ACTIV-2 Outpatient Monoclonal Antibodies and Other Therapies Trial
The ACTG announced today the initiation of the ACTIV-2 Outpatient Monoclonal Antibodies and Other Therapies Trial. ACTIV-2 includes both phase 2 and phase 3 evaluations of multiple promising investigational agents for treating early COVID-19 in a single trial.
ACTIV-2 will evaluate the safety and efficacy of investigational agents to treat adults who have COVID-19 illness but do not require hospitalization. The study will also enable researchers to assess the correlation between changes in viral shedding and clinical outcomes, leading to a better understanding of whether effective medications can reduce or halt the transmission of SARS-CoV-2 (the virus that causes COVID-19) to others. ACTIV-2 is a randomized, blinded, controlled adaptive platform that allows promising investigational agents to be added and removed over the course of the study, in order to efficiently test a variety of new agents against placebo within the same trial infrastructure.
“Early treatment of COVID-19 will be vital to help us prevent advanced illness, hospitalization, and transmission of SARS-CoV-2,” said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles. “ACTIV-2 is designed to help us rapidly identify treatments that have the potential to radically alter the current pandemic landscape. Individuals who have recently been diagnosed with COVID-19 and are not hospitalized have the opportunity to make a huge contribution by participating in this study.”
To read more, please see the complete press release here.
REPRIEVE Studies Featured in Journal of Infectious Diseases
The REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) study, on which ACTG is collaborating, was featured in a series of articles in The Journal of Infectious Diseases that highlighted the first data from the world’s largest study of cardiovascular disease (CVD) prevention in people living with HIV. Massachusetts General Hospital issued a press release about these articles, highlighting the importance of addressing comorbidities among an aging population of people living with HIV.
While REPRIEVE’s primary goal is to reduce major CVD adverse events in people living with HIV through cardiac prevention, it is also assessing non-CVD comorbidities –these were the focus of the six articles published in The Journal of Infectious Diseases. One article reports that while physical function impairment and pre-frailty are common among middle-aged people with HIV, modifying body mass index (BMI) and physical activity may prevent further decline among this population. Another paper highlights data on the participation of transgender participants and cardiovascular risk associated with gender-affirming therapy. Additional papers shed light on patterns of antiretroviral use across the globe, unique associations of weight and immune function, and factors contributing to increased kidney dysfunction and increased ectopic fat deposition in the heart among people living with HIV. Congratulations to the REPRIEVE study team on what we know will only be the first of many publications.
ACTG TRIALS REOPENING
In response to COVID-19, many ACTG trials temporarily closed to accrual to ensure the safety of our participants and staff. We are pleased to announce that the following trials have reopened and are enrolling participants at sites that are able to safely conduct follow-up visits.
A5128: US Genomic Sampling
A5243: Non-US Genomic Sampling
A5300B: PHOENIx
A5321: The ACTG HIV Reservoirs Cohort (AHRC) Study
A5375: Optimize LNG EC
A5381: Observational Cohort to Assess Therapeutic Efficacy and Emergence of HIV Drug Resistance Following Initiation of Tenofovir-Lamivudine-Dolutegravir (TLD) for First- or Second-Line ART
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The ACTG is pleased to offer congratulations to our colleagues on a number of accomplishments this month:
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ACTG 5366: The Role of Women in HIV Cure-Related Research
Women bear a significant burden of the HIV epidemic, yet they remain underrepresented in HIV research. Led by Dr. Eileen Scully of John Hopkins University, ACTG 5366 study is the first HIV cure-related clinical trial conducted entirely in women living with HIV. ACTG 5366 enrolled 31 postmenopausal women living with HIV, the majority of whom were women of color, at locations across the United States.
This paper highlights findings from two online surveys that were administered to participants, one at the beginning and the other at the end of the ACTG 5366 study, to gauge their thoughts and feelings about the trial.
