SEARCH 010 or RV254 is a prospective cohort study in Thailand which has been screening up to 30,000 clients of the Thai Red Cross Anonymous Clinic each year since 2009. Annually up to 120 individuals are identified as being acutely HIV infected (AHI) and 90-100 of them enroll in the study. Acutely infected subjects are those in the earliest stages of HIV infection (so called Fiebig I through Fiebig IV stages), not testing positive yet on every test of a panel used for HIV infection staging. Through diagnosing HIV in the acute stage, investigators are provided with the unique opportunity to understand the events immediately following infection and to look at the virus and the cells' activity at various places in the body early in the infection. All study participants are offered immediate HIV treatment and undergo blood draws and neurological and neuropsychological evaluations. Brain imaging, collection of genital secretions (i.e. semen, rectal swab, vaginal swab), lymph node biopsy, gut biopsy and cerebrospinal fluid collection (lumbar puncture) are done in participants who agree to these procedures. Their samples are tested by virological, immunological and other assays at renowned research institutions in Thailand, the US and Europe. The study has so far included 451 AHI participants who were started on antiretroviral treatment (ART) within 1-2 days and who have been on study for up to 8.5 years. This cohort now serves as a valuable resource for the field of HIV functional cure or HIV remission research. Several studies which explore the potential of HIV remission, incorporating treatment interruption after therapeutic HIV vaccine, monoclonal antibody or drugs targeting the HIV reservoir, have been completed, commenced or are in preparation, enrolling interested participants from SEARCH010/RV254. Substantial papers generated through the SEARCH010/RV254 study have already been presented at conferences or published in peer reviewed journals (see tab 'Publications') and manuscripts continue to be generated.
To answer some important research questions generated in SEARCH010/RV254, comparison to samples of individuals who are chronically HIV infected or not infected is sometimes called for. SEARCH013/RV304 therefore is a longitudinal study enrolling up to 100 HIV-negative and 100 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 SEARCH010/RV254. Enrollment is currently ongoing and the study so far has enrolled 61 HIV-negative volunteers and 29 non-acutely HIV infected volunteers.
SEARCH018/RV408 is 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 compares 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 are 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 lasts 72 weeks for each participant, started in January 2015 and will be completed in January 2018. All subjects continue in study SEARCH010/RV254 after completion of SEARCH018/RV408.
SEARCH023/RV405 is 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 hypothesis is that the vaccines will stimulate the immune system to control HIV infection in the absence of ART. In the study, 27 participants on ART with viral suppression for at least one year will receive 4 injections of vaccine or placebo (sham vaccine) 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 will undergo analytic treatment interruption (ATI) in which all ART drugs are stopped and participants are monitored closely for any virological, immunological, or clinical manifestations of HIV viral replication. ART will be restarted if sustained viral replication is detected, or if participants meet clinical or immunological criteria. The study began enrollment in October 2016 and is expected to be completed in late 2018.
SEARCH024/RV397 is 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, had taken ART for at least 2 years, and had undetectable viral load (<50 copies/mL) for at least 48 weeks undergo ATI while receiving intravenous infusions of VRC-01 every three weeks for up to 24 weeks. During ATI, participants will be monitored closely for virological, immunological, or clinical manifestations of HIV viral replication. ART will be restarted for sustained viral replication (sustained detection of virus in the blood), or if participants meet clinical or immunological criteria. The study began enrollment in August 2016 and is expected to be completed in mid 2017.
SEARCH025/RV412 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). 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, latency reversing agents, 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. 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 were interviewed about their decision to join or not join, and subsequent satisfaction with their decision.
Preliminary results were 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, that the information is adequate and similar reasons were quoted by joiners and non-joiners of functional cure studies, showing similar understanding of information provided but weighing 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.
