HIV cure & Acute HIV
SEARCH is a partnership that began in 2005 with the goal of accomplishing mutual objectives in HIV/ AIDS research and training in the South-East Asia region between the The Thai Red Cross AIDS Research Centre (2005-2020) and now IHRI and the US Military HIV Research Program (MHRP). SEARCH conducted its activities in Thailand under The Thai Red Cross AIDS Research Centre until 2020 before joining IHRI
SEARCH is interested in various aspects of HIV/ AIDS and related infectious diseases. SEARCH has been involved in the following areas of studies as well as serving as a training center for HIV/ AIDS, both adults and pediatrics:
1. Neuro AIDS
2. Acute HIV Infection
3. HIV (functional) Cure
4. HIV Immunology and Virology, and Vaccine Development
5. Sexual Health in Women and Men
6. Opportunistic and Co-infections
SEARCH’s mission is to elucidate the interplay between viral and host factors during the establishment of HIV infection and the mechanisms that underlie its persistence. By understanding these factors, SEARCH aims to identify strategies that can support more effective immunological responses to HIV infection and lead to control or clearance of the virus without the need for lifelong antiretroviral therapy.
SEARCH 010 or RV254 is a prospective cohort study in Thailand which screens around 40,000 participants each year capturing 50 to 100 acute HIV infected (AHI) participants per year. Through diagnosing HIV in the acute stage, investigators are provided with the exceptional opportunity to understand the events following infection. This creates a unique chance to look at the virus and the cells’ activity at various places in the body early in the infection. Study participants undergo neurological and neuropsychological evaluation combined with brain imaging. Blood, plasma, lymph node, gut and cerebrospinal fluid are also captured in consenting volunteers and tested by virological and immunological assays.
The study has so far included 643 AHI participants who started early on antiretroviral medications (1-2 days). This study serves as a valuable resource for the increasing interest in the field of HIV cure research. Several studies which explore the potential of functional cure incorporating treatment interruption with therapeutic HIV vaccine, monoclonal antibody and drugs targeting the HIV reservoir have been completed or are nearing implementation through the participants who joined SEARCH010/RV254. More than 70 substantial papers generated through the SEARCH 010 study have already been published in peer reviewed journals and manuscripts continue to be generated.
Among the 27 publications from 2019/2020 are a report in Nature Medicine by Colby et al. about the first HIV therapeutic vaccine study among this cohort (doi: 10.1038/s41591-020-0774-y); a publication in Lancet HIV by Crowell et al. on the safety and efficacy of VRC01 broadly neutralising antibodies in adults with acutely treated HIV (doi: 10.1016/s2352-3018(19)30053-0); and a manuscript by Leyre et al. published in Science Translational Medicine about abundant HIV-infected cells in blood and tissues being rapidly cleared upon ART initiation during acute HIV infection (doi: 10.1126/scitranslmed.aav3491).
This is a longitudinal study enrolling up to 200 HIV-negative and 200 non-acutely HIV-infected adults to perform immunologic and virologic investigations in the peripheral blood, sigmoid colon, rectum, lymph nodes, genital secretions and central nervous system. The study aims to compare the virological, immunophenotyping and immunohistochemistry findings to the acute HIV infection findings of the SEARCH010/RV254 study. Enrollment is currently ongoing and the study so far has enrolled 80 HIV-negative volunteers and 77 non-acutely HIV infected volunteers. Numerous articles have been published using the data from this study as control to compare to the findings of RV254.
This study is an observational cohort of participants who have completed clinical trials that include analytic treatment interruption (ATI), which is a closely monitored pause in antiretroviral therapy (ART), or interventions aimed at viral remission. ATI is a necessary component in many studies of HIV treatment to test the hypothesis that an innovative treatment for HIV infection can induce a remission in HIV replication in the body in the absence of lifelong ART. New treatment strategies being tested at SEARCH that necessitate ATI include therapeutic vaccines, a monoclonal antibody, novel drug regimens, and combinations of these modalities. The study will provide long-term follow-up on safety and efficacy of ATI, as well as the effect of ATI on the HIV reservoir. The study began in April 2016 with open-ended enrollment.
A behavioral study team independent from the clinical study team and led by Prof. Gail Henderson of the University of North Carolina is conducting SEARCH027/RV436 among SEARCH 010/RV254 participants. The aim is to explore the expectations, intentions, decision making and decision satisfaction of SEARCH010/RV254 participants related to HIV functional cure trials. A total of 250 SEARCH010/RV254 participants completed a survey regarding their ideas about, understanding of, expectations of, and intentions towards functional HIV cure studies. In addition, participants who were actually approached to join functional cure studies have been interviewed about their decision to join or not join, and subsequent satisfaction with their decision.