ACTG 5366 demonstrated that HIV cure-related research can recruit and retain women. It also showed the relevance and feasibility of incorporating patient-centered outcomes into biomedical research. Increasing the representation of women in HIV cure-related research is important to ensure that future treatments are safe and effective for everyone. Understanding how both the biological and social differences between men and women affect HIV is critical to achieving equity and justice in the treatment of HIV. The results of the ACTG 5366 study underscore the need for multidisciplinary collaborations that integrate participant values, perceptions, and lived experiences in HIV cure research.
The results have many possible implications for future trials. Researchers should recognize that people living with HIV join clinical trials for many different reasons, understand the psychological effects of their research, and value the lived experiences of their participants. They should foster altruism and have a deep respect for the stigma that people living with HIV face daily. More emphasis should be placed on ensuring participants understand both the informed consent form and the risks/benefits of the study. Greater attention should be paid to motivators that can help women overcome barriers to trial participation during the planning phase of clinical trials.
Dube K., Hosey L., Starr K., Barr L., Evans D., Hoffman E., Campbell DM., Simoni J., Sugarman J., Sauceda J., Brown B., Diepstra K., Godfrey C., Kuritzkes DR., Wohl DA., Gandhi R., Scully E.Participant Perspectives in an HIV Cure-Related Trial Conducted Exclusively in Women in the United States: Results from AIDS Clinical Trials Group 5366. AIDS Research and Human Retroviruses. 2020 Apr 09;36(4):268-282. doi:10.1089/aid.2019.0284. PubMedID: 32160755
Is Isoniazid Essential for Early Bactericidal Activity (EBA) in TB?
It has long been thought that isoniazid (INH) does most of its bacterial killing in the first two days of therapy. A5307, is a Phase 2a study evaluating four treatment arms:
- The standard regimen of INH+rifampin+ pyrazinamide+ethambutol for 14 days
- Rifampin+ pyrazinamide+ethambutol for 14 days
- INH+rifampin+ pyrazinamide for two days, followed by rifampin+ pyrazinamide+ ethambutol for 12 days
- INH+rifampin+ pyrazinamide+ethambutol for two days, followed by moxifloxacin+ rifampin+pyrazinamide+ethambutol for 12 days
The authors found that all four regimens provided good early bactericidal activity that was not statistically significantly different across arms.
This study casts doubt on the long-held belief that isoniazid is essential for early killing of Mycobacterium tuberculosis during standard therapy. Genomic studies have shown that in most cases of multidrug-resistant tuberculosis, resistance to isoniazid precedes rifampicin resistance, and human studies have shown that the three-drug combination therapy of rifampin + pyrazinamide + ethambutol for six months is effective. These observations, along with high rates of isoniazid mono-resistance, implicate isoniazid as the weak link in preventing the ongoing emergence of multidrug-resistant tuberculosis.
Diacon A., Miyahara S., Dawson Rodney., Sun X., Hogg E., Donahue K., Urbanowsk M., De Jager V., Fletcher CV., Hafner R., Swindells S., Bishai, W.. Assessing whether isoniazid is essential during the first 14 days of tuberculosis therapy: a phase 2a open-label, randomized controlled trial. The Lancet Microbe 2020 Jun; 1(2):e84–e92. doi: 10.1016/S2666-5247(20)30011-2.
A5303/10: Working to Uncover the Causes of Neurocognitive Impairment in People Living with HIV
Many people living with HIV experience deficits in memory, attention, and other aspects of brain function despite being undetectable on effective antiretroviral therapy (ART). For some individuals, this neurocognitive impairment is worse than seen in the general population and can interfere with quality of life, work, and other activities of daily living. The exact cause of this neurocognitive impairment is not known and doctors do not have good ways of treating it. To shed light on this issue, the A5303 investigators examined whether level of inflammation, or the degree of activation of immune cells in blood, was tied to presence and/or severity of neurocognitive impairment in people living with HIV. The study was designed this way because it is well known that inflammation and immune activation often remain elevated in people living with HIV despite effective ART and because elevated levels of these markers have been linked to other chronic diseases.
