ACTIV-2/A5401 Enrolls First Participant
The ACTIV-2 Outpatient Monoclonal Antibodies and Other Therapies Trial (ACTIV-2) trial will evaluate the safety and efficacy of potential new therapeutics for COVID-19, including an investigational therapeutic based on synthetic monoclonal antibodies (mAbs) to treat the infection. The trial is being conducted through the ACTG network. On August 19, 2020, ACTIV-2 enrolled their first trial participant at University of California, Los Angeles – CARE Center, led by Dr. Kara Chew. Congratulations to the team!
Early treatment of COVID-19 can potentially prevent disease progression and subsequent hospitalization or death. Identifying treatments for COVID-19 will play a vital role in our approach to ending the global pandemic. We need an effective treatment for those who continue to become ill from the virus. The ACTG is proud to lead the charge in identifying life-saving COVID-19 treatments and has made the conduct of this trial our highest priority at this time. The protocol team is working around the clock with PPD to bring sites onboard and to ramp-up enrollment to meet the trial goals.
Learn more at www.activ-2.org.
See the latest ACTIV-2 Newsletter sent out on August 28, 2020.
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 the following trials have reopened and are enrolling participants at sites that are able to safely conduct follow-up visits.
A5300B: PHOENIx (Protecting Households On Exposure to Newly Diagnosed Index Multidrug-Resistant Tuberculosis Participants) - Focuses on household contacts at high risk for developing multidrug resistant tuberculosis (MDR-TB), which is an infection that does not get better with standard treatment for TB.
A5321: The ACTG HIV Reservoirs Cohort (AHRC) Study - Studies differences and changes over time in HIV reservoirs (groups of HIV-infected cells that ’hide’ from anti-HIV medications).
A5375: Optimize LNG EC - Determines if a higher dose of levonorgestrel Emergency Contraception (commonly called “Plan B” or the “Morning After Pill”) is needed to achieve high enough drug levels in girls and women who are taking anti-HIV medications known to decrease the effectiveness of this form of birth control.
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 - Determines if people who have HIV qualify to switch to or receive dolutegravir-containing antiretroviral therapy.
Latest Opening:
A5312: Early Bacteriocidal Activity of High-Dose Versus Standard Dose INH for INH-Resistant TB - Determines if different doses of INH can fight INH-resistant TB.
A5377: Tri-Specific Antibody - Studies a broadly neutralizing antibody called SAR441236 in humans to determine if an infusion is safe and tolerable and measures the amount of SAR441236 in the blood over time.
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UPCOMING NATIONAL HIV AWARENESS DAYS
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National HIV/AIDS and Aging Awareness day (#AIDSandAging) - September 18
The ACTG is committed to addressing the challenges people face in their daily lives as they age with HIV.
Written by Kimberly A Wilson – Boston HIV Research Community Advisory Board
Each year, September 18 is set aside to observe the National HIV/AIDS and Aging Awareness Day (NHAAD). This day focuses on educating people 50 years or older about HIV/AIDS prevention, testing, treatment, and the research going on in the HIV/AIDS field by having numerous community events in our neighborhoods. Because people with HIV are living longer and having more overly fulfilling lives, people forget that approximately 17% of new infections in 2018 were people over 50 years of age.
As a highly active woman over 50 years old living with an AIDS diagnosis and having other health problems, I see this day as one that gives people like myself an opportunity to continue the conversation with people about HIV testing and treatment. This is a way to make others aware that even though they are older, they are also at risk of getting HIV/AIDS. This disease is not just for the young. Each year in our respective communities, there are activities to educate people about living with HIV who are over 50. I suggest that everyone identify activities in their own community and participate. This year organizations are having them virtually.
Remember, an educated person is a knowledgeable person. You will gain another tool in your toolbox when you educate yourself and the people around you.
I know because I am living my best life now being over 50 and fabulous!
HIV and Being a Black Gay Man in 2020, National Gay Men's HIV/AIDS Awareness Day (#NGMHAAD) - September 27
From our earliest days, the ACTG has worked in partnership with the gay community to ensure our research reflects and addresses the reality of their lives.