Click here to see the presentation about SEARCH027/RV436
SEARCHXXX/RV398 co-enrolls 24 acutely infected participants from the RV217 study, a cohort study for most-at-risk populations active in 3 east African countries and in Thailand. In Thailand, study RV217 is conducted at the ECHO clinic in Pattaya, managed by the Armed Forces Research Institute for Medical Sciences (AFRIMS). Participants who were identified as being acutely infected in RV217, receive one infusion of the broadly neutralizing HIV-1 monoclonal antibody (VRC-01) or placebo (sham) infusion and are started on antiretroviral therapy (ART). Participants who receive actual VRC-01 will start ART either right away, on the same day as VRC-01 infusion, or one week later. The study aims to determine whether VRC-01 administered very early in infection may help reduce viral load faster or more profoundly at day 7 after infusion and whether the infusion may reduce the longer term HIV reservoir in blood, cerebrospinal fluid and tissue more than ART alone. SEARCH contributes to SEARCHXXX/RV398 by providing VRC-01 infusions in a safe environment and providing biopsy procedures for willing and consenting participants
SEARCH016/RV328 was an exploratory study of 4 vaccinations with AIDSVAX®B/E or placebo (sham vaccine) in 40 healthy adults at low risk of HIV infection. AIDSVAX®B/E was one of two vaccines used in the RV144 study which showed a modest vaccine efficacy at 42 months of 31.2%, the first HIV vaccine regimen ever to show any benefit. As there are limited stored samples available from RV144 subjects for further investigations and none from mucosal compartments, including vagina, rectum and semen, study SEARCH016/RV328 aimed to characterize and compare at different time points immune responses in the blood, tissue (sigmoid colon, cervix and bone marrow) and mucosal compartments following vaccination with AIDSVAX®B/E or placebo. All subjects completed the study with last vaccination administered in May 2016. Analysis of data and samples is ongoing.
SEARCH019/RV409 was a study of analytic treatment interruption (ATI) in participants who had started antiretroviral therapy (ART) during Fiebig stages III/IV of HIV infection, which is before the immune response against the virus has fully developed but virus and early antibodies are already detectable in the blood. Participants from SEARCH010/RV254 were eligible to join if they had viral load of less than 50 copies/ml for at least 2 years.
Ten participants who received the combination of vorinostat/hydroxychloroquine/maraviroc (VHM) for 10 weeks in addition to ART were compared to 5 participants continuing only ART for 10 weeks, after which all 15 started ATI. The VHM combination was chosen for its anticipated ability to reactivate latently HIV infected cells to make them visible to the immune system for clearance, limiting the pool of new target cells for HIV during reactivation, and preventing HIV from adhering to and entering targeted cells. The trial was completed in November 2015 and trial results showed that VHM treatment was generally safe but did not have the desired effect, as all participants experienced reappearance of HIV in the blood. ATI was shown to be safe and well tolerated as none had clinical symptoms, opportunistic infection, severe adverse reaction, new resistance mutations, or treatment failure after restarting ART.
The preliminary results of the studies were presented at the AIDS 2016 Conference in Durban, South Africa while a poster presentation highlighted the neurological sub-study at the same conference.
Click here for the SEARCH019/RV409 conference abstract.
Click here to watch the SEARCH019/RV409 conference oral presentation.
SEARCH022/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 (<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 was completed in June, 2016.
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.
SEARCH031/RV506 is a clinical trial of a therapeutic vaccine regimen, meaning the vaccines are given to participants who are already HIV infected, with or without a toll like receptor 7 (TLR7) agonist. The vaccine combination used in the study is Adenovirus 26 Mosaic Vector Prime (Ad26.Mos.HIV) and Modified Vaccinia Ankara Mosaic (MVA-Mosaic) boost. This combination which decreased infection risk in monkeys, while TLR-7 is a drug that reactivates so-called latently HIV-infected cells, making them visible to the human immune system to be cleared. This study will evaluate in 60 participants whether the combination of the vaccines with or without TLR7 agonist in participants with fully controlled HIV infection on antiretroviral treatment (ART), treated since acute HIV infection, will be safe, elicit the desired immune responses and will reduce markers of viral reservoirs compared to no intervention. The latter implies there will be a placebo arm (sham vaccines and sham drug) in the study as well. In addition, the study will evaluate if either combination will lead to delaying time to viral reappearance in the blood following interruption of ART in participants compared to controls. The study protocol is currently being designed.
