michel Alary Unite de Recherche en Sante Willing to complete questionnaire No des Populations Omega Cohort [39] US Dr Michel Alary Unite de Recherche en Sante Willing to complete questionnaire Yes des Populations CS Trial 2 [40] Benin site, Africa Dr Michel Ala ry Unite de Recherche en Sante Willing to complete questionnaire Yes des Populations SAVVY trial [35] Nigeria Dr Paul Feldblum Family Health International Questionnaire will not be completed Specimens were destroyed at end of trial. No permission for long-term storage of specimens : Seronegative cohort of female sex Kenya Dr R Scott McClelland University of Washington Questionnaire will not be completed: workers in Mombasa, Kenya [26] Investigators would like to access the specimens for future research. Male circumcision for HIV prevention Uganda Dr Ron Gray Johns Hopkins University Willing to complete questionnaire No in men in Rakai, Uganda: RCT [29]
Rakai Community Cohort Study [20] Uganda Dr Ron Gray Johns Hopkins University Willing to complete questionnaire No
Monthly antibiotic chemoprophylaxis Kenya Dr Rupert Kaul Clinical Science Division, Willing to complete questionnaire No & incidence of sexually transmitted University of Toronto infections and HIV-1 infection in Kenyan sex workers: RCT [16] NIMH C -POL HIV/STD Prevention India Dr Sunit Solomon (YRGCARE) YRG Centre for Willing to complete questionnaire Yes Trial (India) 1 AIDS Research and Education HPTN052 (India) 1 India Dr Sunit Solomon (YRGCARE) YRG Centre for Willing to complete questionnaire Yes AIDS Research and Education VIDUS (Vancouver Injection Drug Canada Dr Thomas Kerr British Columbia Centre for Questionnaire will not be completed: Users Study) [24] Excellence in HIV/AIDS Samples have already been committed to own lab/studies SEROCO Study [4] France Jean -Baptiste Hubert Hospital de Bicettre No response received to date ( 26 February 2010)
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Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Hormonal Contraception and HIV Uganda, Zimbabwe Joelle Brown University of California, LA Willing to complete questionnaire No (HC-HIV) study [28] Longitudinal cohort study among Thailand Kachit Choopanya Beth Israel Medical Cent er/CDI No response received to date ( 26 February IDUs in Bangkok [12] 2010) HIV -1 among high risk women in Tanzania A/Prof Saidi Kapiga Harvard School of Public Health No response received to date ( 26 February Northern Tanzania [30] 2010) Botswana TDF/FTC Oral HIV Botswana Lynn Paxton CDC Questionnaire will not be completed: Prophylaxis Trial [42] Cannot grant permission on behalf of CDC to complete questionnaire IAVI HIV incidence cohorts 1 Eastern and Pauli Amornkul IAVI Willing to complete questionnaire Yes Southern Africa CS Trial 2 [40] Kampala site, Professor Florence Makerere University, Kampala. Willing to complete questionnaire No Uganda Mirembe Uganda HIV -1 incidence among commercial South Africa Professor Gita Ramjee South African Medical Research No response received to date ( 26 February sex workers in South Africa [21] Council 2010) CS Trial 2 [40] Durban site, South Professor Gita Ramjee South African Medical Research Willing to complete questionnaire No Africa Council Male circumcision for HIV Kenya Professor Robert School of Public Health, Willing to complete questionnaire No prevention – Kenya [27] Bailey University of Illinois at Chicago HIV -1 incidence among male Malawi Professor Taha Taha Johns Hopkins University No response received to date ( 26 February workers at a sugar estate [7] 2010) HIV -1 infection among reproductive Malawi Professor Taha Taha Johns Hopkins University No response received to date ( 26 February age women [38] 2010) Cellulose Sulfate Vaginal Gel Phase Nig eria Vera Halpern Family Health International Questionnaire will not be completed: III Trial [36] Specimens not suitable for further research - unsuitable storage conditions HIV incidence among patients India Sanjay Mehendale National AIDS Research Willing to comple te questionnaire No attending STI clinics in Pune [31] Institute Health in Men ( HIM ) study [37] Sydney Professor Andrew National Centre in HIV Epidemiology Willing to complete questionnaire No Grulich and Clinical Research, University of Dr Jeff Jin New South Wales HPTN 033 (China) [34] China Yiming Shao State Key Laboratory for Infectious Willing to complete questionnaire Yes Disease Prevention and Control, National Center for AIDS/STD Control and Prevention Prospective cohort of IDUs in China Ch ina Yiming Shao State Key Laboratory for Infectious Willing to complete questionnaire Yes [22] Disease Prevention and Control, National Center for AIDS/STD Control and Prevention
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Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Prospective cohort of MSM in China Yiming Shao State Key Laboratory for Infectious Willing to complete questionnaire Yes Beijing 1 Disease Prevention and Control, National Center for AIDS/STD Control and Prevention Vaccine Trial with ALVAC and Thailand Nelson Michael US Military HIV Research Program No response received to date ( 26 February AIDSVAX in Thailand 1 [62] 2010) 1 Referred study, not identified through the literature 2 Randomized Controlled Trial of 6% Cellulose Sulfate Gel and the Effect on Vaginal HIV Transmission
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Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Appendix 7. Acute cohorts: List of study investigators who were contacted and the studies for which each investigator is responsible for. The response to the initial letter is given as either “no response received to date,” “willing to complete questionnaire” or “questionnaire will not be completed: reason given.” For studies which the study investigators committed to completing a questionnaire, an additional column indicates if the questionnaire has been received to date.