The participants in A5303 received ART for 48 weeks. As outlined in the article published in Journal of Neurovirology, participants with high levels of interleukin-6, a marker of inflammation, were more likely to have neurocognitive impairment before ART was started. Having higher blood levels of proteins that indicate activation of lymphocytes was also linked to an increased likelihood of having neurocognitive impairment before ART initiation. However, the results after 48 weeks of ART were different. Specifically, presence of neurocognitive impairment after 48 weeks of ART was linked to evidence of activation of a different kind of monocytes. These findings suggests that the factors driving impairment before ART is started and those driving impairment while on ART may be quite different. Notably, no associations were found between neurocognitive impairment and the majority of the markers of inflammation and immune activation looked at in this study. Further, the associations found were modest. Taken together, these results mean we still have a lot to learn about the cause(s) of neurocognitive impairment in people living with HIV.
Robertson, K., Landay, A., Miyahara, S., Vecchio, A., Masters, MC., Brown, TT., & Taiwo, BO. Limited correlation between systemic biomarkers and neurocognitive performance before and during HIV treatment Journal of Neurovirology 2020 Feb; 26(1), 107–113. doi: 10.1007/s13365-019-00795-2. PubMedID: 31468473
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ACTG Investigators Expand Focus to COVID-19 Work
Investigators and clinicians in HIV/AIDS know how to respond nimbly and compassionately to a pandemic. Many of our ACTG investigators are using their expertise and leveraging existing structures to quickly research COVID-19 and potential treatments. We have highlighted some of our ACTG investigators’ work on COVID-19 below. For a fuller description of our efforts, please check out our webpage, COVID-19.
- CRS at Pune, India: Dr. Arun Jamkar hosted two webinars in July about AI systems in a pandemic. You can view them by following the links below!
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INVESTIGATOR SPOTLIGHT
Beatriz Grinsztejn, MD
ACTG Investigator Dr. Beatriz Grinsztejn is a physician-scientist with more than three decades of experience in HIV and TB coinfection research. She is currently the Head of the STD/AIDS Clinical Research Center at the Instituto National de Infectologicia (INI)/Fundação Oswaldo Cruz (Fiocruz) and has served as the Fiocruz CTU PI since 2005. Through her involvement in HPTN 052, Dr. Grinsztejn was invited to join the ACTG in 2002 as an investigator on the A5175 study. Since that time, she participated in numerous ACTG trials including A5259 (Vice-Chair) and A5288 (Co-Chair), a phase 4 strategy third-line study conducted in 10 lower and middle income countries. Dr. Grinsztejn is a member of the Antiretroviral Therapy Transformative Science Group (ARTS TSG), the Scientific Agenda Steering Committee (SASC), and is the Latin American Regional Representative to the ACTG. Previously, she served as the Vice-Chair of the Women’s Health Committee, as co-Chair of the WHISC, and as a member of the Executive Committee. In 2009, she was the recipient of the ACTG’s Connie Wofsky Women's Health Investigator Award.
In addition to her ACTG Network activities, Dr. Grinzstejn is also deeply involved with HIV prevention efforts as her CTU has been an HPTN site since 2002 and she is currently the Co-Chair of the landmark HPTN 083 study investigating the use of long-acting injectable ARV for PrEP. She is also the Co-Chair of the ANRS Phase III Reflate TB trial conducted in RLS in Brazil, Cote d'Ivoire and Vietnam, evaluating the efficacy of raltegravir based ART in naive HIV-1-infected patients receiving rifampin for active tuberculosis. She is a technical advisor for the Brazilian Ministry of Health on ART and PrEP, a member of the PAHO HIV Treatment Advisory Committee, the PAHO PrEP Task Force, and a Latin member of the International AIDS Society Governing Council.
Devoted to addressing the dearth on trans-specific knowledge in Latin America, Dr. Grinsztejn facilitated the establishment of the first trans-specific cohort and chaired the first PrEP demonstration study specifically designed for transgender women in the region. She advocates for the inclusion of transgender women in HIV prevention and treatment clinical trials and improving the understanding of ARV and hormone use in this population. Currently, she is participating in several trials looking at possible therapeutics against SARS-CoV-2 and preparing the Fiocruz CTU to contribute to ACTIV-2 when the time comes.