Written by Karl Shaw – Henry Ford Health Systems Community Advisory Board
As we approach National Gay Men’s HIV/AIDS Awareness Day (September 27), it is important to note that HIV/AIDS has provided an additional platform for our community since it began with Stonewall in 1969. We have been oppressed and ostracized by our families and communities. The onslaught of HIV/AIDS, then known as Gay-Related Immune Deficiency (GRID), began to make people rethink the advancements of our brothers and sisters at Stonewall. The nay-sayers began to say, “See, I told you the homosexuals and lesbians are no good. Now they have a terminal disease!” And yet, we survive.
Living through the HIV/AIDS epidemic has been a rollercoaster ride. Watching friends and loved ones succumb to this unknown illness, much like it was during the early part of the COVID-19 pandemic, was difficult. But I learned to live with HIV, not believe that I was dying from it.
Living with HIV has come a long way. I joined the Community Advisory Board (CAB) of Henry Ford Health Systems (HFHS), which led to my becoming the HFHS CAB representative with the community cab of the ACTG, known as the GCAB. This membership enlightened me in the benefits of medical trials, thus I enrolled in the "Long Term Non-Progressors Study.” I became an active participant within the GCAB and the Community Scientific Sub-Committee (CSS), at one point being a co-chair of the CSS. I encourage anyone interested in medical trials from the community side to join a Community Advisory Board at your nearby medical facility.
When I converse with today’s young people, I find that the attitudes haven't changed much. We still have those who are scared of contracting HIV, others have a laissez-faire attitude. But I am finding that many are knowledgeable of HIV and its transmission abilities or inabilities.
I am grateful to God for bringing me this far, free from illnesses related to HIV, free from the ability to transmit it, and free to share my life as a LONG TERM NON-PROGRESSOR.
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NWCS 432: Improving Prediction of Myocardial Infarction in People Living with HIV
Due to complex interactions between HIV, antiretroviral therapy, and the chronic immune activation and inflammation that can be seen in people living with HIV, there is an increased risk for cardiovascular diseases including acute myocardial infarctions (heart attacks). Because traditional risk scores for predicting myocardial infarction (which are based on cholesterol, blood pressure, and smoking status) don’t take these HIV-specific drivers into account, these prediction tools can be inaccurate in people living with HIV. Thus, one of the key issues researchers face is how to identify which individuals are most likely to develop cardiovascular disease and hence might be appropriate to enroll into clinical trials aimed at investigating or reducing cardiovascular risk. NWCS 432 investigated whether biomarkers of inflammation, endothelial function, and microbial translocation (specifically lipopolysaccharide-binding protein) in people living with HIV might be able to help identify those who will go on to develop cardiovascular disease.
The study utilized samples stored in the ACTG specimen repository from a variety of studies. The investigation did not use specimens from a single trial, but innovatively identified individuals across ACTG studies who had experienced a myocardial infarction (MI) while enrolled in a study and pulled their samples. The study then used samples from control participants matched for age and sex who had no history of MI. Participants from 14 different ACTG protocols were ultimately included.
As described in the brief report published in Clinical Infectious Diseases, the study found people living with HIV who experienced an MI were more likely to be current smokers, have higher cholesterol, a family history of heart disease, or high blood pressure, which are all traditional risk factors. Interestingly, the participants with MIs also had higher lipopolysaccharide-binding protein levels, which remained positively associated with further MI events following adjustment for the more traditional cardiovascular risk factors. Lipopolysaccharide-binding protein is an acute phase protein and is associated with the development of fatty streaks in artery walls, likely by prolonging the survival of macrophages (the cells that ingest cholesterol and form the basis of these fatty plaques). Further work is needed to determine if lipopolysaccharide-binding protein can help improve the prediction of MI events or if this biomarker can be affected by anti-inflammatory medications. The possibility of a new biomarker to predict MIs in people with HIV is intriguing.