Study A5354 is organized by the AIDS Clinical Trials Group (ACTG) network of the National Institute of Allergy and Infectious Diseases (NIAID). SEARCH participates in A5354 as a component of the Thai Red Cross AIDS Research Centre ACTG treatment CRS. A5354 is a prospective, open-label study to measure the effects of early antiretroviral therapy (ART) on the establishment of HIV-1 reservoir and HIV-1-specific immunity. The study aims to investigate the size of the HIV reservoir in early treated participants after 60-72 weeks on ART through leukapheresis or large volume blood collection, cerebrospinal fluid collection, and gut biopsy. The study will enroll 150 participants globally with an estimated 25 from Thailand. Since the study's aim and study schedule are similar to that of SEARCH010/RV254, in Thailand at SEARCH participants will co-enroll in SEARCH010/RV254 and A5354 and continue in the SEARCH010/RV254 cohort after completing A5354 after 72 weeks.
Studies A5354 and A5347 are organized by the AIDS Clinical Trials Group (ACTG) network of the National Institute of Allergy and Infectious Diseases (NIAID). SEARCH participates in these studies as a component of the Thai Red Cross AIDS Research Centre ACTG treatment CRS. A5345 is a prospective study of the clinical, virologic, immunologic, and pharmacologic predictors of time to recurrence of HIV in blood during an intensively monitored antiretroviral treatment (ART) interruption (IMAP, similar to ATI). The study will include globally 36 participants who initiated ART during chronic infection and 30 participants who initiated ART during acute/early HIV infection. SEARCH is anticipated to contribute 20 participants to the group who initiated ART in acute infection from the SEARCH010/RV254 cohort. The study will last a maximum of 96 weeks for each participant, depending on time until recurrence of virus in the blood after discontinuing ART. Next to studying the association between HIV reservoir size and return of virus in the blood, the study aims to develop a well-characterized biorepository of specimens to evaluate future biomarkers. Study A5347 is a sub-study of A5345 to collect tissue samples in willing and consenting A5345 participants (rectal biopsy, lymph node biopsy and cerebrospinal fluid -spinal tap- collection).
SEARCH030 is a longitudinal study of HPV (human papilomavirus) infection in HIV-infected men who have sex with men (MSM) and transgender women (TG) who initiate antiretroviral therapy during acute HIV infection. The study will follow participants over time to characterize the incidence of new HPV infection, including the HPV types most likely to cause anogenital cancer, and the incidence and progression of anal intraepithelial neoplasia (AIN), or pre-cancerous lesions. Anogenital cancer caused by HPV infection has been increasing worldwide among both men and women, with the highest rates seen in HIV-infected MSM. Previous studies have demonstrated a high rate of HPV infection among HIV-infected MSM in Thailand, and a high rate of progression of pre-cancerous lesions.1,2 The study will begin enrollment in the second quarter of 2017 with anticipated completion in 2021.
- Phanuphak N, Teeratakulpisarn N, Pankam T, Kerr SJ, Barisri J, Deesua A, et al. Anal human papillomavirus infection among Thai men who have sex with men with and without HIV infection: prevalence, incidence, and persistence. JAIDS. 2013;63(4):472-9.
- Phanuphak N, Teeratakulpisarn N, Triratanachat S, Keelawat S, Pankam T, Kerr SJ, et al. High prevalence and incidence of high-grade anal intraepithelial neoplasia among young Thai men who have sex with men with and without HIV. Aids. 2013 Jul 17;27(11):1753-62.