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HIV-1 Sero­converter Study

Date:  15/08/2024

Study lead Unit 34: Dr. Uwe Koppe

Study lead Unit 18: Dr. Karolin Meixenberger & Dr. Kirsten Hanke

Background

The HIV-1 Seroconverter Study is a multicenter, prospective long-term observational study that has been running at the RKI since 1997. In 2021, an overhaul of the HIV-1 Seroconverter Study was initiated in order to adapt the research questions, data collection and laboratory tests to the current public health situation and the current HIV and STI infection rates in Germany. This enables us to make full use of the strengths and potential of the study and provide study results with the greatest possible benefit for people with HIV in Germany.

Since 2011, the HIV-1 Seroconverter Study has been funded by the RKI and, for special research questions, by the Federal Ministry of Health and the Federal Ministry of Education and Research.

The study investigates important unanswered questions regarding HIV infection among study participants whose time of HIV infection can be defined with reasonable precision based on laboratory diagnostic parameters. Clinical and epidemiological data are collected annually from the study participants and a blood sample is taken for molecular biological and serological examinations.

Currently, about 44 study sites of general practitioners and hospitals are participating in the study. A total of over 3,600 participants have been included in the study and about 1,200 study participants are currently under observation. The study population consists mainly of men who have sex with men and live in urban areas.

Objectives

The following parameters, among others, are to be examined in the context of the HIV-1 Seroconverter Study:

  • Influence of host and viral factors as well as of resistance mutations against antiretroviral therapy on the course of HIV infection
  • Long-term effects of antiretroviral therapy on the course of the disease and the incidence of comorbidities
  • Influence of coinfections on the course of HIV infection
  • Studies on the proviral reservoir and cure options
  • SARS-CoV-2 infection in people with HIV
  • Health-related quality of life in people with HIV and other patient-reported endpoints

A major focus of the study is the long-term observation of the influence of viral characteristics (e.g. resistance mutations, subtype, co-receptor use) and human genetic factors on transmissibility, disease progression and treatment response. In the case of infection with a virus that is already resistant, individual antiretroviral agents or entire drug classes are less effective, meaning that they can no longer be used for initial antiretroviral therapy. Furthermore, some HIV subtypes show limited susceptibility to certain antiretroviral drugs due to natural polymorphisms, and there are reports of subtype-specific properties with regard to transmission or pathogenesis in certain populations or risk groups. By observing the study participants over a longer period of time, resistance developments during therapy and their consequences can be observed over time. Furthermore, the evolution of multi- and superinfections as well as the intra- and inter-patient evolution of HIV in the study cohort can be analyzed. The study also investigates the persistence of resistant HIV and its onward transmission, as well as the significance of resistant minoritarian virus subpopulations.

Another focus of the study is to examine the long-term effects of antiretroviral therapy on disease progression and the incidence of co-morbidities. The long-term follow-up of people on ART is important for evaluating changes in progression to AIDS, survival time, but also the tolerability of ART and the occurrence of comorbidities. Analyses of treatment histories allow investigations about how long patients remain on certain therapies in routine medical care, what risk these patients have for virological failure in real life, and for what reasons therapies are changed. In addition, the occurrence of comorbidities, e.g. cardiovascular diseases, metabolic diseases, kidney and liver diseases, can be examined and possible influencing factors can be further characterized.

Furthermore, co-infections with other sexually transmitted viral and bacterial pathogens, such as hepatitis B, hepatitis C and Treponema pallidum, are examined in the context of the HIV-1 Seroconverter study. The analysis of the occurrence, distribution and treatment of sexually transmitted infections (STI) among study participants with HIV provides important insights into vulnerable groups, testing behavior, therapy, possible resistance developments, possible influences on the transmission potential of the pathogens and possible consequences for the course of the disease. Due to the use of partly identical drugs for therapy and their synergistic or antagonistic effects, knowledge about co-infections and the analysis of the development of resistance is important for recommendations on effective and cost-efficient therapy of co-infections.