Trevillyan, J. M., Moser, C., Currier, J. S., & Sallam, T. (2020). Immune Biomarkers in the Prediction of Future Myocardial Infarctions in People With Human Immunodeficiency Virus. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America, 70(8), 1764–1767. doi.org/10.1093/cid/ciz765
A5335S: What is the Hepatitis C Virus (HCV) Doing in the Liver During HCV Treatment?
Direct-acting antivirals (DAAs) targeting hepatitis C virus (HCV) have revolutionized outcomes in HIV coinfection. A5335S examined early events in liver and plasma with detailed characterization as a substudy of trial A5329. A5329 provided DAAs (paritaprevir/ritonavir, ombitasvir, dasabuvir, with ribavirin) to participants with chronic HCV (genotype 1a) who were coinfected with HIV but virologically suppressed. A5356 evaluated five out of six treatment-naive enrollees in A5329. The mean baseline plasma HCV ribonucleic acid (RNA) level was 6.7 log10 IU/mL before treatment and decreased massively by Day 7. In the liver, single-cell laser capture microdissection (scLCM) was used to quantify the persistence of hepatitis C virions. At liver biopsy 1, the mean %HCV-infected cells in the liver was 25.2% (95% confidence interval [CI], 7.4%-42.9%) and correlated strongly with plasma HCV RNA levels (Spearman rank correlation r = 0.9). At biopsy 2 (Day 7 in four of five participants), the mean %HCV-infected cells decreased to only 1.0% (95% CI, 0.2%-1.7%) (P < .05 for change), and concentrations of the DAA medications were detectable in the liver.
This is the first study to look at the clearance of HCV virions from the liver with administration of DAAs. The study concludes HCV infection is rapidly cleared from the liver with DAA leaving <2% HCV-infected hepatocytes at Day 7. Researchers extrapolate HCV eradication could occur in these participants by 63 days, although immune activation might still persist. This is the first time single-cell longitudinal estimates of HCV clearance from liver have ever been reported, and these findings could be applied to estimating the minimum treatment duration required for HCV infection and in other types of viral hepatitis.
Balagopal, A., Smeaton, L. M., Quinn, J., Venuto, C. S., Morse, G. D., Vu, V., Alston-Smith, B., Cohen, D. E., Santana-Bagur, J. L., Anthony, D. D., Sulkowski, M. S., Wyles, D. L., & Talal, A. H. (2020). Intrahepatic Viral Kinetics During Direct-Acting Antivirals for Hepatitis C in Human Immunodeficiency Virus Coinfection: The AIDS Clinical Trials Group A5335S Substudy. The Journal of Infectious Diseases, 222(4), 601–610. doi.org/10.1093/infdis/jiaa126
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Update from TASK Applied Science CRS
South Africa confirmed its first Coronavirus case on March 5, 2020. We closed our borders two weeks later (18 March) and went into one of the longest and hardest lockdowns seen globally from 27 March. Research, along with any semblance of normal living, was paused indefinitely. In this time of forced inactivity, the TASK team turned our attention to COVID-19. We became acutely aware of an increasingly desperate clinical workforce that was preparing for an almost certainly overwhelming flood of severely ill patients. We examined the research done on Bacille Calmette-Guérin (BCG), the almost a century old vaccine for TB. The literature detailed that BCG could induce epigenetic changes in the innate immune system with resulting accelerated viral and bacterial clearance in prior research. The reported findings were good enough to establish clinical equipoise for a clinical trial exploring whether these effects on the innate immune system could lessen the severity of COVID-19. We decided that the hypothesis that this R4, 50 ($0.26) per dose vaccine could be a potentially lifesaving host-directed therapy was worth investigating in our context.
Within one week we adapted the Dutch BCG protocol for our unique South African context and had submitted it to our regulatory bodies. Both our ethics and health products regulatory authorities showed incredible collaboration in this time. Feedback was received in days (rather than months), and even over a public holiday! Within two weeks of submission we became the first approved clinical trial in Africa to study COVID-19.