Preliminary results were first presented at the 19th Bangkok International Symposium on HIV Medicine in January 2017 and indicated that participation in the SEARCH010/RV254 cohort transformed participants’ identity. They generally felt that they understood the information provided, and that the
information was adequate. Similar reasons were quoted by joiners and non-joiners of functional cure studies, showing they had a similar understanding of the information provided but that they weighed this information differently. ART interruption was seen as both a risk and a benefit, but participants felt safe because of close clinical monitoring. Participants anticipated a benefit for science from their participation and ‘wanted to give back’. Invasive procedures were perceived as more burdensome. The majority of joiners and non-joiners were satisfied with their decision and this did not change over time.
Since then 2 papers elaborating these results have been published:
- Henderson GE, Waltz M, Meagher K, Cadigan RJ, Jupimai T, Isaacson S, Ormsby NQ, Colby DJ, Kroon E, Phanuphak N, Ananworanich J, Peay HL. Going off antiretroviral treatment in a closely monitored HIV “cure” trial: longitudinal assessments of acutely diagnosed trial participants and decliners. Journal of the International AIDS Society. 2019;22(3):e25260. Epub 2019/03/15. doi: 10.1002/jia2.25260. PubMed PMID: 30869203; PMCID: PMC6416664.
- Henderson GE, Peay HL, Kroon E, Cadigan RJ, Meagher K, Jupimai T, Gilbertson A, Fisher J, Ormsby NQ, Chomchey N, Phanuphak N, Ananworanich J, Rennie S. Ethics of treatment interruption trials in HIV cure research: addressing the conundrum of risk/benefit assessment. J Med Ethics. 2018 Apr;44(4):270-276. doi:10.1136/medethics-2017-104433. Epub 2017 Nov 10. PubMed [citation] PMID: 29127137
SEARCH024/RV397 was a randomized, controlled, double-blind trial of the safety and efficacy of a broadly neutralizing HIV-1 monoclonal antibody (VRC-01) to control HIV infection during analytic treatment interruption (ATI). Participants who started antiretroviral therapy (ART) during acute HIV infection, completed at least 2 years, of ART, and had undetectable viral load (<50 copies/mL) for at least 48 weeks underwent ATI while receiving intravenous infusions of VRC-01 every three weeks for up to 24 weeks. During ATI, participants were monitored closely for virological, immunological, or clinical manifestations of HIV viral replication. ART was restarted when sustained viral replication was detected, or if participants met clinical or immunological criteria. The study began enrollment in August 2016 and 18 participants completed the study in mid 2017.
Results of the study were presented at the 9th IAS Conference on HIV Science (IAS 2017) in Paris, France and subsequently published in Lancet HIV. After stopping all ART drugs, participants who received VRC-01 had a longer time to detectable viral load (>20 copies/ml) compared to those who received placebo: 26 vs. 14 days (p=0.51), and a shorter time to viral suppression after restarting ART: 21 vs. 28 days (p=0.83). Although all participants experienced viral rebound and had to restart ART, one participant was able to remain off ART and maintain viral suppression for 44 weeks. In general, the VRC-01 injections were safe and well tolerated with few side effects. However, one participant experienced an allergic reaction to the antibody which resolved with treatment but required withdrawal from further doses of the VRC-01. The conclusion of the study is that VRC-01 is active in delaying viral rebound after ATI but that alone it is not enough to control HIV replication. Future studies will test combinations of anti-HIV antibodies with other treatment modalities.
Crowell TA, Colby DJ, Pinyakorn S, Sacdalan C, Pagliuzza A, Intasan J, Benjapornpong K, Kamonkan T, Chomchey N, Kroon E, de Souza M, Tovanabutra S, Rolland M, Eller MA, Paquin-Proulx D, Bolton DL, Tokarev A, Rasmi Thomas R, Trautmann L, Krebs SJ, Modjarrad K, McDermott AB, Bailer RT, Doria-Rose N, Patel B, Gorelick RJ, Fullmer BA, Schuetz A, Grandin PV, O’Connell RJ, Ledgerwood JE, Graham BS, Tressler R, Mascola J, Chomont N, Michael NL, Robb ML, Phanuphak N, Ananworanich J, for the RV397 Study Group. Safety and efficacy of VRC01 broadly neutralising antibodies in adults with acutely treated HIV (RV397): a phase 2, randomised, double-blind, placebo-controlled trial. The Lancet HIV, Published Online April 15, 2019, http://dx.doi.org/10.1016/S2352-3018(19)30053-0.
RV411 was a study of analytic treatment interruption (ATI) in participants who had started antiretroviral therapy (ART) in the very earliest stage of HIV infection, Fiebig 1, when HIV–RNA is detectable in the blood but HIV antibodies have not yet developed. Participants in the trial were on ART for at least 2 years, with undetectable HIV viral load (<50 copies/mL), CD4 > 400 cells/mm3, and no clinical manifestations of HIV disease. In this study, 8 participants stopped all ART drugs while undergoing careful monitoring for reappearance of HIV in the blood, fall of CD4 count, or clinical symptoms.