The HIV-1 Seroconverter Study also aims to investigate the proviral reservoir and develop treatment options. This will help determine the size of the proviral reservoir in relation to therapy and virological and clinical parameters. In addition, in vitro analyses are used to investigate the reactivation of proviruses in immune cells of people with HIV and chromatin access studies are conducted.

HIV infection can lead to damage of the immune system, which may affect the immune response to other infections, such as SARS-CoV-2. The HIV-1 Seroconverter Study is investigating the extent to which people with HIV develop neutralizing (protective) antibody titers and the persistence of these antibodies. In addition, the study will investigate whether people with HIV develop specific T cell responses against coronavirus after infection with SARS-CoV-2 and how long these are detectable.

Beyond the analysis of clinical and laboratory data, data on patient-reported outcomes (PRO), e.g. on health-related quality of life, are lacking for people with HIV in Germany. A high health-related quality of life is important for all people and can be severely limited in chronically ill individuals. In relation to the UNAIDS 90-90-90 targets, a high health-related quality of life has been proposed as the “fourth 90” – an indicator that people with HIV are not only effectively treated but can also live well with their disease. In the context of the study, the health-related quality of life in people with HIV is repeatedly assessed. The data will be used to identify factors that influence health-related quality of life and to identify approaches to improving the quality of life of people with HIV in Germany.

Methods

The study includes people with HIV for whom either the time of HIV seroconversion can be determined based on a last negative and a first positive HIV antibody test at an interval of no more than three years, or for whom an acute HIV seroconversion has been identified at diagnosis based on defined laboratory parameters. Acute seroconversion can be demonstrated by:

  1. a reactive ELISA and a negative/indeterminate immunoblot
  2. a negative/indeterminate ELISA and a positive NAT (nucleic acid amplification technology) (≥1000 copies/ml)
  3. a positive NAT (≥1000 copies/ml) and a negative/indeterminate immunoblot
  4. a reactive ELISA and a positive immunoblot without p31 band
  5. a positive NAT (≥1000 copies/ml) and a positive immunoblot without p31 band

All participants must be at least 18 years old at the time of inclusion in the study. The study participants will receive oral and written information about the purpose of the study and will provide written informed consent to participate in further follow-up examinations in accordance with the study design. A current ethics vote from Charité, Universitätsmedizin Berlin from 2021 is available.

Data collection
Data is documented without names and based on a defined data collection form. In addition to demographic information, the date of the last negative and the first positive HIV test, information on the route of infection, CD4/CD8 cell count, viral load and other laboratory parameters, HIV-related and AIDS-defining diagnoses and other co-morbidities, antiretroviral therapy and prophylaxis, and co-infections including SARS-CoV-2, HBV and HCV are recorded. Information on the course of HIV infection, including medication, is updated at yearly intervals through follow-up surveys. In addition, patient-reported data, e.g. on health-related quality of life and treatment satisfaction, will be collected directly from the study participants. The identity of the participants will, of course, remain unknown to the RKI. The collection of patient-reported data will be repeated at regular intervals, e.g. every 2-3 years.

Blood samples
In parallel to data collection, blood samples will be taken from all study participants at yearly intervals and plasma and DNA will be stored for later analysis. Before the start of therapy, as close in time as possible to the time of infection, a blood sample will be sent to the Unit 18 HIV Study Laboratory together with the basic data collection form. Various tests are carried out on the blood samples, such as HIV-1 resistance and subtype determination, analysis of genetic host markers and analysis of important coinfections.

Results

The results of the HIV-1 seroconverter study have already been presented at numerous conferences and published in various journals.

In addition, the results of the HIV-1 seroconverter study led to the revision of the directive for the assessment of medical examination and treatment methods in September 2005, in order to enable the best possible initial therapy for people with HIV. This includes the indication for genotypic resistance testing in pregnant women with HIV infection, in the case of high regional transmission rates (>10%) or in certain high-risk groups with a high risk of infection with a resistant virus. In these cases, the costs of HIV resistance testing are covered by the statutory health insurance funds.