Since then, we have recruited more participants per day than in the 15-year history of the institution. We have learned how to adapt to the needs of our participants, transitioning to a mobile recruitment team and overcoming long-established geographic barriers with a little imagination. We have, for the first time in our history, become the sponsor of a multi-center study, taking on additional sites as needed to adapt the sample size to our emerging epidemic. Simultaneously we are developing SOP’s, a database, pharmacy manuals, DSMB charters, consortium agreements and other essential documents. We are exploring digital platforms for recruitment, follow-ups and real time data collection, something not traditionally done in our resource constrained setting.
The BCG team has truly taken this devastating pandemic in stride, using it as an incredible learning opportunity both for the benefit of the global community, the scientific agenda and our organisation as a whole. We have collaborated with new partners, prevailed over obstacles, and cheered our successes through muffled masks together, with the hope that we will save some lives or lungs in the end. We look forward to reporting on the results of this trial to you soon!
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INVESTIGATOR SPOTLIGHT
Jeffrey Jacobson, MD
Jeffrey M. Jacobson, MD, the Principal Investigator of the Case Western Reserve University Clinical Trials Unit, has a long history of clinical HIV research and an extensive involvement in the activities of the ACTG since its founding. He has proposed and overseen the conduct of many ACTG protocols, led many ACTG committees and task forces, and widely published the results of ACTG studies in high-impact journals. He has also played a supportive role in mentoring junior faculty both from his own institution and elsewhere in the conduct of ACTG studies. Dr. Jacobson’s research interests focus on the immunopathogenesis of HIV disease, particularly the role of immune activation in causing disease manifestations and the mechanisms of immune dysfunction in HIV infection, as well as the potential for vaccination, anti-HIV antibodies, and other immune-based therapies to reverse these abnormalities and possibly achieve a functional cure – i.e., long-term control of viral replication in the absence of antiretroviral therapy.
Dr. Jacobson chaired the pivotal ACTG study (251) of thalidomide for the treatment of HIV/AIDS-associated aphthous ulcers of the oropharynx and esophagus, a study that also illuminated the relationship between the induction of pro-inflammatory tumor necrosis factor (TNF) production and the enhancement of HIV replication. A5068 demonstrated the effectiveness of autologous HIV-1 antigen, delivered as pulses of viremia through antiretroviral treatment interruptions, in improving host immune control of HIV-1 replication measured as the new viral load set point at the end of an analytical treatment interruption (ATI). The A5068 team first coined the term “analytical treatment interruption,” and the study’s characterization of the viral kinetics during an ATI has served to guide subsequent studies of immune-based therapies. Dr. Jacobson now chairs A5369, evaluating a conserved epitope DNA-based HIV vaccine designed to re-direct anti-HIV immune responses against epitopes essential for viral viability.
Among his ACTG leadership roles, Dr. Jacobson chaired the Immunology Committee and the Translational Research and Drug Development Committee. He led a group that developed the Data Accountability Report (DAR), now in standard use in the ACTG to monitor the status of patient specimens obtained for the laboratory assays to be performed in ACTG protocols. He co-chaired the Long-Acting Drug Task Force, seeing those therapies as especially valuable for individuals not succeeding on standard oral antiretroviral drug regimens. Dr. Jacobson has chaired and co-chaired a number of other working groups, task forces, and study monitoring committees, and currently serves on the Antiretroviral Treatment Strategy TSG and its Monoclonal Antibody Working Group.
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CAB MEMBER SPOTLIGHT
Rosa Reyes, New York, New York
In launching ACTIV-2, the ACTG formed a COVID-19 community advisory board (CAB), made up of select members from other ACTG CABs, as well as new members who have been personally affected by COVID-19.
One of those members new to ACTG is Rosa Reyes. Rosa joined the COVID CAB because she and her son are fortunate to have survived COVID-19. Unfortunately, Rosa’s husband succumbed to the virus and passed away in April 2020.
“With this virus, there are so many unknowns of who gets affected, who does not, and why. Minority communities are being affected the most. Working in the medical field for so many years, I feel it is my duty and obligation to be a tool in any way I can to help get answers.”
Rosa is a Patient Financial Advisor at New York Presbyterian Hospital/Child Advocacy Center. She will continue to provide insight for the ACTIV-2 team on what it’s like to have COVID-19, to have lost someone to COVID-19, and how we can best reach out to her community.
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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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