The trial results provided evidence that ATI is safe and well tolerated in the population of participants who start ART during acute HIV infection. Although all participants experienced reappearance of HIV in the blood, none had clinical symptoms, opportunistic infection, severe adverse reaction, new resistance mutations, or treatment failure after restarting ART.
The preliminary results of the trial were presented at the 2017 Conference on Retroviruses and Opportunistic Infections and since then published in Nature Medicine:
Colby D, Trautmann L, Pinyakorn S, Leyre L, Pagliuzza A, Kroon E, Rolland M, Takata H, Buranapraditkun S, Intasan J, Chomchey N, Muir R, Haddad EK, Tovanabutra S, Ubolyam S, Bolton DL, Fullmer BA, Gorelick R, Fox L, Crowell T, Trichavaroj R, O’ Connell R, Chomont N, Kim JH, Michael NL, Robb ML, Phanuphak N, Ananworanich J, on behalf of the RV411 study group. Rapid HIV RNA rebound after antiretroviral treatment interruption in persons durably suppressed in Fiebig I acute HIV infection. Nat Med. 2018 Jun 11. doi: 10.1038/s41591-018-0026-6. PMID:29892063.
RV405/SEARCH023 was a randomized, controlled, double-blind trial of a therapeutic vaccine regimen for participants who were started on antiretroviral therapy (ART) during acute HIV infection. The study hypothesis was that the vaccines would stimulate the immune system to control HIV infection in the absence of ART. In the study, 26 participants on ART with viral suppression for at least one year received 4 injections of vaccine or placebo over a period of 48 weeks: two doses of an Adenovirus 26 Mosaic Vector Prime (Ad26.Mos.HIV) and two doses of a Modified Vaccinia Ankara Mosaic (MVA-Mosaic) boost. Twelve weeks after completion of the vaccine series, participants underwent analytic treatment interruption (ATI) in which all ART drugs were stopped and participants were monitored closely for any virological, immunological, or clinical manifestations of HIV viral replication. ART would be restarted if sustained viral replication was detected, or if participants met clinical or immunological criteria.
The study began enrollment in October 2016 and all 26 participants had received all 4 vaccine/placebo doses by the third quarter of 2017 without any serious adverse effects from the study injections and all proceeded onto ATI. The vaccine was safe and generated robust immune responses, but delayed time to viral rebound compared to that in placebo recipients by only several days and did not lead to viremic control after treatment interruption.
The study was first presented at the IAS Towards an HIV Cure initiative, 2019 HIV & HBV Cure Forum ine Mexico City, Mexico and subsequently published in Nature Medicine.
Donn Colby, Michal Sarnecki, Dan H. Barouch, Somporn Tipsuk, Daniel J. Stieh, Eugène Kroon, Alexandra Schuetz5, Jintana Intasan, Carlo Sacdalan, Suteeraporn Pinyakorn, Pornsuk Grandin, Hongshuo Song, Sodsai Tovanabutra, Zhanna Shubin, Dohoon Kim, Dominic Paquin-Proulx, Michael A. Eller, Rasmi Thomas, Mark de Souza, Lindsay Wieczorek, Victoria R. Polonis, Amélie Pagliuzza, Nicolas Chomont, Lauren Peter, Joseph P. Nkolola, Johan Vingerhoets, Carla Truyers, Maria G. Pau, Hanneke Schuitemaker, Nittaya Phanuphak, Nelson Michael, Merlin L. Robb, Frank Tomaka, Jintanat Ananworanich, and the HTX1001/RV405 Study Team. Safety and Immunogenicity of Ad26, MVA vaccines in acutely treated HIV and effect on viral rebound after ART interruption. Nat Med, 23 March 2020; volume 26: 498–501.
SEARCH 018/RV408 was a sub-study of SEARCH 010/RV254 investigating the effect of addition of the drug telmisartan to antiretroviral therapy (ART) in 21 acutely HIV infected study participants. Telmisartan is a so-called angiotensin receptor blocker (ARB) which has anti-inflammatory and anti-fibrotic effects. The study compared 14 participants getting ART+telmisartan to 7 participants receiving standard ART alone to see if addition of telmisartan reduces immune activation and trafficking of activated and HIV-infected cells to the brain, and limits establishment and persistence of the HIV reservoir in the brain. In addition, in participants who were willing to undergo optional inguinal lymph node biopsy, the study will determine whether receiving telmisartan+ART leads to less lymphoid tissue fibrosis than subjects receiving ART alone. The study lasted 72 weeks for each participant, started in January 2015 and was completed in January 2018. All subjects continued in study SEARCH010/RV254 after completion of SEARCH018/RV408 and a manuscript is in preparation.