Name of Acute Cohort/Study Country/countries Primary study Institution Response to letter Questionnaire of study investigator contact received to date (26 February 2010) Primary Acute HIV patients in Italy Andrea Cossarizza University of Modena Willing to complete questionnaire Yes Modena, Italy [49] AIEDRP (US sites) [51] US Dr Martin Markowitz Aaron Diamond AIDS Research No Center, Rockefeller University AIEDRP (Sydney) [51] Australia Professor Tony National Centre in HIV Willing to complete questionnaire No Kelleher Epidemiology and Clinical Research, University of New South Wales Recent HIV -1 seroconvertor s US Dr Eliz abeth Connick University of Colorado Health Questionnaire will not be completed: recruited from 2 cohort studies Sciences Center No specimens remain [48] Longitudinal analysis of clinical US Karen Axten Infectious Diseases Division, Willing to complete questionnaire Yes markers following antiretroviral Dr Eric Rosenberg Massachusetts General Hospital therapy initiated during acute or early HIV type 1 infection [52] Prospective cohort of patients Sweden Hans Gaines Swedish I nstitute for Infectious No response received to date ( 26 with Primary HIV infection [54] Disease Control February 2010) Seroconvertor s of the Community Spain Julia del Amo Departmento de Salud Publica Questionnaire will not be completed: of Madrid Limited volume of specimens remain Cohort of RIS 1 Spain Beatriz Hernández - Departmento de Salud Publica Willing to complete questionnaire Yes Novoa Julia del Amo CAPRISA 002 Acute infection South Africa Koleka Mlisana Centre for the AIDS Programme Willing to complete questionnaire Yes study [55] Dr Sengeziwe Sibeko of Research in South Africa CAPRISA 050 Acute Infection South Africa Koleka Mlisana Centre for the AIDS Programme Willing to complete questionnaire No Study 1 of Research in South Africa Clinical and epidemiologic US Lawrence Corey University of Washington Questionnaire will not be completed: features of primary HIV infection No specimens remain [45, 61]
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Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
Quebec PHI Cohort [43] Canada Dr Mark Wainberg McGill AIDS Centre, Jewish Willing to complete questionnaire Yes General Hospital Treatment of acute HIV infection US Bruce Walker Partners AIDS Research Center , No response received to date (11 to preserve immune function [57] Massachusetts General Hospital February 2010) HIV seroconvertor cohort in US Zabrina Brumme Simon Fraser University, No response received to date (11 Berlin, Germany [44] Canada February 2010) Longitudinal cohort of patients US James (Jim) Mullins University of Washington No response received to date ( 26 with newly diagnosed HIV-1 M. Juliana McElrath Fred Hutchinson Cancer February 2010) – reviewing protocol infection: University of Research Center Washington Primary Infection Clinic [46] UK Register of HIV UK Dr Kholoud Porter MRC Clinical Trials Centre, London No response received to date ( 26 Seroconvertors1 February 2010)
Short Pulse Anti Retroviral UK, Ireland, Sarah Fidler Imperial College London No response received to date ( 26 Therapy at HIV Seroconversion Australia, Italy, February 2010) (SPARTAC) [58] South Africa, Uganda and Spain Immunopathogenesis of Acute US Professor Fred New York University No response received to date ( 26 and Early HIV Infection [56] Valentine February 2010) 1 Referred study, not identified through the literature
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Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for acute and early HIV infection: Final Report
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