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INVESTIGATOR SPOTLIGHT
Wycliffe Esendi, Eldoret, Kenya
Wycliffe Esendi has been a member of the ACTG CAB since 2010, when he joined to fully participate in the research process. "I want to make a difference," he said. He works with his local CAB to read and understand ACTG protocols and has organized a number of community outreach events to help his community-based organizations (CBOs) to advocate for people living with HIV in Kenya and Uganda.
"In my community, stigma remains a huge issue, and there are many myths about research. However, together with my CAB members at Moi University in Eldoret, Kenya, we have made great progress towards overcoming these issues through interactions with the larger community sensitization and outreach work."
To Wycliffe, the most important treatment issue in his community is TB/HIV co-infection. As a sister opportunistic disease, TB still causes a lot of death. In some areas, there is a lack of support for people living with HIV and inadequate access to treatment. Additionally, he recognizes that aging is a vital issue for people living with HIV. Wycliffe wants to be remembered for his work educating the community about HIV and research. "I hope to be remembered as someone who made many people aware of how HIV is transmitted, how HIV can be prevented, and why research matters. I want to be remembered as a warrior who fought and won the war against HIV."
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ACTG SITE SPOTLIGHT
Durban International CRS (DICRS), Durban, South Africa
DICRS first came into existence in 2002 when the first ACTG site was approved in Durban, South Africa (formed by the Enhancing Care Initiative, a program of the University of KwaZulu Natal and under the leadership of Professor Umesh Lalloo). We started with one research site at King Edward Hospital, a 900-bed tertiary hospital in Durban and now have two additional, fully functional research sites in Durban.
We have participated in more than 20 clinical trials over the past 17 years. Currently, we are participating in A5332, A5243, A5302, A5300B, A5375, A5381, and A5324. We are excited to be part of the landmark A5300B study offering prophylactic treatment and using innovative devices to outcomes among those exposed to MDR-TB (South Africa has one of the highest incidence of TB and MDR-TB in the world). Being part of these types of studies has helped our understanding of TB and HIV and has helped our developing country and its people get access to life-saving treatments.
The site has been involved in many groundbreaking studies in the past – most notably the PEARLS, A5199, A5271 and START studies, where we were one of the highest recruiting sites. Other groundbreaking studies include the STRIDE study, which led to a change in guidelines for managing people living with both advanced TB and HIV; A5279, which led to a change in treatment guidelines shortening prophylactic TB treatment; and A5288, which addressed the critical need to define the best third-line regimens for patients in resource limited settings. We have recruited 161 participants into the REPRIEVE study and await outcomes of our innovative TB therapeutic studies including A5300, A5349, and A5332.
It is our motto that when you join us you join a family. This works both ways – the organization aims to protect and nurture you and the staff are most loyal and give of their best. With this ethos, we try to give our staff every opportunity to grow and develop, not just in the research field but in all other aspects of our activities.
Our involvement in studies that looked at interactions between ART, TB treatment, and contraceptives have been most meaningful. This is an area of work that was not commonly done by the ACTG but was embraced through the rigorous scientific team. This study was very important for African society where injectable contraception is so widely used.
The network meetings have always been interesting to attend. The plenaries were a show off of the great minds. It is like you are at a talent show. Over the years, we have tried to give many of our staff the opportunity to attend ACTG meetings in the U.S. For many junior staff, this was the first time they had flown – we threw them into the deep-end with a 22-hour flight. The annual trips and network gatherings have created lifelong friendships apart from the research collaborations that have been fostered.
We are passionate about capacitating young Africans with the skills to make a contribution to HIV and TB care. Too often, the network’s research agenda is driven by the U.S. and while very important international questions have been addressed, we feel it is critical that Africans have the skills and depth of knowledge to drive the research agenda. We have seen that with hard work and commitment, research staff from our site can make a contribution at the Network level.
Finally, the high quality of healthcare and access to research that our sites have provided to our community has been truly an honor and privilege.
 
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NEWS TO SHARE?
Do you have interesting ACTG-related news to share? Has your site done something exceptional? What’s the latest news about your study? Do you have job postings or any other ACTG-related information? We want to know! Please submit your news to ACTG Leadership & Operations Center Communications Specialist Karen Hoffman.
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