| Protocol No: | ECCT/17/09/03 | Date of Protocol: | 19-04-2016 |
| Study Title: | Effect of Antiretroviral Treatment Initiated During Acute HIV-1 Infection on Measures of HIV-1 Persistence and on HIV-1-Specific Immune Responses |
| Study Objectives: |
Primary Objective
1 To compare the amount of cell-associated HIV-1 DNA (CAHD) in 5 million blood-derived CD4+ T-cells (assayed by quantitative PCR [qPCR]) at week 48 among participants who initiated ART in Fiebig I/II versus Fiebig III/IV versus Fiebig V and had sustained suppression of plasma HIV-1 RNA.
Secondary Objectives
1 To evaluate HIV-1-specific CD4+ and CD8+ T-cells by flow cytometry prior to ART initiation and while HIV-1 RNA is suppressed on ART:
a. magnitude and distribution of CD4+ and CD8+ T-cells responses to nef/tat/rev/vpr/vpu, gag, pol and env
b. quality of T-cell responses (ie, frequency and type of polyfunctional responses)
2 To assess the amount of unspliced HIV-1 RNA in 5 million blood-derived CD4+ T- cells prior to ART initiation and while HIV-1 RNA is suppressed on ART.
3 To assess cell-associated HIV-1 RNA to DNA ratio in participants with quantifiable HIV-1 DNA prior to ART initiation and while HIV-1 RNA is suppressed on ART.
Exploratory Objectives
1 To assess the frequencies of non-transmitted epitope escape mutants prior to ART initiation and after 48 weeks of ART.
2 To investigate CAHD in CD4+ T-cells and across subsets (eg, naïve, central memory, effector memory), single copy HIV-1 RNA, and HIV-1-specific immune responses in blood; CAHD in gut; and CAHD and single copy HIV-1 RNA in cerebrospinal fluid (CSF) at any time from week 60 to week 72 in participants who undergo the optional procedures and have available data.
3 To characterize the effects of early ART on innate immune responses during and after AHI, including natural killer cell subset frequencies, phenotype, and function prior to ART initiation and while HIV-1 RNA is suppressed on ART.
4 In participants with detectable CAHD at any time point prior to ART initiation and while HIV-1 RNA is suppressed on ART, to quantify episomal HIV-1 DNA by qPCR for 2-LTR circles and derive the quantity of integrated HIV-1 DNA from the total and unintegrated DNA (unintegrated linear DNA or 1-LTR circles would have a negligible contribution after 48 weeks of therapy).
5 To investigate the relationship between genetic factors (human leukocyte antigen [HLA] typing and CCR5 delta-32 genotyping) and virologic and immunologic outcomes prior to ART initiation and while HIV-1 RNA is suppressed on ART.
6 To investigate integration sites prior to ART initiation and while HIV-1 RNA is suppressed on ART.
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| Laymans Summary: |
Title: Effect of Antiretroviral Treatment Initiated During Acute HIV-1 Infection on Measures of HIV-1 Persistence and on HIV-1-Specific Immune Responses
Lay Title: A study to look at how starting ART as soon as the HIV infection is found affects the amount of HIV-1 in blood and how well the body fights the HIV-1 infection
The HIV virus has the ability to exist as inactive form in the CD4+T cells (infection-fighting cells in the body) of HIV infected person. This ability of HIV virus being inactive starts very early in newly HIV infected person. Although antiretroviral therapy (ART) can reduce the level of HIV in the blood to an undetectable level, the inactive form of HIV continue to survive. Starting ART very early may reduce the amount of inactive HIV in the body and may prevent the cells that fight infection in the body from being destroyed. The purpose of this study is to look at the amount of HIV-1 DNA (genetic material for HIV-1) seen in CD4+ T-cells (infection-fighting cells in the blood) after 48 weeks of ART in those participants who have sustained suppression of HIV virus.
This is a multi-center study that will enroll participants of 18 years of age and above with acute HIV infection and start them on immediate study provided ART which is a single tablet of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/COBI/FTC/TAF). Other non-study-provided ARV regimens provided through the PEPFAR program will be allowed for participants who are pregnant, breastfeeding, or unable or unwilling to take study provided ARV. A total of 150 participants will be enrolled, with Kericho site enrolling up to 10 participants. The study duration is up to 72 weeks. Upon completion of the study, participants will be switched to the ARV regimen that is provided by the ministry of Health through the PEPFAR program. The information obtained from this study will be critical in designing therapeutic strategies and understanding the responses observed in future HIV cure-related studies.
Participants will be informed of all potential risks from the treatment that they will receive which involve the side effects of medicine to be given. Taking blood may cause some discomfort, bleeding, or bruising where the needle enters the body, and in rare cases, fainting or infection.