Information for participants in the HIV-1 Seroconverter Study

Sample material

For the molecular biological and serological examinations as part of the HIV-1 Seroconverter Study, 20-30 ml of EDTA blood must be sent to the HIV study laboratory with each basic and follow-up survey form. The EDTA blood sample must be stored at room temperature until dispatch.

In exceptional cases, at least 8 ml of EDTA plasma can be submitted after consultation with the HIV study laboratory. The EDTA plasma must be stored at 4°C until shipment.

In order to best achieve the study objectives of the HIV-1 Seroconverter Study - such as investigating the influence of resistance mutations, subtype and other viral factors on disease progression and treatment response - we ask you to send blood samples from treatment-naive individuals to the Unit 18 HIV study laboratory when new study participants are enrolled.

Furthermore, in addition to the regular initial and follow-up samples, we ask for additional EDTA blood samples in the event of treatment failure in study participants.

Sample submission form

Please complete the basic or follow-up data collection form for the initial or follow-up samples and place it in the document compartment of the leak-proof shipping bag for the EDTA blood sample.

If the completed case report form is not available at the time of sample shipment, you can alternatively enclose a copy of the completed first page of the case report form with the sample. In this case, please send the completed case report form later in the postage-paid envelope to Unit 34.

For additional EDTA blood samples in the event of treatment failure, please use the Sample information form HIV study laboratory (in German) of the Unit 18 HIV study laboratory.

Sample shipment

We are happy to have samples from treatment-naive study participants or study participants with treatment failure picked up from you by a courier, so that the sample material for genotypic resistance determination arrives at the HIV study laboratory as freshly as possible. Please use the unstamped brown transport boxes for this purpose. To request a pick-up, please contact us by email and provide us with the exact pick-up address and the possible pick-up time frame. Within Berlin, samples can be picked up from Monday to Friday; outside Berlin, from Monday to Thursday. Please note that the last transport orders from the HIV Study Laboratory are placed by 3 p.m. to ensure timely pickup.

Please send blood samples from study participants on antiretroviral therapy in the prepaid white transport boxes by Deutsche Post. Please label the sender's address and seal the shipping boxes using the tuck-in flap.

Study centers outside of Berlin should also use the pre-stamped white shipping boxes and transport with Deutsche Post for EDTA blood samples from treatment-naive study participants on Fridays!

We will provide you with the required shipping material and, on request, monovettes (Sarstedt) for blood collection free of charge.

Submission of HIV sequences

If no treatment-naive EDTA blood sample or, in the case of treatment failure, no additional EDTA blood sample has been sent to the Unit 18 HIV study laboratory upon inclusion of a new study participant, we kindly request that you send us the HIV sequences from the genotypic resistance determination if possible.

Please send us the HIV sequences of all available genome regions from viral RNA or proviral DNA in txt or fasta format, stating the Seroconverter number, blood collection date and therapy status in accordance with data protection regulations using the Cryptshare web application.

If you have any questions regarding the provision of data via Cryptshare, please contact the HIV Study Laboratory by email. We will be happy to send you detailed instructions.

Documents for participation in the HIV-1 seroconverter study

The HIV-1 seroconverter study is conducted in compliance with the DSGVO and with a positive ethics vote. Study participants sign a declaration of consent. A cooperation agreement is concluded with the study centers. The current study documents can be downloaded here:

Contact details

Shipping management (Unit 18)

Sabrina Neumann
Phone: +49 (0)30-18754-2243
E-mail: Serokonverter.HIV [at] rki.de

Data management (Unit 34)

Kerstin Dehmel
Phone: +49 (0)30-18754-2896
E-mail: Serokonverter.HIV [at] rki.de

Study lead Unit 18 (Molecular Epidemiology)

Dr. Karolin Meixenberger
Phone: +49 (0)30-18754-2277
E-mail: Serokonverter.HIV [at] rki.de

Dr. Kirsten Hanke
Phone: +49 (0)30-18754-2639
E-mail: Serokonverter.HIV [at] rki.de

Study lead Unit 34 (Epidemiology)

Dr. Uwe Koppe
Phone: +49 (0)30-18754-2262
E-mail: Serokonverter.HIV [at] rki.de

Further information