Participants will benefit from receiving ART that is more effective compared to the ART that is currently being used and is taken as a one pill every day. Participants will get more detailed information about HIV-1 infection than they could get from local HIV clinics and having this information could help participants get better treatment for HIV-1 infection. Participants will receive frequent health checks for HIV and other infection than at a public hospital, more thorough screening for HIV and other infections that could help identify problems early and hence get good treatment at the right time. For other medical conditions identified as part of the study screening and/or follow-up procedures, participants will be managed at KEMRI WRP CRC or referred to other sources of care available in the community.
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| 3 | The HIV virus has the ability to exist as inactive form in the CD4+T cells (infection-fighting cells in the body) of HIV infected person. This ability of HIV virus being inactive starts very early in newly HIV infected person. Although antiretroviral therapy (ART) can reduce the level of HIV in the blood to an undetectable level, the inactive form of HIV continue to survive. Starting ART very early may reduce the amount of inactive HIV in the body and may prevent the cells that fight infection in the body from being destroyed. The purpose of this study is to look at the amount of HIV-1 DNA (genetic material for HIV-1) seen in CD4+ T-cells (infection-fighting cells in the blood) after 48 weeks of ART in those participants who have sustained suppression of HIV virus. This is a multi-center study that will enroll participants of 18 years of age and above with acute HIV infection and start them on immediate study provided ART which is a single tablet of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/COBI/FTC/TAF). Other non-study-provided ARV regimens provided through the PEPFAR program will be allowed for participants who are pregnant, breastfeeding, or unable or unwilling to take study provided ARV. A total of 150 participants will be enrolled, with Kericho site enrolling up to 10 participants. The study duration is up to 72 weeks. Upon completion of the study, participants will be switched to the ARV regimen that is provided by the ministry of Health through the PEPFAR program. The information obtained from this study will be critical in designing therapeutic strategies and understanding the responses observed in future HIV cure-related studies. Participants will be informed of all potential risks from the treatment that they will receive which involve the side effects of medicine to be given. Taking blood may cause some discomfort, bleeding, or bruising where the needle enters the body, and in rare cases, fainting or infection. Participants will benefit from receiving ART that is more effective compared to the ART that is currently being used and is taken as a one pill every day. Participants will get more detailed information about HIV-1 infection than they could get from local HIV clinics and having this information could help participants get better treatment for HIV-1 infection. Participants will receive frequent health checks for HIV and other infection than at a public hospital, more thorough screening for HIV and other infections that could help identify problems early and hence get good treatment at the right time. For other medical conditions identified as part of the study screening and/or follow-up procedures, participants will be managed at KEMRI WRP CRC or referred to other sources of care available in the community. |
| Abstract of Study: | ABSTRACTHuman Immunodeficiency Virus (HIV) is an important global pandemic with an estimated 36.7 million people currently living with HIV and 2.1 million new HIV infections worldwide as per UNAIDS 2016 updates. In Kenya, the number of people living with HIV has been on the increase, and is currently estimated at 1.6 million while total new HIV infections were estimated to be 100,000 in 2013 as per the Kenya AIDS Response Progress report 2014. Recent studies have shown that early antiretroviral therapy (ART) improves both individual clinical outcomes, and decreases HIV transmission. Despite potent ART, HIV still persist due to the establishment of persistent cellular reservoirs of HIV-1 very early in acute HIV infection (AHI). Most proviral deoxyribonucleic acid (DNA) is in CD4+ T-cells, particularly central and transitional memory T-cells that persist through homeostatic, antigen-driven, or other mechanisms of proliferation. Very early antiretroviral therapy may limit the seeding of cellular reservoirs of HIV-1. Theoretically, ART initiated in the earliest Fiebig stages could limit the size and genetic diversity of the HIV-1 reservoirs, thereby improving the chance of an HIV-1 cure. This is a phase II, prospective, open-label study to measure the effects of early antiretroviral therapy on the establishment of HIV-1 reservoir and HIV-1-specific immunity. This study aims to compare the amount of cell-associated HIV-1 DNA (CAHD) in 5 million blood-derived CD4+ T-cells (assayed by quantitative PCR [qPCR]) at week 48 among participants who initiated ART in Fiebig I/II versus Fiebig III/IV versus Fiebig V and had sustained suppression of plasma HIV-1 RNA. Participants of 18 years and above with AHI will be enrolled and started on immediate study provided ART which is a single tablet of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/COBI/FTC/TAF). Other non-study-provided ARV regimens provided through the PEPFAR program will be allowed for participants who are pregnant, breastfeeding, or unable or unwilling to take study provided ARV. A total of 150 participants will be enrolled, with Kericho site enrolling up to 10 participants. The study duration is up to 72 weeks. The information obtained from this study will be critical in designing therapeutic strategies and understanding the responses observed in future HIV cure-related studies |